EPR evidence for α-triphenylstannylvinyl radicals in the O-directed hydrostannation of dialkylacetylenes with Ph3SnH/cat. Et3B/O2.

Here we provide definitive EPR evidence for the existence of α-triphenylstannylvinyl radicals in the low temperature O-directed free radical hydrostannation of dialkyl propargylic alcohols with Ph3SnH/cat. Et3B and O2 in PhMe. Isotropic hyperfine splitting patterns and spectral simulations confirm the assignments made. In the case of the α-triphenylstannylvinyl radical (Z)-2, an isotopic 119/117Sn hyperfine coupling constant of 9.5 mT (95 G) was measured along with a 1Hß hyperfine coupling constant of 1.1 mT.

Classic highlights in porphyrin and porphyrinoid total synthesis and biosynthesis.

Porphyrins feature prominently in nature, be it as enzymatic cofactors, electron and exciton shuffles, as photoactive dyes, or as signaling substances. Their involvement in the generation, storage and use of oxygen is pivotal to life, while their photochemical properties are central to the biochemical functioning of plants. When complexed to metals, porphyrins can engage in a multitude of contemporary applications ranging from solar energy generation to serving as catalysts for important chemical reactions. They are also able to function as useful theranostic agents, and as novel materials for a wide range of applications. As such, they are widely considered to be highly valuable molecules, and it almost goes without saying that synthetic organic chemistry has dramatically underpinned all the key advances made, by providing reliable access to them. In fact, strategies for the synthesis of functionalized porphyrins have now reached a state of refinement where pretty well any desired porphyrin can successfully be synthesized with the approaches that are available, including a cornucopia of related macrocycle-modified porphyrinoids. In this review, we are going to illustrate the development of this exciting field by discussing a number of classic syntheses of porphyrins. Our coverage will encompass the natural protoporphyrins and chlorophylls, while also covering general strategies for the synthesis of unsymmetrical porphyrins and chlorins. Various industrial syntheses of porphyrins will also be discussed, as will other routes of great practical importance, and avenues to key porphyrinoids with modified macrocycles. A range of selected examples of contemporary functionalization reactions will be highlighted. The various key syntheses will be described and analyzed from a traditional mechanistic organic chemistry perspective to help student readers, and those who are new to this area. The aim will be to allow readers to mechanistically appreciate and understand how many of these fascinating ring-systems are built and further functionalized.

Fast ring-opening of an intermediary α-stannyl-ß-cyclopropylvinyl radical does not support formation of an α-stannylvinyl cation in the O-directed free radical hydrostannation of dialkyl acetylenes.

O-directed hydrostannation of ß-cyclopropyl propargyl alcohol 22 with stannanes and cat. Et3B in THF/H2O or PhMe/MeOH fails to deliver any detectable products of α-stannylvinyl cation capture. Instead only α-stannyl-ß-cyclopropylvinyl radical intermediates can be detected, which undergo fast H-atom abstraction and/or cyclopropane ring-opening as a result of eliminative ß-scission.

The O-Directed Free Radical Hydrostannation of Propargyloxy Dialkyl Acetylenes with Ph3 SnH/cat. Et3 B. A Refutal of the Stannylvinyl Cation Mechanism.

In this Personal Account, we will give an overview of the room temperature O-directed free radical hydrostannation reaction of propargylically-oxygenated dialkyl acetylenes with Ph3 SnH and catalytic Et3 B/O2 in PhMe. We will show how this excellent reaction evolved, and how it has since been used to stereoselectively construct the complex trisubstituted olefin regions of three synthetically challenging natural product targets: (+)-pumiliotoxin B, (-)-(3R)-inthomycin C, and (+)-acutiphycin. Throughout this Account, we will pay special attention to highlighting important facets of the I-SnPh3 exchange processes that have so far been used in the various different steric settings that we have addressed, and we will document the range of cross coupling protocols that have critically underpinned the first successful applications of this method in complex natural product total synthesis. Last, but not least, we will comment on various aspects of the O-directed free radical hydrostannation mechanism that have been published by ourselves, and others, and we will discuss all of the factors that can contribute to the observed stereo-and regio-chemical outcomes. We will also challenge and refute the recent non-directed stannylvinyl cation mechanism put forward by Organ, Oderinde and Froese for our reaction, and we will show how it cannot be operating in these exclusively free radical hydrostannations.

Total Synthesis of the Antitumor Macrolides, (+)-Brefeldin A and 4-Epi-Brefeldin A from d-Glucose: Use of the Padwa Anionic Allenylsulfone [3 + 2]-Cycloadditive Elimination To Construct Trans-Configured Chiral Cyclopentane Systems.

A new synthesis of (+)-brefeldin A is reported via Padwa allenylsulfone [3 + 2]-cycloadditive elimination. Cycloadduct 13 was initially elaborated into iodide 27, which, following treatment with Zn, gave aldehyde 28 whose C(9) stereocenter was epimerized. Further elaboration into enoate 38 and Julia-Kocienski olefination with 5 subsequently afforded 39, which was deprotected at C(1) and O(15). Yamaguchi macrolactonization of the seco-acid thereafter afforded a macrocycle that underwent O-desilylation and inversion at C(4) to give (+)-brefeldin A following deprotection.

Total Synthesis of the GRP78-Downregulatory Macrolide (+)-Prunustatin A, the Immunosuppressant (+)-SW-163A, and a JBIR-04 Diastereoisomer That Confirms JBIR-04 Has Nonidentical Stereochemistry to (+)-Prunustatin A.

A unified total synthesis of the GRP78-downregulator (+)-prunustatin A and the immunosuppressant (+)-SW-163A based upon [1 + 1 + 1 + 1]-fragment condensation and macrolactonization between O(4) and C(5) is herein described. Sharpless asymmetric dihydroxylation was used to set the C(2) stereocenter present in both targets. In like fashion, coupling of the (+)-prunustatin A macrolide amine with benzoic acid furnished a JBIR-04 diastereoisomer whose NMR spectra did not match those of JBIR-04, thus confirming that it has different stereochemistry than (+)-prunustatin A.

Total Synthesis of the Potent HIF-1 Inhibitory Antitumor Natural Product, (8R)-Mycothiazole, via Baldwin-Lee CsF/CuI sp(3)-sp(2)-Stille Cross-Coupling. Confirmation of the Crews Reassignment.

A convenient asymmetric total synthesis of the potent HIF-1 inhibitory antitumor natural product, (-)- or (+)-(8R)-mycothiazole (1), is described. Not only does our synthesis confirm the 2006 structural reassignment made by Crews ( Crews , P. , et al. J. Nat. Prod. 2006 , 69 , 145 ), it revises the [α]D data previously reported for this molecule in MeOH from -13.7° to +42.3°. The newly developed route to (8R)-1 sets the C(8)-OH stereocenter via Sharpless AE/2,3-epoxy alcohol reductive ring opening and utilizes two Baldwin-Lee CsF/cat. CuI Stille cross-coupling reactions with vinylstannanes 8 and 3 to efficiently elaborate the C(1)-C(4) and C(14)-C(18) sectors.

Rules and stereoelectronic guidelines for the anionic nucleophilic displacement of furanoside and furanose O-sulfonates.

Rules for predicting anionic SN2 displacement viability in furanose and furanoside sulfonates are presented.

Carreira alkynylations with paraformaldehyde. a mild and convenient protocol for the hydroxymethylation of complex base-sensitive terminal acetylenes via alkynylzinc triflates.

A new synthetic protocol for the hydroxymethylation of terminal acetylenes is described that involves stoichiometric Carreira alkynylation with solid paraformaldehyde (HO[CH2O]nH) in PhMe at 60 °C. Significantly, the method can be successfully applied on acetylenes that possess base-sensitive ester functionality and heterocyclic rings that readily undergo metalation. While N-methylephedrine (NME) is generally the best Zn(OTf)2-coordinating ligand for promoting hydroxymethylation, TMEDA can serve as a replacement.

An update of the rules for pyranoside sulfonate displacement.

The original 1967 Richardson-Hough rules for predicting SN2 displacement viability in carbohydrate sulfonate derivatives with external nucleophiles have now been updated. Not only do the original rules still hold, but the newly updated rules rationalize why O-triflates (trifluoromethanesulfonate esters) frequently allow many seemingly "disallowed" pyranosidic nucleophilic substitutions to proceed. The new guidelines, which are based on three decades of experimental evidence, allow the feasibility of many pyranosidic O-triflate SN2 displacements to be gauged beforehand.

The absolute configuration for inthomycin C: revision of previously published work with a reinstatement of the (3R)-configuration for (-)-inthomycin C.

Stereochemical evidence is presented to demonstrate that (-)-inthomycin C has (3R)- and not (3S)-stereochemistry. Careful reappraisal of the previously published work2-5 now indicates that the Hatakeyama, Hale, Ryu, and Taylor teams all have synthesized (-)-(3R)-inthomycin C. The newly measured [α]D of pure (-)-(3R)-inthomycin C (98% ee) is -7.9 (c 0.33, CHCl3) and not -41.5 (c 0.1, CHCl3) as was previously reported in 2012.

A new stereocontrolled total synthesis of the mast cell inhibitory alkaloid, (+)-monanchorin, via the Wittig reaction of a stabilized ylide with a cyclic guanidine hemiaminal.

An asymmetric total synthesis of the mast cell inhibitor (+)-monanchorin is reported in which a Sharpless AD on 11 and a cyclic sulfate ring opening with an azide feature as key steps. After further manipulation, a novel guanidine-controlled ester reduction provided the guanidine-hemiaminal 25 which underwent Wittig olefination to give 27. Hydrogenation and a second guanidine-controlled reduction of the ester in 28, to obtain aldehyde 29, then set up a trifluoroacetic acid mediated cyclization to give (+)-monanchorin TFA salt.

Synthesis of the C(7)-C(22) sector of (+)-acutiphycin via O-directed double free radical alkyne hydrostannation with Ph3SnH/Et3B, double I-Sn exchange, and double Stille coupling.

Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne 11. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions by vinyl radical intermediates, the two vinylstannanes of 10 were concurrently constructed with high stereocontrol using Ph3SnH/Et3B/O2. Distannane 10 was thereafter elaborated into the bis-vinyl iodide 9 via O-silylation and double I-Sn exchange; double Stille coupling of 9, O-desilylation, and oxidation thereafter furnished 8.

Asymmetric total synthesis of (+)-inthomycin C via O-directed free radical alkyne hydrostannation with Ph3SnH and catalytic Et3B: reinstatement of the Zeeck-Taylor (3R)-structure for (+)-inthomycin C.

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (-)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive interaction could interfere. Our stereochemical studies on the alkynol (-)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyama's (3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and Taylor's original (3R)-stereostructure for (+)-inthomycin C is correct.

A new mild method for the C-acylation of ketone enolates. A convenient synthesis of ß-keto-esters, -thionoesters, and -thioesters.

A new method for ketone enolate C-acylation is described which utilizes alkyl pentafluorophenylcarbonates, thiocarbonates, and thionocarbonates as the reactive acylating agents, and MgBr(2)·Et(2)O, DMAP, and i-Pr(2)NEt as the reagents for enolization. A wide range of ketones have been observed to undergo clean C-acylation via this protocol.

A new stereocontrolled synthetic route to (-)-echinosporin from D-glucose via Padwa allenylsulfone [3 + 2]-anionic cycloadditive elimination.

A new formal total synthesis of (-)-echinosporin has been developed based upon the Padwa [3 + 2]-cycloadditive elimination reaction of allenylsulfone 4 with the D-glucose-derived enone 14 which provides cycloadduct 12.

Biosynthetic chlorination of the piperazate residue in kutzneride biosynthesis by KthP.

Kutznerides 2 and 8 of the cyclic hexadepsipeptide family of antifungal natural products from the soil actinomycete Kutzneria sp. 744 contain two sets of chlorinated residues, a 6,7-dichlorohexahydropyrroloindole moiety derived from dichlorotryptophan and a 5-chloropiperazate moiety, as well as a methylcyclopropylglycine residue that may arise from isoleucine via a cryptic chlorination pathway. Previous studies identified KtzD, KtzQ, and KtzR as three halogenases in the kutzneride pathway but left no candidate for installing the C5 chlorine on piperazate. On the basis of analysis of the complete genome sequence of Kutzneria, we now identify a fourth halogenase in the pathway whose gene is separated from the defined kutzneride cluster by 12 open reading frames. KthP (kutzneride halogenase for piperazate) is a mononuclear nonheme iron halogenase that acts on the piperazyl ring tethered by a thioester linkage to the holo forms of thiolation domains. MS analysis of the protein-bound product confirmed chlorination of the piperazate framework from the (3S)- but not the (3R)-piperazyl-S-pantetheinyl thiolation proteins. After thioesterase-mediated release, nuclear magnetic resonance was used to assign the free imino acid as (3S,5S)-5-chloropiperazate, distinct from the 3S,5R stereoisomer reported in the mature kutznerides. These results demonstrate that a fourth halogenase, KthP, is active in the kutzneride biosynthetic pathway and suggest further processing of the (3S,5S)-5-chloropiperazate during subsequent incorporation into the kutzneride depsipeptide frameworks.