Regioselective trans-Carboboration of Propargyl Alcohols

Proper choice of the base allowed trans-diboration of propargyl alcohols with B2(pin)2 to evolve into an exquisitely regioselective procedure for net trans-carboboration. The method is modular as to the newly introduced carbon substituent (aryl, methyl, allyl, benzyl, alkynyl), which is invariably placed distal to the −OH group

Total Synthesis of Roseophilin

The first total synthesis of the antitumor agent roseophilin 1 is reported. Its intricate macrotricyclic core 2 is obtained by means of a new palladium-catalyzed manifold for the formation of ansa-bridged pyrroles which proceeds via vinyl oxirane 8 and allyl lactone 11 as key intermediates. After conversion of the latter into pyrrolophane 14, a base-induced elimination of the sulfone group followed by the Michael addition of a zincate onto the resulting enone 18 installs the isopropyl substituent in a stereoselective manner. The pyrrolylfuran side chain 3 of roseophilin is prepared from 4-methoxy-2(5H)-furanone (24) and methyl 4-chloropyrrole-2-carboxylate (26) as the starting materials. The appropriate building blocks 25a and 28 derived thereof are combined via a sequence comprising a directed metal−halogen exchange reaction, transmetalation of the resulting lithiopyrrole to the corresponding organozinc compound, a palladium-catalyzed cross coupling of the latter, and a subsequent acid-catalyzed closure of the resulting ketone 29 leading to the furan entity of the target. The triisopropylsilyl-protected side chain 3b is first deprotonated with n-BuLi and then transmetalated with CeCl3 to give a highly nucleophilic organocerium reagent, which readily attacks the sterically hindered 2-(trimethylsilyl)ethoxymethyl-protected keto pyrrole 2c. Deprotection and final dehydration of the tertiary alcohol derivative 30 thus obtained leads to the intact azafulvene chromophore of the natural product and completes our total synthesis of this alkaloid

Concise Synthesis of the Antidepressive Drug Candidate GSK1360707 by a Highly Enantioselective Gold-Catalyzed Enyne Cycloisomerization Reaction

Out of depression: Indeed, no depressing results are obtained from a gold-catalyzed enyne cycloisomerization controlled by phosphoramidite ligands with TADDOL-related but acyclic backbones (see scheme; Cbz=benzyloxycarbonyl). The “triple-reuptake inhibitor” GSK1360707 was obtained in excellent yield and optical purity, therefore highlighting the relevance of asymmetric gold catalysis for practical applications

Preparation, Structure, and Reactivity of Nonstabilized Organoiron Compounds. Implications for Iron-Catalyzed Cross Coupling Reactions

A series of unprecedented organoiron complexes of the formal oxidation states −2, 0, +1, +2, and +3 is presented, which are largely devoid of stabilizing ligands and, in part, also electronically unsaturated (14-, 16-, 17- and 18-electron counts). Specifically, it is shown that nucleophiles unable to undergo β-hydride elimination, such as MeLi, PhLi, or PhMgBr, rapidly reduce Fe(3+) to Fe(2+) and then exhaustively alkylate the metal center. The resulting homoleptic organoferrate complexes [(Me4Fe)(MeLi)][Li(OEt2)]2 (3) and [Ph4Fe][Li(Et2O)2][Li(1,4-dioxane)] (5) could be characterized by X-ray crystal structure analysis. However, these exceptionally sensitive compounds turned out to be only moderately nucleophilic, transferring their organic ligands to activated electrophiles only, while being unable to alkylate (hetero)aryl halides unless they are very electron deficient. In striking contrast, Grignard reagents bearing alkyl residues amenable to β-hydride elimination reduce FeXn (n = 2, 3) to clusters of the formal composition [Fe(MgX)2]n. The behavior of these intermetallic species can be emulated by structurally well-defined lithium ferrate complexes of the type [Fe(C2H4)4][Li(tmeda)]2 (8), [Fe(cod)2][Li(dme)]2 (9), [CpFe(C2H4)2][Li(tmeda)] (7), [CpFe(cod)][Li(dme)] (11), or [Cp*Fe(C2H4)2][Li(tmeda)] (14). Such electron-rich complexes, which are distinguished by short intermetallic Fe−Li bonds, were shown to react with aryl chlorides and allyl halides; the structures and reactivity patterns of the resulting organoiron compounds provide first insights into the elementary steps of low valent iron-catalyzed cross coupling reactions of aryl, alkyl, allyl, benzyl, and propargyl halides with organomagnesium reagents. However, the acquired data suggest that such C−C bond formations can occur, a priori, along different catalytic cycles shuttling between metal centers of the formal oxidation states Fe(+1)/Fe(+3), Fe(0)/Fe(+2), and Fe(−2)/Fe(0). Since these different manifolds are likely interconnected, an unambiguous decision as to which redox cycle dominates in solution remains difficult, even though iron complexes of the lowest accessible formal oxidation states promote the reactions most effectively

A Practical Procedure for Iron-Catalyzed Cross-Coupling Reactions of Sterically Hindered Aryl-Grignard Reagents with Primary Alkyl Halides

Although iron-catalyzed cross-coupling reactions of arylmagnesium halides with alkyl halides are well established and proceed effectively under a variety of experimental conditions, they often find limitations when working with sterically hindered aryl-Grignard reagents. Outlined in this paper is a practical solution that allows this gap in coverage to be filled. Specifically, it is shown that bis(diethylphosphino)ethane (depe) crafts an effective coordination environment about Fe(+2). This commercially available ligand is slim enough not to interfere with the loading of the iron center even by ortho,ortho-disubstituted arylmagnesium halides, yet capable of preventing premature reductive coupling of the resulting organoiron species, which seem to be hardly basic either. The reaction is compatible with various polar functional groups as well as with substrates containing β-heteroatom substituents. Moreover, the procedure even allows encumbered neopentylic electrophiles to be arylated with donors as bulky as mesitylmagnesium bromide, whereas secondary alkyl halides tend to eliminate

Selective Formation of a Trisubstituted Alkene Motif by trans-Hydrostannation/Stille Coupling: Application to the Total Synthesis and Late-Stage Modification of 5,6-Dihydrocineromycin B

Countless natural products of polyketide origin have an E-configured 2-methyl-but-2-en-1-ol substructure. An unconventional entry into this important motif was developed as part of a concise total synthesis of 5,6-dihydrocineromycin B. The choice of this particular target was inspired by a recent study, which suggested that the cineromycin family of antibiotics might have overlooked lead qualities, although our biodata do not necessarily support this view. The new approach consists of a sequence of alkyne metathesis followed by a hydroxy-directed trans-hydrostannation and a largely unprecedented methyl-Stille coupling. The excellent yield and remarkable selectivity with which the signature trisubstituted alkene site of the target was procured is noteworthy considering the rather poor outcome of a classical ring-closing metathesis reaction. Moreover, the unorthodox ruthenium-catalyzed trans-hydrostannation is shown to be a versatile handle for diversity-oriented synthesis

Total Synthesis of Amphidinolide F

Orchestrated yet nonconsonant: The challenge posed by the “umpoled” 1,4-dioxygenation pattern characteristic for the polyketide frame of amphidinolide F was mastered by a late-stage ring-closing alkyne metathesis followed by a directed transannular hydration under the aegis of a carbophilic π-acid catalyst. This concordant strategy enabled a concise total synthesis of this enticing marine natural product

A Cheap Metal for a "Noble" Task: Preparative and Mechanistic Aspects of Cycloisomerization and Cycloaddition Reactions Catalyzed by Low-Valent Iron Complexes

Reaction of ferrocene with lithium in the presence of either ethylene or COD allows the Fe(0)-ate complexes 1 and 4 to be prepared on a large scale, which turned out to be excellent catalysts for a variety of Alder-ene, [4+2], [5+2], and [2+2+2] cycloadditon and cycloisomerization reactions of polyunsaturated substrates. The structures of ferrates 1 and 4 in the solid-state reveal the capacity of the reduced iron center to share electron density with the ligand sphere. This feature, coupled with the kinetic lability of the bound olefins, is thought to be responsible for the ease with which different enyne or diyne substrates undergo oxidative cyclization as the triggering event of the observed skeletal reorganizations. This mechanistic proposal is corroborated by highly indicative deuterium labeling experiments. Moreover, it was possible to intercept two different products of an oxidative cyclization manifold with the aid of the Fe(+1) complex 6, which, despite its 17-electron count, also turned out to be catalytically competent in certain cases. The unusual cyclobutadiene complex 38 derived from 6 and tolane was characterized by X-ray crystallography