Rhodium-Catalyzed Room Temperature C-C Activation of Cyclopropanol for One-Step Access to Diverse 1,6-Diketones.

A rhodium-catalyzed room temperature C-C activation of cyclopropanol has been demonstrated for the single-step synthesis of a range of electronically and sterically distinct 1,6-diketones. This reaction proceeds efficiently in shorter reaction time following a highly atom-economical pathway. To illustrate the synthetic potential of 1,6-diketones, aldol and macrocyclization reactions have been successfully demonstrated. Preliminary mechanistic studies revealed the involvement of nonradical pathways.

A Palladium-Catalyzed Cascade C-C Activation of Cyclopropenone and Carbonylative Amination: Easy Access to Highly Functionalized Maleimide Derivatives.

We describe herein the first report on palladium-catalyzed C-C bond activation of cyclopropenone and concomitant carbonylative amination to produce maleimides. The interesting aspect of this reaction is that the sacrificial elimination of carbon monoxide from the substrate is efficiently recaptured by one of the intermediates in the catalytic cycle for the formation of maleimides. 18O isotopic studies confirmed that the source of carbon monoxide is from cyclopropenone.

Cobalt-Catalyzed Regioselective Direct C-4 Alkenylation of 3-Acetylindole with Michael Acceptors Using a Weakly Coordinating Functional Group.

Herein, we disclosed the first report on the selective C(4)-H functionalization of 3-acetylindole derivatives using first-row transition metal cobalt where an acetyl group is acting as a weakly coordinating directing group. Selective C(4)-H functionalization has been achieved using diverse Michael acceptors (acrylate and maleimide) simply by switching the additive from copper acetate to silver carbonate. Further the formation of a cobaltacycle intermediate was also detected through HRMS for mechanistic insight.

Cobalt Catalyzed Hydroarylation of Michael Acceptors with Indolines Directed by a Weakly Coordinating Functional Group.

A cobalt(III) catalyzed hydroarylation of Michael acceptors using indolines, selectively at the C-7 position, has been reported. For the selective C-7 functionalization of indoline, we have used a weakly coordinating amide carbonyl group. During the process of optimization, we have also discovered the unusual cocatalytic activity of zinc triflate in the C-H functionalization reaction. Hydroarylation of unprotected maleimide using indolines was a challenging substrate and never accomplished before, we were able to achieve this with our methodology in good yields.

Hexafluoroisopropanol mediated benign synthesis of 2H-pyrido[1,2-a]pyrimidin-2-ones by using a domino protocol.

Domino strategy has been used for the synthesis of 2H-pyrido[1,2-a]pyrimidin-2-ones. Four sequential reactions: aza-Michael addition, water elimination, intramolecular acyl substitution, and [1,3]-H shift were observed in this domino protocol. Hexafluoroisopropanol is used as a promotor and recyclable solvent in this cascade process. Availability of inexpensive 2-aminopyridines and wide variety of Michael acceptors such as commercially available acrylates and unactivated Baylis-Hillman adducts makes this methodology a huge reservoir of novel fused N-heterocycles as bioactive and potential therapeutic agents. The reaction mechanism has been proposed and rationalized by density functional theory calculation. Products are obtained up to 95% yield.

Formal Total Synthesis of Amphidinolide Q.

With the preparation of macrolactone 33a we describe a formal total synthesis of amphidinolide Q. The corresponding seco acid 32 originated from an aldol reaction between methyl ketone 6 and methyl (E)-3-methyl-4-oxobut-2-enoate (5). The synthesis of ketone 6 (C5-C16 fragment) started with desymmetrized meso-diol 9. Chain extension reactions involving cyanide, lithium trimethylsilylacetylide, and a Wittig reaction led to aldehyde 22. The two additional stereocenters at C11 and C13 were set by a Noyori transfer hydrogenation on alkynone 14 and a Feringa-Minnaard methyl cuprate addition on enoate 21. The but-1-ene-2-yl subunit on the side chain terminus was created from an unsaturated aldehyde by a substitution reaction on a derived allylic tosylate.

An unusual chemoselective oxidation strategy by an unprecedented exploration of an electrophilic center of DMSO: a new facet to classical DMSO oxidation.

A conceptually new dimethyl sulfoxide (DMSO) based oxidation process without the use of any activator has been demonstrated for the oxidation of active methylenes and benzhydrols. The developed protocol utilizes the electrophilic center of DMSO for oxidation, which was unexplored before. Mechanistic investigation has confirmed that the source of oxygen is DMSO.

Development of enantioselective synthetic routes to (-)-kinamycin F and (-)-lomaiviticin aglycon.

The development of enantioselective synthetic routes to (-)-kinamycin F (9) and (-)-lomaiviticin aglycon (6) are described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a ß-trimethylsilylmethyl-α,ß-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39→37), and diazo transfer (37→53). The D-ring precursors 60 and 68 were prepared from m-cresol and 3-ethylphenol, respectively. Coupling of the ß-trimethylsilylmethyl-α,ß-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer provided the advanced diazofluorene 63, which was elaborated to (-)-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C(2)-symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome in the coupling is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid-dichloromethane) to form mixtures of the chain isomer of lomaiviticin aglycon 98 and the ring isomer 6. These mixtures converged on purification or standing to the ring isomer 6 (39-41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%). We establish that dimeric diazofluorenes undergo hydrodediazotization 2-fold faster than related monomeric diazofluorenes. This enhanced reactivity may underlie the cytotoxic effects of (-)-lomaiviticin A (1). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC(50) = 500 nM).

Transmissive olefination route to putative "morinol I" lignans.

A series of morinol-type lignans were rapidly assembled using a Grignard-based transmissive olefination. In combination with palladium-catalyzed arylations, the strategy provides stereoselective access to (7Z,7'E), (7E,7'E), and (7E,7'Z) morinol diastereomers and the (7Z,8'E) and (7E,8'E) conjugated analogues. Critical for the E/Z stereoselectivity is a new, general method for converting alkenenitriles to alkenemethanols that circumvents the enal E/Z isomerization commonly encountered during conventional i-Bu(2)AlH reduction.

Alkenenitrile Transmissive Olefination: Synthesis of the Putative Lignan "Morinol I"

Grignard reagents trigger an addition-elimination with α'-hydroxy acrylonitriles to selectively generate Z-alkenenitriles. The modular assembly of Z-alkenenitriles from a Grignard reagent, acrylonitrile, and an aldehyde is ideal for stereoselectively synthesizing alkenes as illustrated in the synthesis of the putative lignan "morinol I."

Allylic and allenic halide synthesis via NbCl(5)- and NbBr(5)-mediated alkoxide rearrangements.

Addition of NbCl(5) or NbBr(5) to a series of magnesium, lithium, or potassium allylic or propargylic alkoxides directly provides allylic or allenic halides. Halogenation formally occurs through a metalla-halo-[3,3] rearrangement, although concerted, ionic, and direct displacement mechanisms appear to operate competitively. Transposition of the olefin is equally effective for allylic alkoxides prepared by nucleophilic addition, deprotonation, or reduction. Experimentally, the niobium pentahalide halogenations are rapid, afford essentially pure (E)-allylic or -allenic halides after extraction, and are applicable to a range of aliphatic and aromatic alcohols, aldehydes, and ketones.

Synthesis of the fully glycosylated cyclohexenone core of lomaiviticin A.

We describe two four-step sequences for conversion of the inexpensive reagent ethyl sorbate to either O-allyl-N,N-dimethyl-D-pyrrolosamine or O-allyl-L-oleandrose, protected forms of the 2,6-dideoxy sugar residues found in the complex bacterial metabolite lomaiviticin A. We also report a gram-scale synthesis of the highly-oxygenated cyclohexenone ring of this metabolite, and show this may be coupled with the aforementioned donors to form the bis(glycoside) 6. The longest linear sequence to 6 is nine steps.

Direct Conversion of Aldehydes and Ketones to Allylic Halides by a NbX(5-)[3,3] Rearrangement.

Sequential addition of vinylmagnesium bromide and NbCl(5), or NbBr(5), to a series of aldehydes and ketones directly provides homologated, allylic halides. Transposition of the intermediate vinyl alkoxide is envisaged through a metalla-halo-[3,3] rearrangement with concomitant delivery of the halogen to the terminal carbon. The [3,3] rearrangement is equally effective for the conversion of a propargyllic alcohol to the corresponding allenyl bromide.