In the panoply of modern synthetic methods for forming carbon−carbon and carbon−heteroatom bonds, the transition metal-catalyzed cross-coupling of organometallic nucleophiles with organic ...electrophiles enjoys a preeminent status. The preparative utility of these reactions is, in large measure, a consequence of the wide variety of organometallic donors that have been conscripted into service. The most common of these reagents are organic derivatives of tin, boron, and zinc, which each possess unique advantages and shortcomings. Because of their low cost, low toxicity, and high chemical stability, organosilanes have emerged as viable alternatives to the conventional reagents in recent years. However, unlike the tin- and zinc-based reactions, which require no activation, or the boron-based reactions, which require only heating with mild bases, silicon-based cross-coupling reactions often require heating in the presence of a fluoride source; this has significantly hampered the widespread acceptance of organosilanes. To address the “fluoride problem”, we have introduced a new paradigm for palladium-catalyzed, silicon-based cross-coupling reactions that employs organosilanols, a previously underutilized class of silicon reagents. The use of organosilanols either in the presence of Brønsted bases or as their silanolate salts represents a simple and mild alternative to the classic fluoride-based activation method. Organosilanols are easily available by many well-established methods for introducing carbon−silicon bonds onto alkenes, alkynes, and arenes and heteroarenes. Moreover, we have developed four different protocols for the generation of alkali metal salts of vinyl-, alkenyl-, alkynyl-, aryl-, and heteroarylsilanolates: (1) reversible deprotonation with weak Brønsted bases, (2) irreversible deprotonation with strong Brønsted bases, (3) isolation of the salts from irreversible deprotonation, and (4) silanolate exchange with disiloxanes. We have demonstrated the advantages of each of these methods for a number of different coupling classes. The defining feature of this new process is the formation of a covalently linked palladium silanolate species that facilitates the critical transmetalation step. We have verified the intermediacy of a critical species that contains the key Si−O−Pd linkage by its identification as the resting state in reaction mixtures, by X-ray analysis, and by demonstrating its competence in thermal cross-coupling with no additives. Our conclusions contradict the long-standing dogma that silicon-based cross-coupling reactions require the generation of a pentacoordinate siliconate prior to transmetalation. This revelation has opened a new vista for discovery of reactions that involve this critical process.
Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C–H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation ...of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.
Total Synthesis of Amphidinolide F Valot, Gaëlle; Regens, Christopher S.; O'Malley, Daniel P. ...
Angewandte Chemie (International ed.),
September 2, 2013, Letnik:
52, Številka:
36
Journal Article
Recenzirano
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.
Concise Total Syntheses of Amphidinolides C and F Valot, Gaëlle; Mailhol, Damien; Regens, Christopher S. ...
Chemistry : a European journal,
February 2, 2015, Letnik:
21, Številka:
6
Journal Article
Recenzirano
The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4‐diketone substructure. This particular motif inspired a ...synthesis plan predicating a late‐stage formation of this non‐consonant (“umpoled”) pattern by a platinum‐catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross‐coupling and a macrocyclization by ring‐closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other π‐systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene‐selective cobalt‐catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two‐directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from D‐glutamic acid by an intramolecular oxa‐Michael addition and a proline‐mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3Sn‐group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate.
Non‐canonical: Amphidinolides C and F are unusual in that these macrolides of polyketide origin comprise an “umpoled” 1,4‐diketone motif. This pattern served as the cornerstone of a uniform blueprint based on a late‐stage ring‐closing alkyne metathesis followed by a platinum‐catalyzed transannular hydroalkoxylation reaction (see scheme).
Total synthesis of (+)-papulacandin D Denmark, Scott E.; Kobayashi, Tetsuya; Regens, Christopher S.
Tetrahedron,
06/2010, Letnik:
66, Številka:
26
Journal Article
Recenzirano
Odprti dostop
A total synthesis of (+)-papulacandin D has been achieved in 31 steps, in a 9.2% overall yield from commercially available materials. The synthetic strategy divided the molecule into two nearly equal ...sized subunits, the spirocyclic
C-arylglycopyranoside and the polyunsaturated fatty acid side-chain. The
C-arylglycopyranoside was prepared in 11 steps in a 30% overall yield from triacetoxyglucal. The fatty acid side-chain was also prepared in 11 steps in a 30% overall yield from geraniol. The key strategic transformations in the synthesis are: (1) a palladium-catalyzed, organosilanolate-based cross-coupling reaction of a dimethylglucal-silanol with an electron-rich and sterically hindered aromatic iodide and (2) a Lewis-base catalyzed, enantioselective allylation reaction of a dienal and allyltrichlorosilane. A critical element in the successful execution of the synthesis was the development of a suitable protecting group strategy that satisfied a number of stringent criteria.
Display omitted
Total Synthesis of Papulacandin D Denmark, Scott E; Regens, Christopher S; Kobayashi, Tetsuya
Journal of the American Chemical Society,
03/2007, Letnik:
129, Številka:
10
Journal Article
Recenzirano
A total synthesis of the antifungal agent papulacandin D is reported. The molecule is representative of a large class of C-aryl glycosides that exhibit significant antifungal activity. The synthetic ...strategy bifurcates the molecule into two nearly equal subunits, the arylglycoside and 18-carbon fatty acid side chain. The key strategic transformations are (1) the palladium catalyzed, organosilanolate-based cross-coupling of a protected glucal silanol and (2) a catalytic enantioselective allylation of a dienal using allyltrichlorosilane. The synthesis was accomplished in 31 steps overall from commercial starting materials to afford over 50 mg of the natural product.
Presented are two case studies where polymorphic behavior of a process intermediate was identified and the relationship was investigated for form control. Case study I: 1 is a process intermediate ...for a novel apoptosis signal-regulating kinase 1 (ASK1) inhibitor that was isolated as an unsolvated hydrochloride salt (1-HCl). Initial research lots and the first delivery batch yielded form I of 1-HCl; however, during process optimization to support a second delivery, form II was identified. This discovery left limited time to map the thermodynamic relationship between the two phases prior to the second production, and based on limited knowledge at the time, form I was selected and successfully scaled even though it was determined to be the room temperature metastable phase. Case study II: 2 is a process intermediate for a novel toll-like receptor 8 (TLR8) agonist. Applying lessons learned from case study I, polymorph screening identified unsolvated forms I and II, whose relative stabilities were mapped so that a crystallization could be designed to ensure phase control for the thermodynamically most stable form at room temperature prior to production, which ultimately benefited superior impurity rejection.
The preparation of π-rich 2-aryl heterocycles by palladium-catalyzed cross-coupling of sodium heteroarylsilanolates with aryl iodides, bromides, and chlorides is described. The cross-coupling process ...was developed through extensive optimization of the following key variables: (1) identification of stable, isolable alkali metal silanolates, (2) identification of conditions for preformation and isolation of silanolate salts, (3) judicious choice in the palladium catalyst/ligand combination, and (4) selection of the protecting group on the nitrogen of indole. It was found that the alkali metal silanolates, either isolated or formed in situ, offered a significant rate enhancement and broader substrate scope over the use of silanols activated by Brønsted bases such as NaOt-Bu. In addition, the optimized conditions for the cross-coupling of 2-indolylsilanolates were readily applied to the cross-coupling of 2-pyrrolyl-, 2-furyl-, and 2-thienylsilanolates.
The development of an effective protocol for the palladium-catalyzed cross-coupling of (
E)-alkenylsilanols with aryl triflates is described. A critical component in the optimization of this method ...was balancing the stability and reactivity of the triflates in the presence of a nucleophilic promoter. This report highlights the use of a slightly soluble Brønsted base promoter that allows for a low, steady-state concentration of alkenyl(dimethyl)silanolate in solution, thus facilitating cross-coupling in preference to S–O bond cleavage of the triflate.
The chiral amino alcohol (R)-2-amino-2-methylhexan-1-ol (1) is a key fragment in the synthesis of selgantolimod, a TLR8 agonist that is being evaluated for the treatment of hepatitis B infection. ...This report describes the development of a robust and scalable synthesis of the targeted amino alcohol featuring a hydrolase-catalyzed kinetic resolution of an α,α-disubstituted amino ester. The results highlight considerations for substrate design for the enzymatic resolution, the impact of pH on the resolution of an unprotected α,α-disubstituted amino ester derivative, and implementation of this substrate within a route to the desired amino alcohol fragment.
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