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1.
Org Lett ; 24(41): 7701-7706, 2022 10 21.
Article in English | MEDLINE | ID: mdl-36227065

ABSTRACT

Herein, we present a strategy for the preparation of 3'-fluorinated nucleoside analogues via the aminocatalytic, electrophilic fluorination of readily accessible and bench-stable 2'-ketonucleosides. Initially developed to facilitate the manufacture of 3'-fluoroguanosine (3'-FG)─a substructure of anticancer therapeutic MK-1454─this strategy has been extended to the synthesis of a variety of 3'-fluoronucleosides. Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.

2.
Org Lett ; 24(27): 4860-4864, 2022 07 15.
Article in English | MEDLINE | ID: mdl-35793545

ABSTRACT

A general and diastereoselective fluorination/glycosylation strategy for the synthesis of 2'-fluorinated nucleosides has been developed. Electrophilic fluorination of a glycal with NFSI provided the 1',2'-difunctionalized furanoside intermediate with high diastereoselectivity. The TBS-protected 2'-deoxyfluorosulfonimide sugar was prepared on an 80 g scale and isolated as a crystalline, bench-stable single diastereomer. This intermediate was found to undergo a subsequent glycosylation reaction with a variety of heteroaryl nucleophiles with generally good diastereoselectivities.


Subject(s)
Halogenation , Nucleosides , Glycosylation , Stereoisomerism
3.
J Am Chem Soc ; 144(13): 5855-5863, 2022 04 06.
Article in English | MEDLINE | ID: mdl-35333525

ABSTRACT

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.


Subject(s)
Biological Products , Biological Products/chemistry , Catalysis
4.
J Org Chem ; 86(11): 7529-7536, 2021 06 04.
Article in English | MEDLINE | ID: mdl-34033478

ABSTRACT

A class of organocatalysts that are highly active for the conversion of 2'-deoxynucleosides to furanoid glycals have been discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH, were shown to effectively mediate persilylation of 2'-deoxynucleosides allowing the elimination of the nucleobase giving the corresponding glycal. These mild conditions were demonstrated in the syntheses of glycals with various substitution patterns while minimizing the formation of undesired byproducts and expanding the scope of this methodology.


Subject(s)
Nucleosides
5.
Chem Sci ; 9(34): 6922-6927, 2018 Sep 14.
Article in English | MEDLINE | ID: mdl-30210766

ABSTRACT

Quantitative structure-activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.

6.
Org Lett ; 20(17): 5431-5434, 2018 09 07.
Article in English | MEDLINE | ID: mdl-30130113

ABSTRACT

A practical synthesis of chiral tryptamines from simple, unprotected indoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with chiral cyclic sulfamidates almost exclusively at the C3-position of indole to form a variety of α- and/or ß-substituted chiral tryptamines in good yield with excellent regioselectivity. The utility of this simple alkylation process has been demonstrated with the practical synthesis of two biologically active targets, cipargamin and TIK-301, which were completed in three steps, starting from the corresponding indole starting materials.

7.
J Am Chem Soc ; 139(31): 10637-10640, 2017 08 09.
Article in English | MEDLINE | ID: mdl-28737937

ABSTRACT

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,ß-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.


Subject(s)
Acetates/chemical synthesis , Antiviral Agents/chemical synthesis , Quantum Theory , Quinazolines/chemistry , Acetates/chemistry , Acetates/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Catalysis , Cyclization , Hydrogen Bonding , Molecular Structure , Quinazolines/chemical synthesis , Quinazolines/pharmacology
8.
Angew Chem Int Ed Engl ; 55(44): 13714-13718, 2016 10 24.
Article in English | MEDLINE | ID: mdl-27690172

ABSTRACT

The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. The high-fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug-discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable-space coverage.


Subject(s)
Organometallic Compounds/chemistry , Pyridines/chemical synthesis , Zinc/chemistry , High-Throughput Screening Assays , Molecular Structure , Principal Component Analysis , Pyridines/chemistry
9.
Org Lett ; 18(9): 1952-5, 2016 05 06.
Article in English | MEDLINE | ID: mdl-27123552

ABSTRACT

Olefin metathesis (OM) is a reliable and practical synthetic methodology for challenging carbon-carbon bond formations. While existing catalysts can effect many of these transformations, the synthesis and development of new catalysts is essential to increase the application breadth of OM and to achieve improved catalyst activity. The unexpected initial discovery of a novel olefin metathesis catalyst derived from synthetic efforts toward the HCV therapeutic agent grazoprevir (MK-5172) is described. This initial finding has evolved into a class of tunable, shelf-stable ruthenium OM catalysts that are easily prepared and exhibit unique catalytic activity.

10.
Org Lett ; 18(6): 1394-7, 2016 Mar 18.
Article in English | MEDLINE | ID: mdl-26950496

ABSTRACT

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Drug Discovery , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/chemistry , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity Relationship
11.
Chemistry ; 18(10): 2948-60, 2012 Mar 05.
Article in English | MEDLINE | ID: mdl-22307837

ABSTRACT

The first stage in the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn/anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.


Subject(s)
Macrolides/chemical synthesis , Alkenes/chemical synthesis , Alkenes/chemistry , Alkynes/chemical synthesis , Alkynes/chemistry , Catalysis , Macrolides/chemistry , Molecular Structure , Stereoisomerism
12.
Chemistry ; 18(10): 2961-71, 2012 Mar 05.
Article in English | MEDLINE | ID: mdl-22307856

ABSTRACT

Herein, we present a full account of our efforts to couple the northern and the southern building blocks, the synthesis of which were described in the preceding paper, along with the modifications required to ultimately lead to a successful synthesis of laulimalide. Key highlights include an exceptionally efficient and atom-economical intramolecular ruthenium-catalyzed alkene-alkyne coupling to build the macrocycle, followed by a highly stereoselective 1,3-allylic isomerization promoted by a rhenium complex. Interestingly, the designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity. We also report a second generation route that provides a more concise synthesis of the natural product.


Subject(s)
Macrolides/chemical synthesis , Alkenes/chemical synthesis , Alkenes/chemistry , Alkynes/chemical synthesis , Alkynes/chemistry , Catalysis , Macrolides/chemistry , Molecular Structure , Rhodium/chemistry , Stereoisomerism
13.
J Am Chem Soc ; 131(47): 17087-9, 2009 Dec 02.
Article in English | MEDLINE | ID: mdl-19891433

ABSTRACT

Laulimalide is a structurally unique 20-membered marine macrolide displaying microtubule stabilizing activity similar to that of paclitaxel and the epothilones. The use of atom-economical transformations such as a Rh-catalyzed cycloisomerization to form the endocyclic dihydropyran, a dinuclear Zn-catalyzed asymmetric glycolate aldol reaction to prepare the syn 1,2-diol, and an intramolecular Ru-catalyzed alkene-alkyne coupling to build the macrocycle enabled us to synthesize laulimalide via an efficient and convergent pathway. The designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity.


Subject(s)
Macrolides/chemical synthesis , Transition Elements/chemistry , Catalysis , Macrolides/chemistry
14.
J Am Chem Soc ; 131(15): 5444-59, 2009 Apr 22.
Article in English | MEDLINE | ID: mdl-19331417

ABSTRACT

Electron capture dissociation (ECD) and electron transfer dissociation (ETD) of doubly protonated electron affinity (EA)-tuned peptides were studied to further illuminate the mechanism of these processes. The model peptide FQpSEEQQQTEDELQDK, containing a phosphoserine residue, was converted to EA-tuned peptides via beta-elimination and Michael addition of various thiol compounds. These include propanyl, benzyl, 4-cyanobenzyl, perfluorobenzyl, 3,5-dicyanobenzyl, 3-nitrobenzyl, and 3,5-dinitrobenzyl structural moieties, having a range of EA from -1.15 to +1.65 eV, excluding the propanyl group. Typical ECD or ETD backbone fragmentations are completely inhibited in peptides with substituent tags having EA over 1.00 eV, which are referred to as electron predators in this work. Nearly identical rates of electron capture by the dications substituted by the benzyl (EA = -1.15 eV) and 3-nitrobenzyl (EA = 1.00 eV) moieties are observed, which indicates the similarity of electron capture cross sections for the two derivatized peptides. This observation leads to the inference that electron capture kinetics are governed by the long-range electron-dication interaction and are not affected by side chain derivatives with positive EA. Once an electron is captured to high-n Rydberg states, however, through-space or through-bond electron transfer to the EA-tuning tags or low-n Rydberg states via potential curve crossing occurs in competition with transfer to the amide pi* orbital. The energetics of these processes are evaluated using time-dependent density functional theory with a series of reduced model systems. The intramolecular electron transfer process is modulated by structure-dependent hydrogen bonds and is heavily affected by the presence and type of electron-withdrawing groups in the EA-tuning tag. The anion radicals formed by electron predators have high proton affinities (approximately 1400 kJ/mol for the 3-nitrobenzyl anion radical) in comparison to other basic sites in the model peptide dication, facilitating exothermic proton transfer from one of the two sites of protonation. This interrupts the normal sequence of events in ECD or ETD, leading to backbone fragmentation by forming a stable radical intermediate. The implications which these results have for previously proposed ECD and ETD mechanisms are discussed.


Subject(s)
Electron Transport , Peptides/chemistry , Base Sequence , Chemical Phenomena , Free Radicals/chemistry , Phosphoserine/chemistry , Quantum Theory , Sulfhydryl Compounds/chemistry
15.
J Am Chem Soc ; 131(14): 5313-20, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19351207

ABSTRACT

A series of ruthenium olefin metathesis catalysts bearing N-heterocyclic carbene (NHC) ligands with varying degrees of backbone and N-aryl substitution have been prepared. These complexes show greater resistance to decomposition through C-H activation of the N-aryl group, resulting in increased catalyst lifetimes. This work has utilized robotic technology to examine the activity and stability of each catalyst in metathesis, providing insights into the relationship between ligand architecture and enhanced efficiency. The development of this robotic methodology has also shown that, under optimized conditions, catalyst loadings as low as 25 ppm can lead to 100% conversion in the ring-closing metathesis of diethyl diallylmalonate.


Subject(s)
Alkenes/chemistry , Methane/analogs & derivatives , Ruthenium/chemistry , Alkenes/chemical synthesis , Catalysis , Ligands , Malonates/chemistry , Methane/chemical synthesis , Methane/chemistry
16.
Org Lett ; 10(13): 2693-6, 2008 Jul 03.
Article in English | MEDLINE | ID: mdl-18510331

ABSTRACT

Ruthenium olefin metathesis catalysts bearing an N-phenyl-substituted N-heterocyclic carbene (NHC) ligand that are resistant to decomposition through C-H activation have been prepared and tested in ring closing metathesis (RCM), cross metathesis (CM), and ROMP reactions. The N, N'-diphenyl-substituted NHC complex proved to be one of the most efficient catalysts in RCM to form tetrasubstituted olefins.


Subject(s)
Alkenes/chemistry , Heterocyclic Compounds/chemistry , Methane/analogs & derivatives , Catalysis , Crystallography, X-Ray , Methane/chemistry , Models, Molecular , Molecular Structure , Ruthenium/chemistry
17.
J Am Chem Soc ; 128(32): 10358-9, 2006 Aug 16.
Article in English | MEDLINE | ID: mdl-16895388

ABSTRACT

A Mannich-type addition of propargylic alcohols and N-methoxycarbonylimines has been achieved by using a vanadium catalyst. The reactivity of the vanadium catalyst could be modulated by modifying the silanol ligands to avoid the background reaction. The strategy described herein provides an atom-economical access to beta-aryl-substituted Z-enones with an allylic amino functional group, which are not readily accessible with other methods.


Subject(s)
Alkynes/chemistry , Imines/chemistry , Propanols/chemistry , Vanadium/chemistry , Catalysis , Molecular Structure
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