Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

The protecting-group free selective 3'-functionalization of nucleosides.

The direct and chemoselective 3'-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 3'-phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings allowed us to develop a predictive computational model that accurately assesses the potential for 3'-functionalization for a broad range of nucleosides and nucleoside mimetics. The synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible via a protection/deprotection sequence or an enzymatic approach.

Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189.

A general and efficient method for the synthesis of pronucleotide (ProTide) 5'-phosphoramidate monoesters is reported. This method consists of a highly stereoselective 5'-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing 3'-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated.

Gasometric titration for dimethylaluminum chloride analysis.

A gasometric titration method was developed to quantitate active alkylaluminum content in dimethylaluminum chloride solution to perform the stoichiometry calculation for the reaction charge. The procedure was reproducible with good precision, and the results showed good correlation with ICP-MS method. The gasometric titration is a simple, inexpensive alternative to analysis via ICP-MS which provides more selective analysis of methylaluminum species without the need for inertion.

Collective synthesis of natural products by means of organocascade catalysis.

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

Nine-step enantioselective total synthesis of (+)-minfiensine.

An enantioselective total synthesis of the Strychnos alkaloid (+)-minfiensine has been accomplished. Prominent features of this synthesis include (i) a new enantioselective organocatalytic Diels-Alder/amine cyclization sequence to build the central tetracyclic pyrroloindoline framework in four steps from commercial materials and (ii) a 6-exo-dig radical cyclization to forge the final piperidinyl ring system. This total synthesis of (+)-minfiensine was completed in nine chemical steps and 21% overall yield.

Highly efficient asymmetric synthesis of sitagliptin.

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

Cycle-specific organocascade catalysis: application to olefin hydroamination, hydro-oxidation, and amino-oxidation, and to natural product synthesis.

United in effort: The combined application of iminium (Im) and enamine (En) catalysts can effect a range of valuable asymmetric transformations including 1,2-hydroamination, -hydro-oxidation, and -amino-oxidation of olefins (see picture). An enantioselective organocascade catalysis was also applied in the synthesis of a complex natural product.

Chlorination/cyclodehydration of amino alcohols with SOCl2: an old reaction revisited.

A simple, one-pot preparation of cyclic amines via efficient chlorination of amino alcohols with use of SOCl(2) has been developed. This approach obviates the need for the classical N-protection/O-activation/cyclization/deprotection sequence commonly employed for this type of transformation. The reaction pathways and the general scope of this method have also been investigated.

Stereocontrolled synthesis of trisubstituted cyclopropanes: expedient, atom-economical, asymmetric syntheses of (+)-Bicifadine and DOV21947.

[reaction: see text] An expedient, atom-economical, asymmetric synthesis of 1-aryl-3-azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.

Practical preparation of 3,3-difluoropyrrolidine.

A practical and cost-effective synthesis of 3,3-difluoropyrrolidine is reported. The synthesis involves the isolation of two intermediates, which are prepared via two efficient through processes: (1) a Claisen rearrangement followed by a Ru(VIII)-catalyzed oxidation to prepare the 2,2-difluorosuccinic acid and (2) an efficient cyclization to form N-benzyl-3,3-difluoropyrrolidinone followed by BH(3).Me(2)S reduction.

Preparation of C-3,5-acyl furanoses via highly selective intramolecular acyl migration.

A practical synthesis of C-3,5-acyl furanose via a base-catalyzed, highly selective intramolecular acyl migration in alcohol solvents is reported.

Mechanistic evidence for an alpha-oxoketene pathway in the formation of beta-ketoamides/esters via Meldrum's acid adducts.

A practical, one-pot process for the preparation of beta-keto amides via a three-component reaction, including Meldrum's acid, an amine, and a carboxylic acid, has been developed. Key to development of an efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process. Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis which provided a means of profiling the concentration of both the anionic and free acid forms of the Meldrum's adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest that formation of beta-keto amides from acyl Meldrum's acids occurs via alpha-oxoketene species 2 and rule out other possible reaction pathways proposed in the literature, such as via protonated alpha-oxoketene intermediates 3 or nucleophilic addition-elimination pathways.

Selective synthesis of the para-quinone region of geldanamycin.

[structure: see text] The quinone portion of the ansamycin geldanamycin was made with complete selectivity from the 1,4-dihydroquinone generated from a 1,4-bis-methoxymethyl (MOM) ether intermediate. Palladium catalysis with air gave the desired product in 98% isolated yield. The structure was established using NMR, UV, and X-ray analysis with comparisons to geldanamycin, ortho-quino-geldanamycin and a model compound.

Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin: asymmetric glycolate aldol reactions and biological evaluation.

The total synthesis of (+)-geldanamycin (GA), following a linear route, has been completed using a demethylative quinone-forming reaction as the last step. Key steps include the use of two new asymmetric boron glycolate aldol reactions. To set the anti-C11,12 hydroxymethoxy functionality, (S,S)-5,6-bis-4-methoxyphenyldioxanone 8 was used. Methylglycolate derived from norephedrine 5 set the C6,7 methoxyurethane stereochemistry. The quinone formation step using nitric acid gave the non-natural o-quino-GA product 55 10:1 over geldanamycin. Other known oxidants gave an unusual azaquinone product 49. o-Quino-GA 55 binds Hsp90 with good affinity but is less cytotoxic compared to GA.

Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin with use of asymmetric anti- and syn-glycolate aldol reactions.

Geldanamycin (GA), an antitumor Hsp90 inhibitor, was made for the first time by using an oxidative demethylation reaction as the final step. A biaryldioxanone auxiliary set the anti C11-12 hydroxy-methoxy functionality and a methylglycolate auxiliary based on norephedrine was used for the syn C6-7 methoxy-urethane. p-Quinone-forming oxidants, CAN and AgO, produced an unusual aza-quinone product. Nitric acid gave GA from a trimethoxy precursor in 55% yield as a 1:10 mixture with nonnatural o-quino-GA. [structure: see text]