Zdenko Casar

Iridium‐Catalyzed Chemoselective and Enantioselective Hydrogenation of (1‐Chloro‐1‐Alkenyl) Boronic Esters

Organoboron compounds play important roles in chemistry, especially in the field of organometallic catalysis where boronic acids, boronic esters, and trifluoroborates are invaluable for the construction of C O, C N, or C C bonds through various coupling reactions. a-Amino boronic acids, primarily obtained from (a-chloroalkyl) boronic esters, are a recent addition to this class of compounds, expanding them into completely new areas of use. They are a crucial structural element in a new class of anti-cancer peptide drugs. One member of this class of drugs, which contains a “borleucine” moiety, is marketed under the name bortezomib (Scheme 1).

Lactone Pathway to Statins Utilizing the Wittig Reaction. The Synthesis of Rosuvastatin

The first entry to statins via lactonized side chain is reported, exemplified by the synthesis of rosuvastatin. The key step is Wittig coupling of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-carbaldehyde and phosphonium salt of an appropriately functionalized pyrimidine heterocycle. One-pot deprotection and hydrolysis of the resulting 4-O-TBS rosuvastatin lactone provided rosuvastatin in high yield.

A highly productive, whole-cell DERA chemoenzymatic process for production of key lactonized side-chain intermediates in statin synthesis.

Employing DERA (2-deoxyribose-5-phosphate aldolase), we developed the first whole-cell biotransformation process for production of chiral lactol intermediates useful for synthesis of optically pure super-statins such as rosuvastatin and pitavastatin. Herein, we report the development of a fed-batch, high-density fermentation with Escherichia coli BL21 (DE3) overexpressing the native E. coli deoC gene. High activity of this biomass allows direct utilization of the fermentation broth as a whole-cell DERA biocatalyst. We further show a highly productive bioconversion processes with this biocatalyst for conversion of 2-substituted acetaldehydes to the corresponding lactols. The process is evaluated in detail for conversion of acetyloxy-acetaldehyde with the first insight into the dynamics of reaction intermediates, side products and enzyme activity, allowing optimization of the feeding strategy of the aldehyde substrates for improved productivities, yields and purities. The resulting process for production of ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (acetyloxymethylene-lactol) has a volumetric productivity exceeding 40 g L−1 h−1 (up to 50 g L−1 h−1) with >80% yield and >80% chromatographic purity with titers reaching 100 g L−1. Stereochemical selectivity of DERA allows excellent enantiomeric purities (ee >99.9%), which were demonstrated on downstream advanced intermediates. The presented process is highly cost effective and environmentally friendly. To our knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme. Finally, applicability of the presented process is demonstrated by efficient preparation of a key lactol precursor, which fits directly into the lactone pathway to optically pure super-statins.

CuII and Cu0 Catalyzed Mono Borylation of Unsaturated Hydrocarbons with B2pin2: Entering into the Water

Organoboron compounds 2] actuate an on-going interest in chemistry owing to their versatile applicability. Indeed, in recent years biological significance of these compounds has been clearly established. A breakthrough advance in this area was achieved when bortezomib 5] was approved as the first proteasome inhibitor for human use in the frontline treatment of multiple myeloma. This encouraged further development in the area and many new compounds of this type are currently being investigated, among which ixazomibe and delanzomibe are in advanced clinical stages. Moreover, dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor that contains an a-aminoboronic acid moiety, has been investigated for treatment of type 2 diabetes mellitus (Figure 1). In addition, nowadays organoboranes find important applications in chemistry of materials and as essential reagents in important chemical transformations. The unique reactivity of C B bond makes this class of compounds distinct in many ways. Namely, the creation of C B bonds in organic frameworks offers many interesting possibilities for the subsequent functional group transformations and application in the synthesis of complex molecules. The most prominent examples of these transformations are oxidations, cross-couplings, allylborations, 16] homologation sequences, 1,2-migrations, 19] amine synthesis, Petasis reaction, carbonylations, and many others others 23] (Scheme 1).

Cobalt-Catalyzed Cross-Coupling of Grignards with Allylic and Vinylic Bromides: Use of Sarcosine as a Natural Ligand.

Sarcosine was discovered to be an excellent ligand for cobalt-catalyzed carbon-carbon cross-coupling of Grignard reagents with allylic and vinylic bromides. The Co(II)/sarcosine catalytic system is shown to perform efficiently when phenyl and benzyl Grignards are coupled with alkenyl bromides. Notably, previously unachievable Co-catalyzed coupling of allylic bromides with Grignards to linearly coupled α-products was also realized with Co(II)/sarcosine catalyst. This method was used for efficient preparation of the key intermediate in an alternative synthesis of the antihyperglycemic drug sitagliptin.

Acid promoted Ir–P^N complex catalyzed hydrogenation of heavily hindered 3,4-diphenyl-1,2-dihydronaphthalenes: asymmetric synthesis of lasofoxifene tartrate

In this report we present the first successful homogenous asymmetric hydrogenation of heavily hindered and minimally functionalized tetrasubstituted cyclic olefins bearing three aromatic substituents, which represent key precursors of lasofoxifene tartrate. The success of our hydrogenation method is based on the surprising discovery that Bronsted acids or Lewis acids can significantly enhance the reactivity of these substrates towards hydrogenation with Ir–P^N complexes. Iterative screens of Ir–P^N catalysts, additives and reaction conditions led to high to full conversions with high ee. The obtained hydrogenation products are easily converted to optically pure selective estrogen receptor modulator lasofoxifene tartrate in significantly higher overall yield compared to previously reported methods.

Recent Progress in the Synthesis of Super-Statins

Super-statins now represent a mature class of marketed drugs that faces the patent cliff, as has already occurred for fluvastatin and atorvastatin and is approaching for rosuvastatin and pitavastatin. However, they continue to trigger huge scientific interest in terms of their efficient preparation. This is not surprising, as easier accessibility of super-statins will promote even bigger demand in the market and consequently the need for higher rates of the production and productivity. Therefore, the stimulus for the development of even more efficient synthetic approaches to the heterocyclic moieties of super-statins and their chiral lateral-chain precursors is at a peak, as also for the assembly of the these two parts into super-statins. The present report summarizes recent developments in the field of the synthesis of super-statins published from 2010 to 2015. Emphasis is given to the analysis of novel approaches to the formation of the chiral statin lateral chain, with detailed discussion of the development of new routes to respective heterocyclic cores and the assembly of these key units into the final super-statin structure.

En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole

A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1) has been reported. Compound 1a is a key impurity of reverse transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges, dead ends, and detours are discussed.

Development of concise two-step catalytic approach towards lasofoxifene precursor nafoxidine

We have elaborated a two-step catalytic approach to nafoxidine, a key precursor to lasofoxifene. Firstly, an efficient α-arylation of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one with chlorobenzene was developed, which operates at low 0.1 mol% Pd-132 catalyst loading in the presence of 1.9 equivalents of sodium tert-butoxide at 60 °C in 1,4-dioxane and provides 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one in 90% yield. Secondly, we have demonstrated that 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one can be converted to nafoxidine in 61% yield via CeCl3 promoted reaction with (4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)lithium, which is formed in-situ from the corresponding arylbromide precursor and n-butyllithium. Altogether, the shortest two-step approach to nafoxidine from simple tetralone commodity starting material has been developed with overall 55% yield. The developed synthetic approach to nafoxidine has several beneficial aspects over the one used in the synthetic route primarily developed for the preparation of lasofoxifene.

3-Mercaptopropionic acid as a new reagent for the industrially applicable synthesis of highly pure O-desmethylvenlafaxine from venlafaxine

3-Mercaptopropionic acid was introduced as a cheap new O-demethylating agent as exemplified by its application in the synthesis of antidepressant O-desmethylvenlafaxine from venlafaxine. The application of 3-mercaptopropionic acid allowed high conversion of venlafaxine to O-desmethylvenlafaxine and a facile workup, which enabled the isolation of the desired O-desmethylvenlafaxine with a high >99.8% chromatographic purity and 76% yield by a simple extractive workup followed by the precipitation. GRAPHICAL ABSTRACT