Jean-François Betzer

Phosphine Organocatalysis in the Synthesis of Natural Products and Bioactive Compounds

During the last few years, synthetic methods based on phosphine organocatalysis have experienced extremely fast developments. This short overview is intended to demonstrate that these methods can afford suitable tools for the constitution of either focused or diversity‐oriented‐synthesis (DOS) inspired libraries of small molecules for biological screening. It also reports selected examples where these organocatalytic methods have been used conveniently as key steps in the formal or total synthesis of complex natural products. Especially, synthetic applications of the inter‐ and intramolecular cyclizations of unsaturated substrates have been considered in this review.

Efficient preparation of (Z)-alkenyl derivatives from (Z)-vinyl (N, N-diisopropyl)carbamate via Ni-catalysed coupling reactions

A (Z)-vinyl (N,N-diisopropyl)carbamate treated with Grignard reagents, under Wenkert Nickel-catalysed conditions, gave access to several substituted (Z)-alkenyl derivatives. These Nickel-catalysed reactions, carried out with vinyl-, phenyl-, p-methoxyphenyl-, trimethylsilylmethylmagnesium bromide and benzylmagnesium chloride, led to the corresponding (Z)-alkenyl derivatives in good yields and high stereoselectivities.

Planar Chiral Phosphoramidites with a Paracyclophane Scaffold: Synthesis, Gold(I) Complexes, and Enantioselective Cycloisomerization of Dienynes

The key structural feature of the new phosphoramidites is a paracyclophane scaffold in which two aryl rings are tethered by both a 1,8-biphenylene unit and a O-P-O bridge. Suitable aryl substituents generate planar chirality. The corresponding gold(I) complexes promote the cycloisomerization of prochiral nitrogen-tethered dienynes. These reactions afford bicyclo[4.1.0]heptene derivatives displaying three contiguous stereogenic centers, with very high diastereoselectivity and up to 95u2009%u2005ee.

Planar Chiral Phosphoric Acids with Biphenylene-Tethered Paracyclophane Scaffolds: Synthesis, Characterization, and Catalytic Screening

Phosphoric acids with planar chiral paracyclophane scaffolds have been prepared in optically pure form starting from 1,8-dibromobiphenylene, by means of a chiral phosphorodiamidate as the phosphorylating agent. Structural characterization and configurational assignment have been performed by X-ray diffraction studies. The acids promote the organocatalytic enantioselective H-transfer reduction of α-arylquinolines with up to 90% enantiomeric excess.

Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting

G-quadruplex structures (G4) are promising anticancerous targets. A great number of small molecules targeting these structures have already been identified through biophysical methods. In cellulo, some of them are able to target either telomeric DNA and/or some sequences involved in oncogene promotors, both resulting in cancer cell death. However, only a few of them are able to bind to these structures G4 irreversibly. Here we combine within the same molecule the G4-binding agent PDC (pyridodicarboxamide) with a N-heterocyclic carbene-platinum complex NHC-Pt already identified for its antitumor properties. The resulting conjugate platinum complex NHC-Pt-PDC stabilizes strongly G-quadruplex structures in vitro, with affinity slightly affected as compared to PDC. In addition, we show that the new conjugate binds preferentially and irreversibly the quadruplex form of the human telomeric sequence with a profile in a way different from that of NHC-Pt thereby indicating that the platination reaction is oriented by stacking of the PDC moiety onto the G4-structure. In cellulo, NHC-Pt-PDC induces a significant loss of TRF2 from telomeres that is considerably more important than the effect of its two components alone, PDC and NHC-Pt, respectively.

Chapter 3 – Discodermolide: Total Synthesis of Natural Product and Analogues

This account describes an efficient and modulable total synthesis of (+)-discodermolide and analogues. Particularly notable is the repeated application of a crotylation reaction of aldehydes, with α-oxygenated crotyltitanium reagent to ensure the stereocontrolled elaboration of syn–anti methyl-hydroxy-methyl triads connected to a Z-O-enecarbamate. This particular group allowed direct and easy access to either a triple bond or terminal Z-diene function. The stereocontrolled generation of the trisubstituted Z-double bond, representing a significant synthetic challenge, is ensured by a 1,2-dyotropic rearrangements on dihydrofuran with organocopper reagents. The synthesis of natural product was achieved in 21 steps with 1.6% overall yield. The same methodologies and synthetic strategy were applied for the preparation of five original analogues. The biological activities of natural product and synthetic analogues have also been studied.

Preparation of the three C1-C7, C8-C15, and C16-N22 fragments of the Hsp90 inhibitor herbimycin A

The construction of the three C16-N22 2, C1-C7 6 (as 23) and C8-C15 5 (as 32) segments of the Hsp90 inhibitor herbimycin A (1) is reported. 1-Iodo-3-nitro-2,5-diphenol compound 2 was obtained in 55% yield for 3 steps fromthe commercially available diiodo derivative 7. Reaction between 1,1-dibromo-alkene 22 and vinyltin 17a using Pd(PPh 3 ) 4 or Pd(CH3CN) 2 Cl 2 /CuI/diisopropylethylamine, in toluene or DMF at 85 °C, led to enyne 23 in 63% yield (19% overall yield from isopropylidene glyceraldehyde). The synthesis of the C8-C15 sub-unit 32 was performed in 3.4% overall yield for 13 steps, from the commercially available ester 24, with a Hoppe crotylation as a key step.

Palladium-catalysed coupling reactions: (Z)-vinyl (N, N-diisopropyl)carbamate group as an efficient precursor of a (Z)-vinyl triflate function

A (Z)-vinyl (diisopropyl)carbamate group, generated from a Hoppe allylation reaction, was easily transformed either into the corresponding (Z)-vinyl phosphate or (Z)-vinyl triflate function in good yield and high selectivity. It was also shown that the result- ing (Z)-vinyl triflate compound could be utilized successfully in palladium-catalysed coupling reactions with vinyl-, phenyl- and acetylenic tin derivatives, without loss of the (Z)-geometry of the double bond.

IMDA reaction in a synthetic approach towards a natural kijamicin aglycon analog

Abstract In our program of new macrocyclic antibiotic derivatives synthesis, a natural kijamicin analog was isolated, disclosing important antibiotic and antiviral properties, which are under investigation. In this paper we describe a synthesis of the bottom half C1-C14 ( n xa0=xa01) of its aglycon. This strategy was based on the preparation of a tetraene derivative via a palladium catalyzed Stille coupling reaction, the final step involving an IMDA cyclization key step.