Alkaloids fluorination

Quatemarization of the tertiary Nb atom with fluorine-containing alkyl groups furnished a series of quaternary salts. However, none of them was reported to be more active than the parent alkaloid (387). 

Hydroxypiperidine alkaloids have been synthesized via anodic methoxylation that allowed the regio- and stereoselective introduction of substituents [213]. A highly diastereoselective fluorination was achieved with chiral l,3-oxathiolan-5-ones derived from camphorsulfonamide. In dimethoxyethane containing Et4NF-4HF, the monofluorinated product (9) was obtained as a single diastereomer [214]. 

This present chapter is devoted to the recent advances, for the last decade, in fluorinated analogues of natural products developed as pharmaceuticals and now/ marketed or in development (registered or in clinical development). These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids and prostaglandins. 

Fluorination of vinorelbine was thus performed in super acid medium (HF-SbFs). A super electrophilic agent, such as a chloromethyl or a Br+ cation is generated in s/fu from a chloromethane (CHCI3, CCI4) or from N-Bromo Succinimide (NBS). It is able to abstract a hydrogen from the protonated alkaloid, leading to a cation that can be trapped by an halide anion present in the medium [105,106], Difluorination remarkably occurs selectively at C-4 of the clavamine fragment (Fig. 37) [105]. 

Syntheses of only a few fluorinated derivatives of alkaloids have been reported in the literature. This is probably due to the difficulty of synthesizing such structurally complex compounds. Most fluorinated alkaloids have been synthesized within the frame of antitumor drugs research. 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

Vinflunine (Javlor ) is a member of the second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinorelbine in several cancers. It is now in Phase III clinical trials as a chemotherapeutic agent targeted at a variety of cancers (non-small-cell lung and bladder cancers). However, the role of fluorine substitu-... 

Fluorination of cinchona alkaloids has also been investigated. For instance, fluorination of quinine acetate under similar superacidic conditions (HF—SbFs/CHCls) affords a mixture of difluorocompounds in the 10 position that are ephners in 3 (60% yield, 1 1 ratio). This reaction involves a mechanism similar to the one described earlier (protonation, isomerization of carbenium ions, and Cl— F exchange). Curiously, when the reaction is performed on quinine itself, fluorination does not occur and an unprecedented rearrangement takes place (Figure 4.51). ... 

Trifluoro-apovincamic ester Figure 4.54 Synthesis of fluorinated alkaloids. 

Camptothecin, an alkaloid isolated from a Chinese tree Camptotheca acuminate), is a potent cytotoxic agent, acting by the inhibition of DNA topoisomerase I. Derivatives that are fluorinated on the aromatic ring A have been studied, leading to two drug candidates for cancer therapies (Figure 8.7) ° exatecan is in Phase IB development,and diflomotecan is an E-homocamptothecin currently in Phase II trials for several solid cancers. 

One method used for the control of hypertension is reduction of the impulses flowing from the CNS to the sympathetic nervous system which controls the tone of the cardiovascular system. The veratrum alkaloids do this at doses that are near the emetic dose, and reserpine acts both centrally and peripherally. The imidazoline clonidine (175) and some analogues in which the chlorine is replaced by fluorine or methyl groups decrease sympathetic outflow and cause vasomotor relaxation. However, they cause sedation, lack of saliva and renewed hypertension on withdrawal of the drug. 

These tropical trees, shrubs, and lianas are known for their ability to accumulate fluorine in the form of fluoroacctic acid. They are toxic to stock and some are actually cultivated for poisons used on pest animals in Africa. Alkaloids of the pyridine type have been recorded in the family. 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

An enantioselective fluorination method with catalytic potential has not been realized until recently, when Takeuchi and Shibata and co-workers and the Cahard group independently demonstrated that asymmetric organocatalysis might be a suitable tool for catalytic enantioselective construction of C-F bonds [78-80]. This agent-controlled enantioselective fluorination concept, which requires the use of silyl enol ethers, 63, or active esters, e.g. 65, as starting material, is shown in Scheme 3.25. Cinchona alkaloids were found to be useful, re-usable organocata-lysts, although stoichiometric amounts were required. 

A first attempt to realize catalytic asymmetric fluorination under phase transfer conditions goes back to attempts by Cahard et al. [20] Quaternary ammonium salts of cinchona alkaloids were used as catalysts in the presence of TosNFtBu as F-source and 23 was employed as substrate. Unfortunately, enantioselectivities remained rather low. Very recently, Kim and Park have described a closely related system (Scheme 4) [21]. 

The direct enantioselective organocatalytic a-fluorination can also be performed with cinchona alkaloid derivatives as catalyst under phase-transfer reaction conditions [25]. The fluorination reaction by NFSI of / -ketoesters 21, readily enolizable substrates, generated a stereogenic quaternary C-F bond in high yields and with enantioselectivities up to 69% ee for the optically active products 26 (Eq. 6). 

VFL is a novel vinca alkaloid obtained by semisynthesis using super-acidic chemistry to introduce two fluorine atoms selectively at the 20 position of VRLB. The preclinical evaluations of the new derivative VFL have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identifled properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semisynthetic vinca alkaloids. VFL is presently in phase III experimentation for treatment of bladder cancer and nonsmall-cell lung cancer (NSCLC) [72]. 

Atropa belladonna plants have been transformed with an H6H clone from H. niger. A. belladonna normally produces high levels of hyoscyamine, the precursor for the more pharmaceutically valuable alkaloid scopolamine (Fig. 3b). However, after transformation with the H6H gene, transgenic A. belladonna plants were shown to accumulate scopolamine almost exclusively (164). Additionally, the levels of tropane alkaloid production in a variety of hairy root cultures were altered by overexpression of methyltransferase putrescine-N-methyltransferase and H6H. Overexpression of both of these enzymes in a hairy root cell culture resulted in significant increases in scopolamine production (164, 165). Fluorinated phenyllactic acid substrates... 

Kruczynski A, Barret JM, Erievant C, Colpaert F, Fahy J, Hill BT. Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem. Pharmacol. 1998 55 635-648. 

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