Selective fluorination of natural products

Compounds derived from natural sources including animals, plants, and micro-organisms have been widely used for pharmaceuticals, materials, and agrochemicals. The use of these natural products has grown increasingly over the years and the demand for more improved, biologically active, and safer derivatives of natural products has been investigated by many researchers in the areas of synthetic and medicinal chemistry. Due to the unique characteristics of fluorinated compounds, and the increased or more favorable biological activity which usually accompanies fluorinated analogues of medicinally-important compounds, the fluorination of natural products has gained much attention. This review aims at exploring the range of specific natural product types that have been selectively fluorinated as well as how fluorination was expected to affect their biological activities and physiochemical properties.


Introduction
Utilizing natural products in the medicinal world has proven to be beneficial in society today.With many pharmaceuticals containing natural products or natural product derivatives as the biologically active compounds of interest, the search to improve these compounds has drawn a great deal of attention.Fluorination of these compounds has been one area of research that has grown tremendously and has been limited by only the types of fluorination reagents, their availability, and the sensitivity of the natural substrate.Fluorine itself exhibits potent characteristics, including a small van der Waals radius of 147 ppm and the highest electronegativity of 3.98 in the periodic table. 2 Compounds that have been fluorinated therefore display beneficial properties that set them apart.Metabolic stability, binding affinity, lowering of surface tension, hydrophobicity and lipophobicity are just some of the properties that accompany the fluorination of a compound thereby contributing to unique biological properties. 3This overview provides a visualization of several advances in the selective fluorination of natural product with referenced works ranging from the 1980s to the present year.While late-stage fluorinations are emphasized, synthetic schemes showing incorporation of fluorinated intermediates are included for contrast. 4,5,6 Pe 119 © ARKAT USA, Inc

Fluorinating Reagents 2.1 Nucleophilic fluorinating reagents
Nucleophilic fluorination is characterized as a fluoride ion behaving as a nucleophile which attacks an electrophilic substrate or its activated complex.Both alkali metal fluorides and HF-based reagents have been utilized as fluoride sources (Figure 1).The most straightforward example is an alkyl chain which bears a suitable leaving group that can readily react with a nucleophilic fluoride ion (Scheme 1).

Scheme 1. Nucleophilic fluorination reaction.
Although many traditional nucleophilic fluorination reagents have been used in the past, the majority of natural products have either been fluorinated by HF-based reagents or more commonly were selectively fluorinated by deoxofluorinating reagents.The deoxofluorinating reaction is a modified nucleophilic fluorinating reaction which involves the generation of an activated alcohol as well as a fluoride ion. 7The fluoride ion participates in a nucleophilic attack, generally an SN2 reaction, to produce an alkyl fluoride (Scheme 2).With this form of selective fluorination, many deoxofluorinating reagents have been developed.The reagents that have been developed for such reactions, including DAST 8 , Deoxofluor ® 9 , Fluolead TM 10 , and Phenofluor TM 11 are shown in Figure 2.

Electrophilic fluorinating reagents
An electrophilic fluorination reaction is characterized as the fluorine source behaving as an electrophile and the substrate is that of a nucleophile.The most common form of F + originates from fluorine gas, where the electrophilic fluorinating reagents are highly oxidizing, 12 including fluorine gas and hypofluorites.The advance in reagents that can react via electrophilic fluorination and embody a certain specificity of conditions has not only improved the selectivity of fluorination but has also improved the tolerance of functional groups. 13The developments of reagents such as N-fluoropyridium salts (FP-T300) 14 , N-fluorobis(phenyl)sulfonimide (NFSI) 15 , 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2] octane bis(tetrafluoroborate) (Selectfluor®, F-TEDA-BF4), 16 and derivative F-TEDA-PF6 17 have been great innovations to the introduction of a fluorine atom (Figure 3).

Terpenoids
Terpenoids, the largest class of natural products, are diverse in origin, structure and function.Whether derived from plant or animal, such compounds have roles involved in an organism's defense mechanism as well as a form of interaction or chemical communication between organisms.With many terpenes containing natural biological activities, the derivatization of such compounds can lead to enhancing these features and potentially increasing drug like properties.The simplest of terpenoids are the monoterpenes, which consist of two isoprene units and are highly aromatic molecules with limited functionality.Borneol and camphor, both bicyclics, are amongst the simplest of terpenes that have been fluorinated.Borneol 1 was fluorinated by the Middleton group while investigating fluorination reactions which utilize DAST. 8As expected, carbonium ion type rearrangements are problems that can occur while replacing an alcohol group with a fluoride.Although carbonium ion type rearrangements are less likely to occur while using DAST as a fluorinating reagent, exo-and endo-borneol is more easily rearranged in order to yield compound 2. The fluorination of borneol using DAST led to a rearranged fluoride 2 (Scheme 3).Camphor 3 was fluorinated by the Britton group as described in a 2014 communication through the use of a photocatalytic fluorination reaction as detailed in Scheme 4. 18 Fluorination occurred at positions that were most remote from the carbonyl group.Scheme 4. Fluorination of camphor 3. Reagents/Conditions: (a) 1.5 equiv NFSI/0.1 equiv NaHCO3/0.02equiv TBADT/ MeCN/365 nm, 16 h.Myrcene, a commercially available monoterpenoid, has also been fluorinated with the goals of utilizing fluorinated terpenes in a wide variety of general cleaning and degreasing applications. 19Myrcene 6, combined with trifluorochloromethane and fluorine gas, was then passed through a sodium fluoride trap to yield fluorinated compounds 7 and 8 (Scheme 5).The preparation of fluorinated natural sesquiterpenoids based on the drimane system has been reported and has focused on the production of 9--fluoro derivatives 9-14. 20Abad's group sought to prepare several fluorinated analogues of the drimane framework and investigate how these changes could affect their chemical properties and biological activity.Fluorinated albicanic acid 11 was prepared from the starting fluorodecalone 9 which underwent a Wittig methylenation to afford ,-unsaturated ester 10 (Scheme 6).Ester cleavage of 10 with NaSPr in DMF yielded 9-fluoroalbicanic acid 11.The 9-fluorinated albicanol 12 was also synthesized from fluorodecalone 9 in which the methylenated compound 10 was reduced with lithium aluminum hydride to provide alcohol 12. Acetylation of 9-fluoroalbicanol, 12, afforded 9-fluoroalbicanyl acetate, 13.Conversion of alcohol 12 to corresponding aldehyde 14 was performed using the Dess-Martin periodinane oxidation reagent and resulted in 9-fluoroalbicanal 14 (Scheme 6).
Preparation of 9-fluorodrimenin 18 was accomplished from fluorodecalone 9. Preparation of diester 16 occurred through converting decalone 9 to the corresponding enol triflate 15 with potassium hexamethyldisilazane/N-phenyltriflamide.The triflate 15 was then treated with a palladium catalyst to undergo a palladium-catalyzed carbonylation thereby providing the dimethyldiester 16.Arrival at 9-fluorodrimenin 18 was accomplished through lactonization of hydroxester 17 using DBU and molecular sieve (Scheme 7).More complex terpenoids and their derivatives have undergone selective fluorination, including taxol, forskolin, tocopherol, artemisinin, and nerolidol and the potential benefits are self-explanatory, especially when applied to anticancer compounds such as taxol and antimalarials such as the artemisinins.Due to the wide use of fluorinated aromatic compounds in pharmaceuticals, agrochemicals, materials, and as tracers for positron emission tomography (PET), the Ritter group investigated new ways to form carbon-fluorine bonds.The methods were developed while exploring the specific application of silver catalysts.In turn, the mild conditions resulted in good functional group tolerance and wide substrate scope. 21Biologically active molecules, including natural products, have been fluorinated using Ritter's catalysis technology successfully and in good yields.The use of the silver catalyst with the electrophilic fluorination can occur with aromatic rings in the presence of other functional groups, such as alcohols, dienones, vinyl ethers, esters, and oxetanes, proving this to be a beneficial fluorinating option for.Taxol 19 has been selectively fluorinated on the aromatic ring using the electrophilic fluorinating reagent, F-TEDA-PF6 in the presence of a silver catalyst (Scheme 8).The fluorination of natural sclareolide 27 was investigated by Britton's group as shown in Scheme 11.One may note that the fluorination system was highly efficient and the (2S)-2-fluorosclareolide 28 was produced as the major product while the 1-fluorosclareolide 29 was the minor product (Scheme 11).Sclareolide was also fluorinated by the Groves group using a manganese porphyrin-catalyzed selective C-H fluorination with silver fluoride to yield title tricyclic fluorinated lactone 30 (Scheme 12). 24heme 12. Fluorination of sclareolide 27.Reagents/conditions: (a) Mn(TMP)Cl (8 mol%)/AgF (3 eq.)/TBAF (0.3 eq.)/PhIO (10 eq.).
Forskolin 31, an adenylyl cyclase activator, was fluorinated utilizing the reaction of its lithium enolate which was generated by lithium hexamethyldisilazide.The enolate was reacted with acetyl hypofluorite to produce 12-fluoroforskolin 32 as a single diasteriomer (Scheme 13). 25

Aliphatic natural products
One of the most important subgroups of aliphatic natural products are the semiochemicals.These compounds facilitate communication between many species of organisms and are vastly different amongst themselves in structure but are similar in their functionality, typically alcohols and ethers.With semiochemicals embodying many of the aliphatic compounds with the greatest biological importance, they are widely studied due to the biological responses they stimulate.Whenever metabolically permissible, semiochemicals can be released on purpose by the organism on an 'as needed' basis so fluorinating these compounds can produce effects on the activity and can therefore cause changes in the response of the individuals especially insects. 26Bombykol 33 is a female sex pheromone of the silkworm moth Bombyx mori whereby an understanding of its pheromone biology and chemistry has been widely explored. 26The Svatos group monofluorinated bombykol at two separate positions, at C6 and C16.Bombykol was also difluorinated at C6.The synthesis of both mono and difluoro derivatives of bombykol 34, 36 respectively is shown in Scheme 14. Alcohol 33 was synthesized from (E)-iodohexan-6-ol followed fluorination using DAST.Cleavage the THP group with p-toluenesulfonic acid, yielded title alcohol 34.The oxidation of alcohol 33 with PCC yields ketone 35, which then upon fluorination with DAST followed by deprotection with PTSA, the target compound 36 is obtained.Unfortunately, similar fluorination occurred on the terminal alcohol as well to form 36b. 16 Frontalin 39, a bioactive compound and aggregation pheromone of the Scolytidae insect family, plays a significant role in chemical communication between insects.Replacement of the hydrogen atoms with fluorine atoms in pheromones can cause a variety of effects on an insect's response, thereby altering their activity.Moreover, replacing the hydrogens with fluorine is advantageous in the fact that a large change in electronic distribution occurs without a great steric difference.Along with fluorinated analogues increasing bioactivity, these compounds can be used as tracers for metabolic pathways.

Acetogenins
Annonacin 62 is a neurotoxic natural product which was isolated from the fruit pulp of the Caribbean soursop and the North American pawpaw, both species of the family Annonacea.In general, annonacin is a member of the annonaceous acetogenin family of natural products whereby the compounds possess lipid-like structures that may bear single or multiple THF rings as well as a terminal butenolide ring.The compound was found to be toxic to rat cortical neurons and is suspected to cause atypical Parkinson's syndrome in populations in which there is a high consumption rate of the fruit.Naturally-derived annonnacin is also antiangiogenic in the rat aortic ring assay at 30 µM.Preliminary results suggest that an excess of DAST in dichloromethane is useful for tetrafluorination of 62 at each of its hydroxyl positions as indicated by 1 H 400MHz spectroanalysis of the reaction product 63 (Scheme 19). 29While one may anticipate inversion of stereochemistry at each of the fluorination sites, it has yet to be determined.

Steroids
Fluorinated steroids are active components of a number of important pharmaceuticals. 30Studying the fluorination of naturally occurring steroids can lead to new innovations in hormone medicine as well as discovering new methods of fluorinating these polycyclic lipids.Estrone 64, one of several naturally occurring estrogens, is a hormone secreted from the ovaries.This well-known steroid has been fluorinated in multiple accounts by Ritter's group utilizing a silver catalyst. 21,22In their first account Ritter's group utilized a similar approach that they used to fluorinate δ-tocopherol (Scheme 9) in order to selectively fluorinate estrone 64 (Scheme 20).The conversion of estrone 64 to 3-fluoro-3-deoxyestrone 66 first involves the triflation of estrone followed by a palladium-mediated stannylation giving the intermediate stannylated steroid 65.Fluorodestannylation of the aromatic ring leading to the title compound employed the electrophilic fluorinating agent F-TEDA-BF4 or F-TEDA-PF6 in the presence of silver triflate (Scheme 20). 22One year later, Ritter's group performed another late stage fluorination on estrone (Scheme 21).Estradiol 67 another naturally occurring estrogen, has also been fluorinated in multiple accounts, in which Selectfluor ® is utilized as an electrophilic fluorinating reagent (Scheme 22). 31,32heme 22. Fluorination of estradiol 67.Reagents/Conditions: (a) Selectfluor ® /bmimBF4 /CH3OH/20 ˚C.Allo-Pregnanedione 69 an endogenous progestogen, has been fluorinated by the MacMillan group utilizing an enantioselective organocatalytic -fluorination reaction to give product 70. 33After successfully investigating multiple cyclohexanone compounds, the MacMillan group utilized their findings to fluorinate a more complex cycloketone as seen in Scheme 23.Depending on which catalyst is used the selectivity of fluorination can be manipulated.The Ritter group selectively fluorinated steroids, testosterone 71 and epi-androsterone 73 as reported in 2013 and employed a late-stage deoxofluorination of alcohols with Phenofluor TM as previously mentioned earlier. 23Both compounds underwent replacement of the alcohol group with a fluorine atom in which inversion of stereochemistry occurred to provide 72 and 74 (Schemes 24, 25).In the concise synthesis of 6-α-fluoroursodeoxychlolic acid 79 (Scheme 26), a Novartis process group used Selectfluor ® to fluorinate the enol ether of 77 which resulted in total desilylation and provided the αfluoroketone 78 (Scheme 26). 34Subsequent steps which gave a key intermediate included equilibration to the 6α-fluoroketone with sodium methoxide/methanol, formation of the methyl ester using methanol/chlorotrimethyl silane, acetylation of the 3-hydroxyl group (Ac2O/DMAP).6α-Fluoroketone 78 was then reduced with H2/platinum oxide followed by mesylation (mesyl chloride/DMAP) and mesyl displacement (KO2/DMSO) giving inversion at C-7 and thus the title compound 79.The Novartis synthesis was in contrast to the previous synthesis of 79 by an Italian group whereby DAST in dichloromethane was used to fluorinate followed by desilylation of TBDMS-protected hydroxyketone 80 (Scheme 27). 35The resulting α-fluoroketone 81 was saponified with KOH in methanol which afforded ketocarboxylic acid 79.The 6-ketogroup of 79 was then reduced with sodium borohydride in methanol to give title compound 82.

Polyketides
Structurally complex as well as highly bioactive, the polyketide family has become a great area of research within the biochemical community.This class of secondary metabolites, produced by living organisms, are structurally diverse from one another and are potent pharmaceuticals.Avermectin B1A 83 is a representative polyketide that has been widely used for the treatment of parasites in animals, plants, and humans and is known for its high biological activity and complex structure.Based on this knowledge, new derivatives that even further enhance these properties have been developed.The fluorination technique of naturally occurring Avermectin B1A was carried out by the Meinke group. 36As part of their initiative to determine new avermectin derivatives with enhanced biological activity, the Meinke group explored the option of preparing a gem-difluoro derivative of the parent natural product.Starting compound 100 was fluorinated at position 23 across the alkene, using fluorinating reagent, DAST, noted in Scheme 28.Title compound 83 was successfully fluorinated and analyzed in a pentamethylenetetrazole (PTZ) mouse epilepsy model.The results portrayed a three-fold increase for the difluoro derivative in protecting against PTZ induced seizures compared to ivermectin, a non-fluorinated avermectin derivative.Although the fluorination derivative did not display greater activity than known drug, diazepam, compound 84 lacks the sedative effects of diazepam, a notable positive feature.Again, the Ritter group investigated the fluorination of natural products to generate optimized derivatives that can be optimized with increased pharmacological profiles. 23Specifically, late stage fluorination is being examined, where oligomycin A 87 was fluorinated with commercially available PhenoFluor TM , a deoxyfluorinating reagent that can be utilized on a multi-functional group level.The selective deoxyfluorination of polyketide oligomycin A is shown in Scheme 30, and is an example of a chemoselective introduction of fluorine into a complex molecule thereby yielding secondary fluoride 88.Scheme 30.Fluorination of oligomycin 87.Reagents/Conditions: (a) Phenofluor TM /2.0 equiv.EtN i Pr2/ 2-20 h.Being central to many fundamental biological processes, carbohydrates are an important class of compounds to investigate in terms of fluorinated analogues.Selectively-fluorinated carbohydrates may be used as tools to elucidate glycoprocessing mechanisms and have been useful in medicinal chemistry, pharmacology and biochemistry.Research groups have looked into decreasing polarity of sugars through replacing CHOH groups with CF2 groups, therefore creating a more hydrophobic environment. 37 A de novo synthesis of trifluoroglucose 110 was reported by O'Hagan's group in an effort to provide a more expedient route to this target compound (Scheme 33). 38Butynediol 97 was monosilylated to afford butynyl silylether 98 which was then reduced to the TBDMS-protected trans-silyl ether 99.Sharpless epoxidation of 99 gave TBDMS-protected epoxyalcohol 100.Swern

Pyranosides
Carbohydrates, including sugars and fatty acids are widely abundant in the natural product arena, providing the energy sources for organisms through fueling their metabolism.Due to their biological activity, fluorinated nucleosides and their analogues are of interest in the science community-especially as antivirals.The substitution at the carbon-8 position has not received much attention, and the few that have been reported utilize the halex reaction with the substitution occurring by a bromine or a chlorine.Protected 8-fluoro

General Oxygen Heterocycles
7.1 Furanoids/benzofuranoids Ascorbic acid 122, or better known as Vitamin C, is a compound well known to the science community as well as to the public.With research into the biochemistry involving ascorbic acid new insights have been revealed, including the information that the 6-hydroxy group is unimportant while the 2-hydroxy group is at the center of the reaction site in redox mechanisms of ascorbic acid. 40With this in mind chemical manipulation at the 2position of ascorbic acid can have an effect on the biological properties of this compound.2-Fluoro-2-deoxy-Lascorbic acid 126 was prepared through halogenation of 2-deoxy-L-ascorbic acid 122 by Kirk and coworkers using NBS (Scheme 39).Fluorination of 123 using F-TEDA-BF4 resulted in a 95% yield of 124, in which reductive debromination using tri-n-butyltin hydride followed and resulted in the formation of 2-deoxy-2-fluoro-Labsorbic acid 126 after workup.Unfortunately, the desired 2-fluoro analogue 125 was not the sole product, and tautomerization between the enol 125 and the hemiketal 126 was a result, primarily due to the strong electronegativity of the fluorine atom (Scheme 36).

Pyranoids/benzopyranoids
Flavones and chromones are found in many plants and are abundant chemical components of the human diet. 41These naturally occurring compounds are beneficial to the human body, decreasing the risks of multiple diseases.Unfortunately, recent studies have proven that these compounds have a very short lifetime in the body for 10 hours before being metabolized.With that in mind, Rozen's group examined the fluorination of flavones and chromones in an attempt to provide derivatives which are somewhat resistant to normal metabolic processes. 41

Aromatic Natural Products and Cyclic Ketones
Acetophenone 135, a simple organic compound which occurs naturally occurring in certain foods, underwent an electrochemical aromatic fluorination as shown in Scheme 40. 42The main fluorination products were orthoand meta-isomers 136 and 137 respectively.

Amino acids and peptides
Hunter's group recently investigated the stereoselective syntheses of -difluoro--amino acids in order to provide a scalable reaction sequence. 44Deoxofluor ® and HF in pyridine were employed in a series of reactions in order to provide new synthetic approaches toward the backbone-fluorinated amino acids 141 and 142 (Figure 5).The cyclic peptide, maculosin 150 was fluorinated by Ritter's group in 2010 by utilizing F-TEDA-PF6 in the presence of a silver catalyst, (Scheme 42). 21Maculosin is formed from tyrosine and proline and is a fungal and bacterial metabolite.

Alkaloids and Nitrogen Heterocycles
Alkaloids are a large class of nitrogen-containing naturally occurring compounds which arguably have the greatest range of biological activities.Naturally-occurring quinine 152, one of the simpler alkaloids, was fluorinated by Ritter's group according to two different reports. 21,22 oth reactions embody the use of an electrophilic fluorinating reagent, F-TEDA-PF6 in the presence of a silver catalyst.The overall reaction provides for the addition of a fluoride atom to the 6'-position of the aromatic ring thereby giving analogue 153 (Scheme 43).Strychnine 154 was also selectively fluorinated by the Ritter group and utilized a similar protocol as that employed with quinine as described above (Scheme 44). 21Strychnine's structure was difficult for Ritter's group to fluorinate utilizing a silver catalyst due to the fact it doesn't contain a phenol functionality.Utilization of an in situ N-benzylation followed by the silver-catalyzed fluorination resulted in an ammonium salt derivative of strychnine which immediately underwent hydrogenolysis yielding 2-fluorostrychnine 155.The fluorination of camptothecin 156, another natural product with anticancer activity, was accomplished by utilizing Ritter's silver catalyzed fluorination approach as well and gave 10-fluorocamptothecin 157 (Scheme 45). 22

Tannins/Lignans
Podophyllotoxin 172, a non-alkaloid toxic lignan, is an effective topical treatment of external genital warts caused by the human papillomavirus (HPV).Podophyllotoxin was fluorinated using NFSI to form 2fluoropodophylotoxin 173. 25 This potent antitumor agent was obtained by a completely diastereoselective fluorination of the sodium enolate formed with NFSI (Scheme 49).

Conclusions
The synthesis and biological evaluation of fluorinated analogues and derivatives of natural products provides new in-roads in the field of medicinal chemistry and developmental therapeutics.Natural products are continuously being altered or modified in an effort to optimize their efficacy or probe their biochemical disposition.The development of new reactions and reagents have allowed for the fluorination of many sensitive substrates and have been useful on a drug discovery scale.On a manufacturing or otherwise process scale, the procedures for carbon-fluorine bond-forming reactions will still rely on older, more established technology due to costs and procedural ease.The examples of more recently employed techniques and strategy for the introduction of fluorine into natural products take into account the complexity of some of the chemical intermediates and late-stage substrates and may possibly be applied to starting materials used in the pharmaceutical industry once optimized.The selective fluorination of natural products has proven beneficial to date, and research will be continuing into the most prime 'areas' of fluorination of these complex molecules as the science advances.

Scheme 5 .
Scheme 5. Fluorination of myrcene 6. Reagents/Conditions: (a) CFCl3/F2.7: X is hydrogen or fluorine and at least two of X are fluorine.8: Y is hydrogen or fluorine and at least two of Y are fluorine.
Treatment of chromone 127 with fluorine gas resulted in a mixture of difluorinated products in which spontaneous elimination of hydrogen fluoride from intermediate 128 resulted in the formation of 3-fluorochromone 129 (Scheme 37).Fluorination of isoflavone 130 occurred similarly to that as 127 and gave fluoroisoflavone 132 through intermediate difluoride 131 (Scheme 38).