Matthew A. J.
Duncton†
*
Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. E-mail: mattduncton@yahoo.com; Tel: +1 917-345-3183
First published on 22nd August 2011
The addition of a radical to a heteroaromatic base is commonly referred to as a Minsici reaction. Such reactions constitute a broad-set of selective CH-functionalization processes. This review describes some of the major applications of Minisci reactions and related processes to medicinal or biological chemistry, and highlights some potential developments within this area.
To aid discussion, the review is divided in to several sections. First, some historical perspective is given. This is followed by a discussion of scope and limitations. The main-body of the review describes some specific examples of Minisci reactions and related processes, with a focus on their use within medicinal, or biological chemistry. Finally, brief mention is given to potential future applications, some of which may be beneficial in providing ‘high-content’ diverse libraries for screening.
Scheme 1 Gomberg-Bachmann raction (1924) and addition of aryl radicals to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridine (ca. 1893–1960)2a,4,5 |
Scheme 2 Use of COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridine-N-oxide to enhance regio-selectivity for aryl radical addition to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridine (1961)2a,7 |
A bigger breakthrough in understanding the rate of reaction, and in controlling the regiochemistry of aryl additions to heteroaromatic bases, emerged in 1964 from the work of Lynch and Chang,8,9 and later, from Lynch and Dou.10–13 For example, Lynch and Chang proposed that the rate of addition of phenyl radical to pyridinium (and imizolium) ions was greatly enhanced when compared to that of the neutral heteroaromatic base.9 By considering calculated localization energies for radical substitution of pyridinium and imidazolium ions, which strongly favored high reactivity at the 2-position,14 Lynch and Chang also proposed that ionic species could dominate the orientation of radical substitution in these heteroaromatic systems. This led to the proposal of investigating the reactivity and selectivity of conjugate acids of heteroaromatic compounds with phenyl radicals, in order to test the above predicitions.9 A short-time later, in 1965, Lynch and Dou published the first in a series of papers, in which they gained experimental support for this conjugate acid hypothesis.10–13 As well as radical phenylation undertaken with pyridines (Scheme 3), COMPOUND LINKS
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Download mol file of compoundN-methylimidazole and COMPOUND LINKS
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Download mol file of compoundthiazole, Dou and Lynch also found that protonation enhanced reaction rates and positional selectivity for phenyl radical addition to other heteroaromatic bases such as COMPOUND LINKS
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Download mol file of compoundquinoline, COMPOUND LINKS
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Download mol file of compoundisoquinoline, COMPOUND LINKS
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Download mol file of compoundbenzothiazole, COMPOUND LINKS
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Download mol file of compoundpyrazine, COMPOUND LINKS
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Download mol file of compoundpyrimidine, COMPOUND LINKS
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Download mol file of compoundquinoxaline and COMPOUND LINKS
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Download mol file of compoundN-methylbenzimidazole.10 These results led Dou and Lynch to conclude that the use of acidic conditions would make radical additions to heteroaromatic bases a synthetically-viable transformation.10
Scheme 3 Use of conjugate acids to enhamce regio-selectivity for radical addition to heteroaromatic bases (1964–1968)8–15 |
Later, Minisci would also demonstrate the benefit of acidic conditions to reaction rate and positional selectivity for radical additions to heteroaromatic bases.1,15 Through a series of developments and refinements that has persisted to the present day, Minisci and other organic chemists, have refined such reactions to the point where they constitute a very effective set of distinct transformations. For this reason, radical additions to heteroaromatic bases are sometimes referred to as “Minisci reactions” in the chemical literature (this description is used throughout this review). Formally, Minisci reactions represent a powerful method of CH-functionalization for heteroaromatic bases. The reactions are considered complementary to other CH-functionalization processes such as carbo-cation mediated reactions. For example, Punta and Minisci have desscribed the radical-based methods as, ‘a Friedel–Crafts-type process with opposite reactivity and selectivity’.1a
In the ensuing sections we attempt to demonstrate that Minisci reactions are attractive methods for medicinal chemists. We will detail some select examples of Minisci transformations within medicinal chemistry, and will consider some recent developments along the way, including the potential of such reactions for preparing diverse libraries from a common scaffold.
5-Membered rings | 6-Membered rings | 6,5-Bicyclics | 6,6-Bicyclics | Polycyclic systems | Non-basic systems |
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Functional group | Common radical precursor(s) | |||||
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R: Alkyl or Cycloalkyl | R-CO2H | R-I | R-Br | R-CHO | RCH2OH | RCH(OR)2 |
R-BF3K | R-B(OH)2 | RSePh | Barton ester | RSC(S)OR(xanthate) | ||
Aryl | Ar-N2+ | Ar-I | ArB (OH)2 | Ar-M (M = COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundBi, COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundHg, etc.) |
||
CF3 | F3C-I | |||||
F3C(CF2)n | F3C(CF2)n-I | |||||
Oxetan-3-yl or Azetidin-3-yl | ||||||
Acyl | ||||||
Amide (CONR1R2) | ||||||
Ester (CO2R) | ||||||
CH2OH, CHR1OH, CR1R2OH | H3COH | HCHR1OH | HCR1R2OH | |||
CH2NR1R2 or CH2NR1Ac | ||||||
SiR3 | R3Si–H |
When the examples in Table 1 and Table 2 are considered in combination, it is apparent that there is considerable scope to these reactions; essentially, any heteroaromatic system can be open to addition of a radical, providing that a suitable position for its attack is free. Likewise, the choice of radical coupling partner is huge and varied. Since radicals are involved as reactive intermediates, protection and deprotection strategies are rarely needed, as the rate of side-reactions arising from free functionalization, is slower than the rate of attack on the heteroaromatic system. This feature of Minisci chemistry makes the reactions especially appealing for industrial applications, since time is an important economic factor.
Scheme 4 Regio-isomers encountred in a Minisci reaction17 |
The second issue with Minisci chemistry concerns the yields. In many cases, the isolated yields can be modest (<50%), even when an excess of the less valuable reacting partner (heteroaromatic base or radical precursor) is used. It is also our experience that reactions can progress to a certain point then stop - the addition or further reagents or heating making little, if any, difference. For example, in our studies on the addition of the oxetan-3-yl or azetidin-3-yl groups to heteroaromatic bases,18 the vast majority of reactions did not go to completion and starting material, along with desired product, was usually isolated. A neat solution to reactions that progress only so-far, then stop, can be found in the synthesis of CGS 19755 (section 3.7).
The final drawback is really a manifestation of the above two limitations. Since reactions do not always completely consume the starting material, and since more than one regioisomeric product can be obtained, purifying individual target compounds to a level suitable for biological testing can sometimes be challenging. As an example, consider the addition of the oxetan-3-yl group to COMPOUND LINKS
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Download mol file of compoundhydroquinine 1 (Scheme 5).18 Although it was found that this reaction was very facile, and most of the starting material appeared to convert to addition products by LC/MS analysis, obtaining those products in a pure form required extensive purification by high-performance liquid chromatography. The result, was that a 27% yield of the 2-substituted product 2, together with a small quantity of the presumed 2,8-disubstituted isomer 3 were obtained, even though the reaction appeared to work better than the isolated yields would suggest.
Scheme 5 Addition of an COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundoxetane group to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundhydroquinine: a challenging separation of the products18 |
On balance, even with some genuine limitations in less favorable examples, Minisci reactions are extremely useful. It should also be remembered that this chemistry is used to undertake some very selective CH-functionalizations (vide infra), and that protection and deprotection sequences are not always required, potentially saving time. Additionally, a vast array of diverse functionalization processes can be undertaken, meaning that more ‘chemical space’ can be investigated by judicious choice of coupling partners. Taken together, the benefits of Minisci chemistry certainly outweigh the limitations.
In the next section the utility of Minisci methodology for medicinal chemists in illustrated by examining specific cases that have been used in medicinal or biological applications.
Scheme 6 Synthesis of the marketed drug, Irinotecan, a Topoisomerase I inhibitor20 |
Scheme 7 Representative applications of Minisci chemistry to Topoisomerase I inhibitors22–26 |
Subsequent to the very impressive Minisci chemistry used to prepare COMPOUND LINKS
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Download mol file of compoundcamptothecin derivatives, there have been other noteworthy uses of the reaction to introduce alkyl groups to give compounds with pharmacological activity. For example, Jain has used Minisci reactions to effectively introduce alkyl and cycloalkyl groups in to histidines and histamines, in an unparalleled regio-specific manner.27–33 Similar reactions have also been used to introduce alkyl groups in to 1,2,4-triazoles.34 One application of this work is in the synthesis of selective Thyrotropin-Releasing Hormone (COMPOUND LINKS
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Download mol file of compoundTRH) Receptor 2 agonists with in vivo activity.30,32,33 Thus, compound 7 was synthesized using a Minisci reaction of a protected COMPOUND LINKS
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Download mol file of compoundhistidine with a cyclopropyl radical (derived from COMPOUND LINKS
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Download mol file of compoundcyclopropyl carboxylic acid) as the key step (Scheme 8).31 Compound 7 was shown to be a potent agonist for THR-2 receptors (EC50 = 0.41 μM), with >250-fold selectivity over related THR-1 receptors.31 Additionally, 7 was active in an in vivo model of pentobarbitol-induced sleeping time at a dose of 10 μmol/kg. Interestingly, a close analogue 8, which was also prepared using a similar Minisci reaction as a key step (Scheme 8), showed an increase in pentobarbitol sleeping time.33
Scheme 8 Synthesis of Thyrotropin-Releasing Hormone Receptor-2 agonists30,32,33 |
Jain and colleagues have continued with their studies on the application of Minisci chemistry within a medicinal setting by preparing new COMPOUND LINKS
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Download mol file of compoundquinoline compounds with anti-tuberculosis activity.35–38 Such agents are sorely needed as TB kills many millions of individuals each year.39 Jain's work has led to the identification of several new anti-TB agents, such as compounds 9–11. These molecules are believed to exert their biological effect through a novel mechanism of action, since they do not inhibit M-tuberculosis-purified DNA-gyrase (a target of COMPOUND LINKS
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Download mol file of compoundquinolone anti-TB compounds). Some features of the Minisci reactions used to synthesize these analogues is worthy of discussion. As mentioned previously (Section 2.3), it is sometimes possible to obtain more than one addition product in certain instances. In the present work this ‘limitation’ of Minisci chemistry had a fortuitous outcome. Thus, radical alkylation of COMPOUND LINKS
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Download mol file of compoundlepidine under traditional Minisci conditions (a COMPOUND LINKS
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Download mol file of compoundcarboxylic acid serving as the radical precursor), led to the isolation of mono- and di-alkylated products (Scheme 9). The di-alkylated product 10, was shown to have a more favorable biological profile than its mono-alkylated congener 9. Similarly, compounds 12 and 13 were shown to be particularly interesting analogues, from another set of Minisci reactions; other leading anti-TB compounds were also synthesized in an analogous manner (Scheme 10). Overall, the results from this work may open another avenue of opportunity for finding new treatments for TB patients.
Scheme 9 Quinolines with anti-tuberculosis activity35–38 |
Scheme 10 Quinolines with anti-tuberculosis activity35–38 |
Another excellent example of the utility of Minisci chemistry for the introduction of alkyl or cycloalkyl groups, concerns the synthesis of selective GABAA α2/α3 selective agonists from Carling, Street, Castro and their colleagues at Merck.40 Such α2/α3 agonists were of interest as they were shown to retain anxiolytic properties, but were non-sedating in animal models. The synthesis of a development candidate TPA023 14 is shown in Scheme 11. It is noteworthy that the tert-butyl group could be introduced by Minisci chemistry at a late- or early-stage of the synthesis (radical precursor tBuCO2H), thus allowing for some flexibility in examing structure–activity relationships (SAR). Cycloalkyl groups were also introduced using the same methodology. However, the biological profile for these compounds was not as favorable to that of TPA023. A somewhat similar example concerns the investigation of COMPOUND LINKS
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Download mol file of compoundHistamine H2-Receptor antagonists as detailed by Lipinski, LaMattina and Hohnke (Scheme 12).41
Scheme 12 Minisci chemistry to provide an H2-Receptor antagonist41 |
The application of Minisci chemistry has also found novel uses in biological chemistry. For instance, Minisci reactions have been used to prepare functional organo-receptors via a tri-directional coupling of cis-1,3,5-cyclohexane-tri-COMPOUND LINKS
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Download mol file of compoundcarboxylic acid and a heteroaromatic building block (Scheme 13). The resulting tripodal adducts functioned as carbohydrate receptors, with particular sensitivy for α-octyl-glucopyranoside. For example, receptor 15 displayed the highest binding affinity for noncovalent binding of an α-glucopyranoside in COMPOUND LINKS
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Download mol file of compoundchloroform, reported by 2008. Significantly, receptor 15 could also bind monosaccharides in polar solvents such as COMPOUND LINKS
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Download mol file of compoundmenthanol.42
Scheme 13 Preparation of carbohydrate organo-receptors42 |
As a final offering in this section, it has been shown that Barton esters and alkyl xanthates may be used as radical precursors for Minisci reactions.43–45 For example, Barton and co-workers showed that reactions may be used to introduce alkyl groups in to biologically-active molecules such as COMPOUND LINKS
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Download mol file of compoundcaffeine, and other purines (Scheme 14). Jarman and colleagues have used this particular variant of Minisci chemistry to synthesize steroid 16, a relative of the marketed compound, Abiraterone 17, a recently approved treatment for prostate cancer (Scheme 15). Compound 16 was shown to be a reversible inhibitor of human cytochrome P45017α, (IC50 = 27nM), compared to the irreversible inhibition observed with Abiraterone (IC50 = 5nM).46
Scheme 14 Barton esters in Minisci-type alkylations43–45 |
Scheme 15 Synthesis of reversible inhibitors of human cytochrome P45017α related to the marketed prostste cancer treatment COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundAbiraterone46 |
Scheme 16 Trifluoromethylation of uracils using Minisci chemistry49–51 |
Yamakawa has also broadened the scope of this trifluoromethylation procedure, so that other heteroaromatic bases may be used as starting materials.50,51 For instance, pyridines, pyrimidines, pyrazines, thiazoles, triazoles, thiadiazoles, pyrazoles, COMPOUND LINKS
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Download mol file of compoundpyrazolone and oxazoles, amongst others, have all been successfully employed (Scheme 17). One important difference for the trifluoromethylation reactions, when compared to their traditional Minisci counterparts, concerns the nature of the radical intermediate. The introduction of COMPOUND LINKS
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Download mol file of compoundfluorine changes the nature of the COMPOUND LINKS
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Download mol file of compoundcarbon-centered radical to an electrophilic species, rather than a nucleophilic radical encountered in most Minisci transformations.52 Thus, activating groups such as amino substituents were sometimes needed in order to increase the reactivity of the heteroaromatic base,51 although the role of these substituents may be somewhat more complicated (vide infra). The scope of such reactions has also been extended further to encompass the synthesis of ethoxycarbonyldifluoromethyl analogues. For example, a fluorinated COMPOUND LINKS
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Download mol file of compoundazaindolone derivative 21 could be prepared by reaction of a difluorocarboxylate radical with COMPOUND LINKS
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Download mol file of compound2-aminopyridine (Scheme 18).53 As to be expected for an electrophilic process, reaction took place at the position ortho- to the amine substituent, in this case, the 3-position of a pyridine ring.
Scheme 17 Trifluoromethylation of heteroaromatic systems using Minsci chemistry50,51 |
Scheme 18 Preparation of a fluorinated COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundazaindolone,52 |
The work from the above studies will undoubedly be useful, and will complement other methodology to introduce a trifluormethyl group based upon well-known cuprate and COMPOUND LINKS
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Download mol file of compoundpalladium methodology.47 A couple of extensions for this chemistry may also be worthy of investigation. For example, it may be interesting to investigate the use of COMPOUND LINKS
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Download mol file of compoundtrifluoroacetic acid rather than COMPOUND LINKS
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Download mol file of compoundiodotrifluoromethane as the radical precursor in Schemes 16 and 17. Second, extending the reaction to prepare COMPOUND LINKS
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Download mol file of compoundpentafluorosulfur analogues could also be considered, as COMPOUND LINKS
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Download mol file of compoundbromopentafluorosulfane (F5SBr) and COMPOUND LINKS
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Download mol file of compoundchloropentafluorosulfane (F5SCl) are known to be precursors of the F5S radical (F5S˙).54 Therefore, it may be possible to substitue CF3I for BrSF5, or ClSF5, in a Minisci-type reaction, to enable facile introduction of SF5 in to heteroaromatic systems. Since there has been increasing interest in the biological properties of SF5-containing molecules,55 a one-step process to introduce this group could present an interesting opportunity.
Related radical processes to selectively introduce perfluoroalkyl substituents in to electron-rich heteroaromatic systems such as COMPOUND LINKS
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Download mol file of compoundpyrrole are also known (Scheme 19).56 In contrast, perfluoroalkylation of electron-deficient heteroaromatic bases can result in poor chemo- and regio-selectivity. For example, perfluoroalkylation of COMPOUND LINKS
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Download mol file of compoundquinoline results in the formation of eight addition products by GC-MS analysis.57a This result was ascribed to enthalpic-effects acting as the driving-force for the reaction with the electrophilic perfluoroalkyl radical, as opposed to the usual situation in Minisci transformations, where kinetic polar-effects dominate, and selective reaction with nucleophilic radicals occurs.57a This suggested a method for controling the selectivity in the addition of perfluoroalkyl radicals to heteroaromatic bases, by undertaking the reaction in the presence of an alkene. The perfluoralkyl radical reacts faster with an electron-rich alkene, than with an electron-poor protonated heteroaromatic base (because both enthalpic and polar effects are favorable for reactions with alkenes). The new radical intermediate from addition of the perfluoroalkyl group to the alkene posesses sufficient nucleophilic character, such that kinetic polar-effects can control a further selective addition to a protonated heteroaromatic base, resulting in formation of a single perfluoralkylated addition adduct (Scheme 19).57a In a further demonstration of how consideration of enthalpic and polar effects can be utilized to control reactivity and selectivity with perfluoroalkyl radicals, Minisci and colleagues have also undertaken selective reactions with quinones.57b Since perfluoroalkyl groups are also useful in medicinal chemistry settings, and have also been used for separations by fluorous technology,58 perfluoroalkylation methodology will also be of interest to a broad chemistry audience. Presumably, consideration of enthalpic and polar effects for the transformations outlined in Schemes 16–18 may similarly account for the reactivity and selectivity observed in these processes.
Scheme 19 Perfluoroalkylation using Minsci chemistry56,57 |
Scheme 20 Radical addition to a COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpteridine heteroaromatic59 |
Recently, other methods for generating an aryl radical have been developed. For example, mild conditions to undertake radical formation from aryl iodides using COMPOUND LINKS
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Download mol file of compoundpotassium tert-butoxide have been reported.60 The resulting radical could be added to heteroaromatic bases to give the coupled products in 56–98% yield, although the heteroaromatic base was used in a 40-fold excess (Scheme 21).
Scheme 21 Radical addition to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyrazine promoted by COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpotassium tert-butoxide60 |
At this juncture, it would also be appropriate to discuss some new developments using COMPOUND LINKS
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Download mol file of compoundboron species as radical precursors. Boranes, boronic acids or boronic esters are well-known radical precursors, although radical reactions with boranes or boronic esters are more common than other COMPOUND LINKS
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Download mol file of compoundboron species.61 Minisci-type chemistry with trialkylboranes has also been known for sometime. For instance, reaction of COMPOUND LINKS
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Download mol file of compoundtriethylborane with COMPOUND LINKS
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Download mol file of compoundlepidine furnished a 62% yield of the addition adduct 22 using an aqueous acidic system (Scheme 22).62 More recently, a number of research groups have began to examine the use of boronic acids in Minisci-type reactions. Formally, such processes represent a change of the radical precursor from the commonly-encountered COMPOUND LINKS
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Download mol file of compoundcarboxylic acid, to a COMPOUND LINKS
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Download mol file of compoundboronic acid. Demir, Reis and Emrullahoglu were the first to investigate these processes.63 They found that reaction of a heteroaromatic base with an aryl radical, generated from a COMPOUND LINKS
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Download mol file of compoundboronic acid precursor and 3 equivalents of Mn(OAc)3, furnished the expected biaryl products in moderate yield (Scheme 23). Similar results have been observed by Guchhait et al.,64 and again by Demir et al.,65 using a microwave-assisted variant of the reaction (Scheme 23). However, there are some drawbacks to the Mn(OAc)3 reactions as currently practised. For example, the heteroaromatic base tends to be used in large excess with respect to the COMPOUND LINKS
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Download mol file of compoundboronic acid radical precursor. Additionally, high temperatures are frequently used for the reactions. These limitations may restrict the above processes in medicinal chemistry applications.
Scheme 22 Radical addition to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundlepidine using a COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundborane as a radical precursor62 |
Scheme 23 Boronic acids as radical precursors in Minisci-type reactions63–65 |
Considerably more mild conditions to effect a Minisci-style arylation with boronic acids have recently been described by Baran and co-workers.66 The reactions employ 1.5 equivalents of an arylboronic acid, 1.0 equivalent of a protonated heteroaromatic base, and utilize Minisci's AgNO3 and K2S2O8 oxidation conditions at room temperature. Some impressive examples were undertaken. For instance, similar to our own experience of Minisci reactions with cinchona alkaloids,18 Baran found that unprotected substrates could participate in such reactions. For example, the anti-malarial natural product COMPOUND LINKS
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Download mol file of compoundquinine was cleanly arylated in 40% yield with 4-phenoxyboronic acid (Scheme 24).
Scheme 24 Boronic acids as radical precursors in Minisci reactions66 |
The use of COMPOUND LINKS
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Download mol file of compoundboron species in Minisci reactions will likely prove to be a valuable addition for medicinal chemists, since many departments carry large collections of these building blocks, due to their widespread use in Suzuki reactions. This area of Minisci chemistry is also ripe for further development. For example, it would be interesting to see whether other boronic acids such as alkyl-, cycloalkyl- (e.g. cyclopropyl), or heteroaryl-boronic acids can be used as radical precursors in Minisci reactions.67 Additionally, the possibility of using COMPOUND LINKS
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Download mol file of compoundN-methyl iminodiacetic acid (COMPOUND LINKS
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Download mol file of compoundMIDA) boronates, and COMPOUND LINKS
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Download mol file of compoundpotassium trifluoroborates, as alternatives to boronic acids would also be worthwhile, as these compounds benefit from increased bench-top stability compared to their COMPOUND LINKS
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Download mol file of compoundboronic acid counterparts.68,69 On this theme, Molander has recently reported the use of alkyl trifluoroborates as radical precursors in Minisci reactions, the processes employing Mn(OAc)3 to promote radical formation (Scheme 25).70a Importantly, the trifluoroborates and heteroaromatic bases are used in equimolar quantities, and proceed under relatively mild conditions (AcOH, COMPOUND LINKS
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Download mol file of compoundH2O, COMPOUND LINKS
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Download mol file of compoundTFA, 50 °C).70a These features may render the Molander conditions more attractive for medicinal chemists than the alternative Mn(OAc)3 reactions described above. It will also be interesting to see whether Molander's conditions can be transferred to arylboronic species, be they trifluoroborates, boronic acids, or boronic esters (including COMPOUND LINKS
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Download mol file of compoundMIDA esters).
Scheme 25 COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundPotassium trifluoroborates as radical precursors in Minisci reactions70 |
Recently, our own research group has described the use of a Minisci reaction to introduce both oxetan-3-yl and azetidin-3-yl groups, using the appropriate iodides as the radical precursor (Scheme 26).18 The reactions could be undertaken on some highly functionalized substrates such as the anti-malarial, COMPOUND LINKS
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Download mol file of compoundhydroquinine 1 (Scheme 5), and the marketed anti-cancer compound, COMPOUND LINKS
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Download mol file of compoundGefitinib COMPOUND LINKS
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Download mol file of compound23 (Scheme 26). The product from the addition to COMPOUND LINKS
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Download mol file of compoundGefitinib, compound 24, has been tested in biological screens and results will be disclosed soon. In addition to the reactions above, a wide-range of heteroaromatic bases could also be utilized, with isolated yields of the oxetan-3-yl, or azetidin-3-yl products ranging from 5–50%.
Scheme 28 Synthesis of acylpurines using Minisci chemistry80 |
Scheme 29 Preparation of ant phermones81 |
Scheme 30 Preparation of an anti-convulsant and a naturally-occurring pigment using Minisci acylations82,83 |
Radical-based formylation reactions have also been developed.86 Although there are few examples on the use of these reactions in medicinal chemistry, the aldehyde (or masked aldehyde) products are useful for reductive-amination chemistry, and other functionalizations (e.g. reaction with Grignard reagents and other organometallics).
Scheme 31 Synthesis of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundNMDA antagonist CGS 1975588 |
Another important example for the introduction of an amide group concerns the synthesis of the marketed multi-kinase inhibitor, COMPOUND LINKS
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Download mol file of compoundSorafenib COMPOUND LINKS
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Download mol file of compound31, which is approved to treat advanced renal cell carcinoma and advanced primary hepatocellular carcinoma.89 COMPOUND LINKS
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Download mol file of compoundSorafenib, which is classified as a multi-kinase inhibitor, can be prepared using Minisci chemistry on an early precursor, albeit in a very low 5% yield (Scheme 32).90 In an interesting modification, it has recently been shown that the primary amide can be introduced on a large-scale, the product also serving as a precursor to Sorafeninib (Scheme 32).91 Similar industrial utilities of Minisci chemistry to introduce amides have appeared frequently in both the patent and primary literature. For example, BAY 50-9193 33, an amide analogue of the clinical VEGFR-2 inhibitor, PTK787 32, was prepared in modest yield using Minisci chemistry (Scheme 33).92 The introduction of an amide group in to the pyridine ring of PTK787, to give compound 33, may have beneficial effects upon CYP3A4 inhibitory activity. In other examples, researchers from Roche have used an amidation reaction to prepare compound 34 (possibly, an intermediate to endothelin receptor antagonists) on a 132g scale (Scheme 33),93 and a group from BASF have used a Minisci amidation, on a 42kg-scale, in a synthesis of a highly potent thromin inhibitor 35 (Scheme 33).94
Scheme 32 Preparation of COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundSorafenib, a marketed multi-kinase inhibitor using Minisci chemistry90,91 |
Scheme 33 Preparation of kinase and thrombin inhibitors using Minisci chemistry92–94 |
Amidation reactions have also been useful to prepare natural products with pharmacological activity. For example, Göksh and colleagues have used an amidation process in their studies of Vertilecanin natural products, which have shown antibacterial activity against Bacilus subtilis (ATCC 6051), amongst other biological properties.95 Thus, amide 37 was synthesized in 50% yield from precursor 36 (Scheme 34). The amide product could be elaborated to Vertilecanin C 38 in one step. The methodology was short and flexible, which allowed for the synthesis of alternative analogues related to the Vertilecanin family. In a similar manner, amidation reactions can also be undertaken with the thioquinanthrene core (Scheme 34).96
Scheme 34 Synthesis of Vertilecanin natural products and thioquinathrece amides95, 96 |
Finally, in this section, Minisci reactions can be used to introduce both esters and amides (Scheme 35).83a,92 Such reactions may be valuable for gaining access to COMPOUND LINKS
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Download mol file of compoundpteridine analogues that function as Ricin A chain inhibitors.97
Scheme 35 Minisci esterification and amidation applied to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpteridine analogues83a,92 |
Scheme 36 A modified Minisci hydroxymethylation reacion en route to inhibitors of gastric acid secretion100 |
Although bis-hydroxylation may be observed in some circumstances, it is not always encountered. For instance, an interesting example of a radical mono-hydroxymethylation was provided in the synthesis of a transition state analogue inhibitor of adenosine deaminase.102 Addition adducts 44–46 were synthesized by a UV-induced reaction of COMPOUND LINKS
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Download mol file of compoundmethanol with purine ribonucleoside 43, a known reversible inhibitor of adenosine deaminase (Scheme 37). Similar to early results with radical additions to DNA-bases (Section 3.12), the products from the reaction were shown to be a diasteromeric mixture of dihydro-derivatives in a combined yield of 54% (25% diastereomer A COMPOUND LINKS
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Download mol file of compound44 and 29% diastereomer B 45), together with an oxidized addition product 46 (yield not disclosed). The diastereomers COMPOUND LINKS
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Download mol file of compound44 and 45 could be separated, and one diastereomer (COMPOUND LINKS
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Download mol file of compound44) was shown to be an exceptionally potent inhibitor of adenosine deaminase from calf duodenum (Ki = 0.76 × 10−6).102
Scheme 37 Preparation of inhibitors of adenosine deaminase102 |
Another application of the hydroxymethylation reaction has also been provided in the preparation of COMPOUND LINKS
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Download mol file of compoundtetrahydro-1,8-naphthyridol analogues of COMPOUND LINKS
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Download mol file of compoundα-tocopherol that function as antioxidants of lipid peroxidation. Since lipid peroxidation has been associated with pathologies such as cardiovascular disease, neurodegeneration and cancer,103 such compounds may be very valuable. For example, in the synthesis of a key compound known as N-TOH 49, a COMPOUND LINKS
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Download mol file of compoundnaphthyridine starting material COMPOUND LINKS
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Download mol file of compound47 was selectively hydroxymethylated to provide addition adduct 48 in 88% yield (Scheme 38).104
Scheme 38 Preparation of antioxidant N-TOH104 |
Introduction of aminomethyl groups has also been undertaken successfully. A particularly useful procedure was developed by Cowden at Merck and COMPOUND LINKS
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Download mol file of compoundCo.105 Thus, reaction of COMPOUND LINKS
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Download mol file of compounddichloropyrazine with a protected amino acid affords the aminomethylated product 50 in good yield (Scheme 39). Minisci hydroxymethylation and aminomethylation reactions have been used extensively in COMPOUND LINKS
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Download mol file of compoundcamptothecin, COMPOUND LINKS
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Download mol file of compoundpteridine and COMPOUND LINKS
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Download mol file of compoundnicotine chemisty (see also Sections 3.1, 3.6 and 3.7).21a,106–111 For instance, such reactions are used as key steps in the synthesis of gimatecan 51 and COMPOUND LINKS
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Download mol file of compoundwater soluble aminomethyl camptothecin analogue 52 (Scheme 39). Gimatecan is currently being examined in clinical trials. Analogous reactions can also provide analogues of the natural COMPOUND LINKS
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Download mol file of compoundpterin, asperopterin-B, as well as intermediates en-route to COMPOUND LINKS
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Download mol file of compoundfolic acid, and “aza-COMPOUND LINKS
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Download mol file of compoundnicotine” analogues 53 (Scheme 39). A further illustration of such chemistry, with many similarities to the chemistry outlined in Scheme 37, concerns the hydroxymethylation and aminomethylation of the natural nucleoside, COMPOUND LINKS
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Download mol file of compoundnebularine, protected as a tri-O-benzoate ester (compound 54).112 The benzoate esters were removed after the Minisci reactions to provide C-alkylated derivatives of COMPOUND LINKS
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Download mol file of compound55 and 56 (Scheme 39).
Scheme 39 Synthesis of medicinally important compounds via Minisci aminomethylation or hydroxymethylation chemistry105,21a,106–112 |
Other useful applications of Minisci chemistry to introduce functionalized methyl groups include the synthesis of licofelone 59 (ML3000), a compound that recently completed Phase III clinical trials as an analgesic and anti-inflammatory agent.113 Thus, advanced intermediate 57 was alkylated under radical conditions using COMPOUND LINKS
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Download mol file of compoundiodoacetonitrile, or a haloacetate as the radical precursor, and a COMPOUND LINKS
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Download mol file of compoundDMSO/FeSO4.7H2O system (Fenton conditions) to provide addition adduct 58 (Scheme 40).114,115 Other sulfoxides were also investigated for an ability to promote the reaction of 57 to 58, but none proved as effective as COMPOUND LINKS
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Download mol file of compoundDMSO. The use of Minisci chemistry was especially noteworthy in the above synthesis, as previous transformations of 57 to licofelone 59 used COMPOUND LINKS
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Download mol file of compounddiazoacetate reagents, or COMPOUND LINKS
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Download mol file of compoundoxalyl chloride.113
Scheme 40 Synthesis of the analgesic COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundlicofelone (ML3000) and a 13C-labelled COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundbilin113,116 |
Another particularly interesting application of a similar heteroaryl COMPOUND LINKS
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Download mol file of compoundacetate functionalization has been undertaken to provide 13C-labelled COMPOUND LINKS
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Download mol file of compoundbilin compounds, e.g.60 (Scheme 40).116 The labelled bilins synthesized in this study could be incorporated in to biological photoreceptors such as phytochromes, and may be useful for following conformational changes induced by photoisomerization of COMPOUND LINKS
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Download mol file of compoundbilin chromophores.116
An example from 1948 details the use of an Emmert reaction to prepare substituted pyridines as histamine antagonists.120 A key intermediate 61 was prepared from COMPOUND LINKS
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Download mol file of compoundbenzaldehyde in 39% yield. Intermediate 61 could be elaborated to the desired target histamine antagonist 62 (Scheme 41). Similarly, α-methyl congener 63, which was also a potent histamine antagonist, was synthesized starting from COMPOUND LINKS
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Download mol file of compoundpyridine and COMPOUND LINKS
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Download mol file of compoundacetophenone, although a slightly modified procedure was used for the key radical-addition step. A similar use of an Emmert reaction has recently provided COMPOUND LINKS
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Download mol file of compound2-pyridyl-benzopyran derviatives, such as COMPOUND LINKS
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Download mol file of compound64, as potassium channel openers (Scheme 41).121
Scheme 41 Use of Emmert reactions to provide histamine antagonists and potassium channel openers120,121 |
Scheme 42 Topoisomerase I inhibitors with COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundsilicon or COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundgermanium substituents125–127 |
One of the earlier examples of an intramolecular Minisci reaction, in the synthesis of a biologically-important scaffold, was provided by the synthesis of an aza-COMPOUND LINKS
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Download mol file of compoundergoline ring structure COMPOUND LINKS
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Download mol file of compound70, available in three-steps from commercially-available COMPOUND LINKS
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Download mol file of compoundindole-4-boronic acid COMPOUND LINKS
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Download mol file of compound68; the key cyclization step used a Minisci reaction of an acyl radical (Scheme 43).128 Of note, was the absence of an COMPOUND LINKS
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Download mol file of compoundindole protecting group in this short reaction sequence, clearly supporting the idea that Minisci chemistry does not necessarily benefit from a protecting group. Similar intramolecular radical reactions have very recently been described by Bennasar and Roca to obtain COMPOUND LINKS
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Download mol file of compoundergoline-related COMPOUND LINKS
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Download mol file of compoundindole-fused isoquinolines (Scheme 43).129
Scheme 43 Intramolecular Minisci reactions to provide “aza-COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundergoline” ring structures128,129 |
Intramolecular Minisci chemistry is also useful for undertaking multi-step “tandem” syntheses. For example, González and Molina-Nazarro have described a beautiful cascade-sequence, terminating in a Minisci-type reaction, in their attempted synthesis of Spongidines (e.g. Spongidine A 74), which are a group of anti-inflammatory pyridinium alkaloids.130 Thus, reaction of keto-ester precuror 71, with Mn(OAc)3 in AcOH gave the tetracyclic product 72, in a very respectable 40% isolated yield (Scheme 44). Tetracycle 72 was isomeric with the Spongidine natural product, as the final cyclization had occurred exclusively at the 2-position of the pyridine ring, rather than the desired 4-position. The authors proceeded to prepare compound 73, an isomeric relative of Spongidine A, and are currently trying to prepare an appropriate derivative of 73 to measure its biological activity.
In a similar vein to the work in Scheme 44, Rouden and colleagues have used an intramolecular Minisci cyclization to synthesize a COMPOUND LINKS
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Download mol file of compoundcytisine/COMPOUND LINKS
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Download mol file of compoundepibatidine hybrid, for in vivo imaging of nicotinic acetylcholine receptors (nAChRs), particularly those of the α4β2 subtype (Scheme 45). The desired cyclized compounds 75 and 76 were tested as racemic mixtures for inhibition of α4β2 nAChRs and showed Ki values of 3.5 nM and 0.5 nM respectively.131
Scheme 45 Intramolecular Minisci reactions to provide ihibitors of nicotinic acetylcholine receptors131 |
In a further demonstration of intramolecular Minisci reactions to prepare compounds of biological significance, Zard and Gagosz have provided compounds related to the anti-tumor agent PB1 77 (Scheme 46),132 and Bennesar et al. have synthesized the potent anti-malarial/anti-tumor COMPOUND LINKS
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Download mol file of compoundquinone Calothrixin B COMPOUND LINKS
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Download mol file of compound78,133 and ellipticine quinones, such as 79 (Scheme 46), which may also be useful as anti-tumor agents, or as a precursor of ellipticine itself.134
Scheme 46 Preparation of anti-tumor and anti-malarial agents by intramolecular radical additions132–134 |
As mentioned in Section 2.1, radicals can add to heteroaromatic systems that are not basic. Intramolecular variants of this reaction have provided some of the earliest examples on the use of Minisci reactions to prepare cyclic structures. For example, a number of cyclized products, including the ant pheromone (-)-Monomorine 80 were prepared using this method (Scheme 47).135–137 Similar reactions could also be extended to the cyclization of COMPOUND LINKS
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Download mol file of compoundpyridone derivatives (Scheme 47).138,139 As another illustration of this chemistry, albeit using traditional radical-generating conditions, potent tricyclic 5-HT2C agonists, such as 81, were synthesized from N-substituted indoles (Scheme 47).140 The cyclization conditions were based upon prior work by Moody and Norton.141 More recently, similar chemistry has been used to prepare other bicyclic COMPOUND LINKS
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Download mol file of compoundazole derivatives, such as Withasomnine 82, which is used in ayurvedic alternative medicine (Scheme 47).142
Scheme 47 Intramolecular radical additions providing biologically-active natural products and 5-HT2C agonists135–142 |
The reaction of nucleic heteroaromatics with alkyl radicals is a huge and diverse field. A full discussion of this chemistry, which is important in biological systems, is well-beyond the scope of this review, and readers are directed to a selection of other articles for a more in-depth account of these processes.143 However, a few selective examples are shared here for illustrative purposes.
The addition of COMPOUND LINKS
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Download mol file of compoundcarbon-centered radicals to DNA or RNA bases has been known for over 40 years. For example, in 1968 Linschitz and Connolly reported the addition of alkoxymethyl radicals to COMPOUND LINKS
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Download mol file of compoundpurine, to give COMPOUND LINKS
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Download mol file of compounddihydro-purine products (Scheme 48).144 Contemporaneous studies were also reported by Yang et al., and by Elad and colleagues, who examined the reaction of purines, or purine nucleosides, with amines and alcohols respectively, under the influence of UV-radiation. The products from these reactions were also shown to be addition adducts resulting from radical attack on the heteroaromatic base (Scheme 48).145,146 Subsequently, modifications of nucleic acid bases with other alkyl and aryl radicals have been investigated by those in the chemical toxicology and biological chemistry fields. For example, in 1974 Kawazae and co-workers detailed the addition of methyl and amide groups to various nucleic acid bases, using Minisci's conditions for radical-formation, as a model of DNA-damage caused by carcinogenic peroxides (Scheme 49).147,148 Further studies have elucidated the site of radical attack for all four DNA-heteroaromatics (Scheme 50).149 The relevance of these radical reactions to in vivo biology is an area of current interest.143 Thus, the study of Minisci-type reactions in biological systems provides a nice illustration of how a one-time nineteenth century chemical curiosity, rarely encountered in simply-equipped organic chemistry laboratories, has blossomed, to encompass the modern-day study of such processes in highly-sophisticated cellular systems (complex chemistry laboratories!).
Scheme 49 Use of Minisci methylation and amidation to model DNA damage with radicals147,148 |
Scheme 51 Library synthesis using Baran's version of a Minisci reaction66 |
The second approach, and one highlighted by our own research group, is to use different variations of Minisci functionalization to introduce diverse substituents within a pharmacologically-active scaffold.18 Thus, one could introduce diverse substituents such as alkyl, cycloalkyl (e.g. cyclopropyl), fluoroalkyl (e.g. CF3), aryl, carbamoyl, oxetan-3-yl, azetidin-3-yl, trialkylsilyl, hydroxymethyl, C-glycoside, and other groups, from a common starting material (Scheme 52). One possible application of such a strategy would be the functionalization of approved drugs containing appropriate heteroaromatic cores. Since it has been said that the best way to find a new drug is to start from an existing one,150 such an exercise may give-rise to a ‘high-content’ library for screening against multiple biological targets, with an aim of unearthing new pharmacology, or optimizing against a known biological target. The adoption of Minisci chemistry to introduce diverse substituents is also attractive from a synthetic perspective. As has recently been discussed, medicinal chemists tend to use a relatively small variety of reactions in their syntheses.151 Minisci chemistry provides a formidible set of transformations which would make a fine addition to the compendium of routine organic reactions employed by medicinal chemists.
Scheme 52 Potential synthesis of a ‘high content’ library by functionalization of pharmacologically-active heteroaromatics using Minisci chemistry to introduce multiple and diverse substituents18 |
Footnote |
† Current address: Rigel, Inc., 1180 Veteran's Blvd, South San Francisco, CA 94080, United States |
This journal is © The Royal Society of Chemistry 2011 |