Photoredox Cross-Coupling: Ir/Ni Dual Catalysis for the Synthesis of Benzylic Ethers
† Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
‡ Department of Chemistry, Faculty of Sciences and Letters, Osmaniye Korkut Ata University, 80000 Osmaniye, Turkey
Org. Lett., 2015, 17 (13), pp 3294–3297
DOI: 10.1021/acs.orglett.5b01463
Publication Date (Web): June 16, 2015
Copyright © 2015 American Chemical Society
*E-mail: gmolandr@sas.upenn.edu.
Abstract
Single-electron transmetalation has emerged as an enabling paradigm for the cross-coupling of Csp3 hybridized organotrifluoroborates. Cross-coupling of α-alkoxymethyltrifluoroborates with aryl and heteroaryl bromides has been demonstrated by employing dual catalysis with a combination of an iridium photoredox catalyst and a Ni cross-coupling catalyst. The resulting method enables the alkoxymethylation of diverse (hetero)arenes under mild, room-temperature conditions.
Visible-light mediated photoredox catalysis has become recognized as an empowering technology for radical-mediated chemistry in recent years.(1-3) By transiently generating catalytic quantities of both a single-electron oxidant and reductant within the confines of the same flask, typically inert substrates can be activated for reaction. Furthermore, the controlled radical generation afforded by these catalysts opens the door to a host of net redox neutral transformations that would have been previously impossible using stoichiometric reagents, where unproductive reductant/oxidant quenching and radical side products are an inevitable shortcoming.(4) To date, many new and innovative reactions have been designed around the use of photoredox single-electron transfer (SET) catalysts, leading to a resurgence in radical-mediated methods for C–C bond formation.
Of particular note, dual catalytic photoredox/Ni cross-coupling has recently emerged as a powerful tool for the construction of Csp2–Csp3 bonds.(5, 6) Here, a single-electron activation mode has served as an ideal platform to circumvent the problems associated with traditional alkyl cross-coupling.(7) By exploiting the greater stability of Csp3 derived radicals and their propensity to combine with Ni complexes,(8) a new paradigm for the transmetalation of traditionally obstinate alkyl nucleophiles has been established. Cross-couplings that historically defaulted to sensitive reagents(9-11) or harsh conditions(12, 13) to overcome the high activation energy for transmetalation can now be achieved at ambient temperatures with mildly basic additives. Consequently, since the initial report, several methods for the cross-coupling of Csp3 radicals (α-alkoxy,(14) α-amino,(15) benzylic,(5) secondary alkyl(6)) with various electrophiles (aryl,(5, 6, 15) alkenyl(14)) have been demonstrated.Moving forward, we sought to apply this chemistry broadly to primary α-alkoxymethyl systems. Stabilized by donation from the α-oxygen, these radicals are well-behaved and facile to generate.(16) Furthermore, their generation through chemical and photochemical oxidation of potassium organotrifluoroborate salts has already been well established.(17-19)
Knowing the chemical characteristics of these radicals, we recognized an opportunity to take commercially available and readily accessible primary α-alkoxymethyltrifluoroborates and show more broadly the advantages of a radical mediated cross-coupling. Through this approach to late stage ether synthesis, there was an effort to highlight the broad functional group tolerance and mild conditions employed. Moreover, benzylic ethers are an important motif in pharmaceutical(20-22) and supramolecular chemical architectures,(23, 24) and dissonant approaches to their synthesis are useful in their own right. Although the use of α-alkoxy anions(25, 26) as a disconnection in cross-coupling has been reported previously for alkoxymethylzincs,(27, 28) alkoxymethylstannanes,(29-32) and alkoxymethylboron derivatives,(33, 34) the current methods are severely limited by the use of toxic and/or air- and moisture-sensitive reagents under often harsh conditions that inhibit the incorporation of reactive functional groups.
Consequently, successful application of a photoredox cross-coupling with these reagents serves the dual purpose of (1) providing a platform to expand and improve a currently under-utilized disconnection and (2) validating photoredox cross-coupling as a general manifold for engaging alkyl-based radicals in cross-coupling, where similar reduction potentials are a single unifying feature among structurally dissimilar reagents (Figure 1).
Figure 1. Photoredox cross-coupling as a general manifold for cross-coupling of diverse Csp3 derived radicals; proposed catalytic cycle for photoredox cross-coupling. ‡Reduction potentials are reported against the saturated calomel electrode (SCE).
As noted previously,(36) calculations suggest that oxidative addition may occur either from Ni0 or NiI-alkyl at room temperature. In addition, the generated NiIII intermediate is predicted to exist in equilibrium with free radical 4 and ArNiIIX complex 12 through reversible homolysis of the Ni–C bond. Based on the low barrier for radical addition at Ni0, the currently favored pathway is outlined in blue (Figure 1).
Initial evaluation of the proposed α-alkoxymethyl cross-coupling commenced with an extensive solvent screen. It should be noted for these reactions that solubility of the reagents is a crucial component for productive reactivity because insoluble material disrupts light penetration and can serve to decouple the integrated catalytic cycles. In our experience, maintaining the homogeneity of the reaction mixture has led to significant improvements. Using methyl 4-bromobenzoate, potassium [(benzyloxy)methyl]trifluoroborate (1.2 equiv), NiCl2·dme (5.0 mol %), dtbbpy (5.0 mol %), and Ir catalyst 1 (2.0 mol %), a cosolvent system consisting of dioxane with added DMA was determined to provide the right balance of solubility and reactivity for the dual catalytic cross-coupling.
An investigation of additives, proposed to be key for sequestering generated BF3 during trifluoroborate oxidation, also improved the yields significantly. Without added base, the reactions tend to stall out around 40–60% conversion (∼10 h), leading us to suspect that byproduct inhibition is principally responsible. Among those bases examined, K2HPO4 led to full consumption of the starting material after 16 h.
With reasonably effective conditions in hand, alternate ligands and Ni sources were examined to identify scaffolds that might be useful in extending this chemistry. Although a number of these Ni sources and ligands served as competent catalysts (see Supporting Information for full details), our model ligand remained a clear front-runner in both conversion and yield. Considering the commercial availability and low cost of this established catalytic system (NiCl2·dme, dtbbpy), we moved forward with this combination to evaluate the full scope of this reaction.
Beginning with the aryl bromide partner (Figure 2), it was important to emphasize the ability of this catalyst system to engage a range of electronically differentiated aryl bromides. Reaction with electron-withdrawing 4-bromoacetophenone and electron-neutral 4-bromotoluene led to isolation of 15 and 24 in 95 and 62% yields, respectively. Even electron-rich bromides were competent electrophiles, as reaction with 4-bromoanisole gave rise to product 23, albeit in a modest 52% yield.
Figure 2. α-Alkoxymethyltrifluoroborate photoredox cross-coupling: halide scope. ‡Using 1.0 mol % Ir catalyst 1, 1.5 mol % Ni/ligand, 48 h.
The generality for the cross-coupling with heteroaryl substructures makes this method particularly attractive for late-stage diversification. In addition to the products derived from well-behaved benzofuran- and benzothiophene-containing bromides (25, 26), more challenging pyrazine-, pyrimidine-, quinoline-, and isoquinoline-containing bromides gave the desired products in excellent yields (33–36). Bromopyridines substituted at all regioisomeric positions could also be used to access products 28–32 in good yields. Even 8-bromocaffeine could be used to access product 39 in excellent yield. Unfortunately, protection was required for indazole- and azaindole-containing bromides, affording products 37 and 38, respectively. Although satisfactory methods for cross-coupling of these protic heteroaryl bromides remain elusive, it should be noted that previous Pd complex-catalyzed conditions [3 mol % Pd(OAc)2, 6 mol % RuPhos, 3 equiv of Cs2CO3, dioxane/H2O, 100 °C] have proved wholly ineffective or low yielding for a number of the heteroaryl bromides shown.(33) Therefore, this method represents a marked improvement over the current state of the art.
To highlight further the heteroaryl tolerance of this coupling, 5-bromopyrimidine was used as an electrophile to evaluate the alkoxymethyltrifluoroborate scope (Figure 3). To this end, a pyridyl-containing organotrifluoroborate was successfully employed to yield compound 41 in reasonable yield, showing tolerance of a heteroaryl functional unit in both reaction partners. Aryl chlorides were also tolerated on the trifluoroborate partner to give the dichlorinated arene 42 with no competitive reaction at the chlorides.
Figure 3. α-Alkoxymethyltrifluoroborate photoredox cross-coupling: organotrifluoroborate scope.
Beyond the largely aliphatic functional groups shown, amides and alkyl chlorides were untouched under the reaction conditions, leaving a site for further manipulation in products 48 and 50. Also to be noted is that products containing alkenes and alkynes were isolated in excellent yields (51–53). Considering the intermediacy of radical intermediates during this process, the tolerance of these functional handles for later derivatization is particularly intriguing.
As a final testament to the utility of this transformation, a number of α-alkoxymethyltrifluoroborates substituted with simple protecting groups were prepared (Figure 4). Currently, the facile preparation of many benzylic alcohols is predicated on commercial access to the corresponding esters and aldehydes. Even in cases where these precursors are readily available, the generated alcohols can be sensitive to ambient oxidation to afford a mixture of alcohol, aldehyde, and other oxidation byproducts.(39, 40) Consequently, a method for the preparation of protected benzylic alcohol variants from the far more widely available aryl and heteroaryl halides serves as an attractive method for reliable synthesis and long-term storage. To that end, allyl-, para-methoxybenzyl-, tert-butyl-, and trimethylsilylethyl-protected α-alkoxymethyltrifluoroborates were synthesized and employed as cross-coupling partners to give products 53–56. Subsequent deprotection of these protected alcohols allows the formation of benzylic alcohols in two steps from readily accessible bromoarenes.
Figure 4. α-Alkoxy photoredox cross-coupling: formation of protected alcohols.
Finally, although the products derived from these reactions can often be made by other means, the use of these reagents serves to validate further the photoredox cross-coupling manifold as a means of engaging Csp3 nucleophiles in alkyl transfer under mild conditions. Most importantly, the ability to cross-couple late stage bromides with an ever-expanding library of Csp3 hybridized nucleophiles using a single robust catalyst system is anticipated to enable practitioners to diversify their synthetic molecular architecture quickly and expand three-dimensional chemical space.(41)
Supporting Information
Experimental procedures and spectra data. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b01463.
The authors declare no competing financial interest.
Acknowledgment
This research was generously supported by the National Institute of General Medical Sciences (R01-GM113878) and TÜBİTAK. We thank Frontier Scientific for providing several organoboron reagents used in this research and Aldrich for iridium salts used in the preparation of the photoredox catalysts.
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Miyazawa, Kazuki; Yasu, Yusuke; Koike, Takashi; Akita, MunetakaChemical Communications (Cambridge, United Kingdom) (2013),Hydroalkoxymethylation of electron-deficient alkenes R1CH:CR2R3 (R1R2 = CH2CH2CO, CH2CH2OCO, etc.,; R1 = H, R2 = CN, CO2Me, CONMe2, 2-pyridyl, etc.; R3 = H, CO2Et, etc.) using alkoxymethyltrifluoroborates R4OCH2BF3K (R4 = Ph, 4-MeOC6H4, PhCH2, 1,3-benzodioxol-5-yl, etc.) by photoredox catalysis giving access to functionalized ethers R4OCH2CHR1CHR2R3 has been developed. Highly reactive alkoxymethyl radicals can be easily generated from oxidn. of alkoxymethyltrifluoroborates via a visible-light-induced SET process. - 20.
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Gueven, Oezden Oezel; Erdogan, Taner; Goeker, Hakan; Yildiz, SulhiyeBioorganic & Medicinal Chemistry Letters (2007),In this study, a series of novel phenyl- and benzimidazole-substituted benzyl ethers, e.g., I, were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Escherichia coli, Candida albicans, and Candida krusei. I exhibited the most potent antibacterial activity with lowest MIC values of 3.12 and 6.25 μg/mL against S. aureus and MRSA, resp. - 23.
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Percec, Virgil; Heck, James; Lee, Myong; Ungar, Goran; Alvarez-Castillo, AlbertoJournal of Materials Chemistry (1992),The synthesis of 2-(vinyloxy)ethyl 3,4,5-tris[[4-(n-dodecanyloxy)benzyl]oxy]benzoate, its cationic polymn. to poly[2-vinyloxyethyl 3,4,5-tris[4-(n-dodecanyloxy)benzyloxy]benzoate] (I) with relative no.-av. d.p. of 3.7-16 and narrow mol.-wt. distributions (i.e. Mw/Mn ≤1.28), and the characterization of I by a combination of techniques consisting of DSC, thermal optically polarized microscopy, and x-ray scattering expts. are presented. Regardless of mol. wt., I displays an enantiotropic columnar hexagonal (Φh) mesophase and an enantiotropic nematic (N) mesophase. The structural unit of I has a tapered shape. At low DP values (i.e. DP ≤4), the tapered side-groups of I self-assemble into a disk-like supramol. architecture which generates the Φh and the N mesophases. At DP ≤4, I self-assembles directly into a column-like supramol. architecture. In this last case the backbone of the polymer penetrates through the middle of the column from which the tapered side groups are radiating out to the edge of the column. It is believed that the disk-like and column-like supramol. architectures exist in the Φh, N, and for the isotropic phases (except that in the last one) the structure lacks long-range positional order. The mechanism of self-assembly of I resembles that of the tobacco mosaic virus except that in the 1st case the tapered side groups are linked to the polymer backbone via covalent bonds and in the latter case via non-covalent bonds. - 25.
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Hutchinson, D. K.; Fuchs, P. L.Journal of the American Chemical Society (1987),[(Benzyloxy)methyl]- and [[(tetrahydropyran-2-yl)oxy]methyl]lithium reagents were synthesized via transmetalation of the corresponding α-alkoxystannanes. These lithium reagents were converted into a no. of organocopper reagents, and their reactivity with three enones of differing steric demand was examd. The effect of Cu(I) precursor as well as additives such as BF3·OEt2 and Me3SiCl was examd. in detail. Application of this technol. to a pair of isomeric tri-n-butylstannyl glucopyranosides reveals the scope and limitations for the stereospecific synthesis of C-glycosides via conjugate addn. reactions to enones. - 26.
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Tamao, Kohei; Ishida, Neyoshi; Ito, Yoshihiko; Kumada, MakotoOrganic Syntheses (1990),A reagent for nucleophilic hydroxymethylation of carbonyl compds., alcs., org. halides, and epoxides was developed. Thus, reaction of (Me2CHO)Me2SiCH2Cl with Mg in THF contg. a few drops of BrCH2CH2Br followed by treatment of the Grignard soln. thus obtained with cyclohexanone in THF gave cyclohexanone deriv. I (R = Me2CHOSiMe2). Desilylation-hydrolysis of I (R = Me2CHOSiMe2) with 30% H2O2 contg. KHCO3 and KF in MeOH-THF gave 77% I (R = OH). - 27.
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Blanc, Romain; Groll, Klaus; Bernhardt, Sebastian; Stockmann, Paul N.; Knochel, PaulSynthesis (2014),(Pivaloyloxymethyl)zinc chloride, obtained by an iodine-magnesium exchange and subsequent transmetalation, shows a much higher reactivity in a Negishi cross-couplings than the corresponding zinc organometallic, prepd. by direct zinc insertion. Furthermore, a substituted deriv. of (pivaloyloxymethyl)zinc chloride is prepd. starting from pivaloyloxymethyl sulfoxide using TMPZnCl·LiCl [i.e., chloro(2,2,6,6-tetramethyl-1-piperidinyl)zinc-lithium chloride], followed by a sulfoxide-magnesium exchange. The synthesis of the target compds. was achieved by a reaction of zinc reagent prepd. from 2,2-dimethylpropanoic acid iodomethyl ester (iodomethyl pivalate) with isopropylmagnesium chloride-lithium chloride complex [i.e., lithium dichloro(1-methylethyl)magnesate(1-)] and zinc chloride (ZnCl2). Starting materials included bromobenzonitrile (aryl bromide), 1-iodo-4-(trifluoromethyl)benzene (aryl iodide), N-cyclopropyl-4-iodobenzamide. The title compds. thus formed included pivalate benzyl esters, such as 2,2-dimethylpropanoic acid (4-cyanophenyl)methyl ester and related substances. - 28.
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Majeed, Amera J.; Antonsen, Oeyvind; Benneche, Tore; Undheim, KjellTetrahedron (1989),Pyrimidines, e.g., I (X = Cl, Br) were stannylated in the activated 4-position by thermal decarboxylation of the corresponding carboxylic organotin esters. The decarboxylation can be catalyzed by PdCl2(MeCN)2. 4-Iodopyrimidines are 4-stannylated either by substitution reactions with tributyltin-copper or by coupling reaction with hexamethyl- or hexabutylditin and Pd(II) catalysis. The stannylated pyrimidines form new carbon-carbon bonds by Pd(II)-catalyzed cross-couplings. tert-Butyldimethylsilyl-, dimethylthexylsilyl- and tert-butyldiphenylsilyloxymethyl(tributyl)tin were synthesized and used in Pd(II)-catalyzed cross-coupling reactions with 4-chloropyrimidines. The silyl groups were not cleaved off during exposure to fluoride ions in aq. media but were readily removed by fluoride ions in THF to yield the 4-hydroxymethylpyrimidine. - 31.
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Falck, J. R.; Patel, Paresh K.; Bandyopadhyay, AnishJournal of the American Chemical Society (2007),Racemic and scalemic PTC-protected α-hydroxystannanes (PTC = pyrrolidinylthiocarbamoyl) cross-couple with alkenyl/aryl/heteroaryl iodides in moderate to good yields using copper(I) thiophene-2-carboxylate (CuTC) in THF at or below room temp. Simple aryl iodides and 1-iodocyclohexene, two classes of electrophiles that typically react sluggishly, are also good substrates. Cross-couplings proceed with retention of configuration at the alkenyl- and stannyl-substituted stereocenters. - 32.
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Goli, Mohan; He, Anyu; Falck, J. R.Organic Letters (2011),Racemic and scalemic α-(acyloxy)-tri-n-butylstannanes undergo Pd-catalyzed cross-couplings with alkenyl/aryl/heteroaryl iodides, bromides, and triflates in moderate to good yields in THF at 45 °C. Simple aryl iodides and unprotected aza-arenes, two classes of electrophiles that typically react sluggishly, are also good substrates. Cross-couplings proceed with retention of configuration at the alkenyl and stannyl-substituted stereocenters. - 33.
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Molander, Gary A.; Canturk, BelginOrganic Letters (2008),A wide variety of alkoxymethyltrifluoroborate substrates were prepd. via SN2 displacement of potassium bromomethyltrifluoroborate with various alkoxides in excellent yields. These alkoxymethyltrifluoroborates were effectively cross-coupled with several aryl chlorides. This method provides a unique dissonant disconnect that allows greater flexibility in the design of new and improved synthetic pathways. - 34.
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Murai, Norio; Yonaga, Masahiro; Tanaka, KeigoOrganic Letters (2012),Suzuki-Miyaura cross-coupling reactions of aryl halides and triflates with potassium acetoxymethyltrifluoroborate afforded the corresponding aryl and heteroaryl methanol products in moderate to excellent yields. - 35.
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Koike, Takashi; Akita, MunetakaInorganic Chemistry Frontiers (2014),A review. Photoredox catalysis by well-known ruthenium(II) polypyridine complexes and the relevant Ir cyclometalated derivs. has become a powerful tool for redox reactions in synthetic org. chem., because they can effectively catalyze single-electron-transfer (SET) processes by irradn. with visible light. Remarkably, since 2008, this photocatalytic system has gained importance in radical reactions from the viewpoint of not only a useful and selective protocol but also green chem. In this review, we will describe recent developments of radical reactions involving various carbon-centered radicals through photoredox processes mediated by Ru- and Ir-based photocatalysts. - 36.
Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 4896
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Gutierrez, Osvaldo; Tellis, John C.; Primer, David N.; Molander, Gary A.; Kozlowski, Marisa C.Journal of the American Chemical Society (2015),The cross-coupling of sp3-hybridized organoboron reagents via photoredox/ nickel dual catalysis represents a new paradigm of reactivity for engaging alkylmetallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using d. functional theory. Calcns. bring to light a new reaction pathway involving an alkylnickel(I) complex generated by addn. of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism. Anal. of the enantioselective variant of the transformation reveals an unexpected manifold for stereoinduction involving dynamic kinetic resoln. (DKR) of a Ni(III) intermediate wherein the stereodetermining step is reductive elimination. Furthermore, calcns. suggest that the DKR-based stereoinduction manifold may be responsible for stereoselectivity obsd. in numerous other stereoconvergent Ni-catalyzed cross-couplings and reductive couplings. - 37.
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Wang, Anwei; Yang, Zhiyong; Liu, Jidan; Gui, Qingwen; Chen, Xiang; Tan, Ze; Shi, Ji-ChengSynthetic Communications (2014),Facile and selective redn. of arom. aldehydes as well as aliph. aldehydes to alcs. was achieved using formic acid as the H donor in the presence of a catalytic amt. of Pd(OAc)2 and Cy3P. It was found that both hydrogen atoms in the formic acid mol. can serve as the hydride source. - 38.
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Harris, J. Milton; Chess, Robert B.Nature Reviews Drug Discovery (2003),A review. Protein and peptide drugs hold great promise as therapeutic agents. However, many are degraded by proteolytic enzymes, can be rapidly cleared by the kidneys, generate neutralizing antibodies and have a short circulating half-life. PEGylation, the process by which polyethylene glycol chains are attached to protein and peptide drugs, can overcome these and other shortcomings. By increasing the mol. mass of proteins and peptides and shielding them from proteolytic enzymes, PEGylation improves pharmacokinetics. This article will review how PEGylation can result in drugs that are often more effective and safer, and which show improved patient convenience and compliance. - 39.
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Urakami, Koji; Kobayashi, Chiaki; Miyazaki, Yoshihiko; Nishijima, Koji; Yoshimura, Yoshinobu; Hashimoto, KeijiChemical & Pharmaceutical Bulletin (2000),Benzyl alc. used as the sample prepn. solvent in the detn. of residual solvents in pharmaceutical bulks yielded benzene, toluene, and benzaldehyde on capillary gas chromatog. (GC) by sonication. The factors responsible for compds. generated are discussed. The quality of benzyl alc. and the type of sonicator were not involved in the generation of benzene, toluene, and benzaldehyde, whereas matrix contributions were obsd. The degrdn. profiles of benzyl alc. and its analogous compds. obtained by pyrolysis-GC/mass spectrometric anal. were similar to those obtained by sonication, suggesting that benzyl alc. is degraded by the high local heat generated by sonication. Consequently, no matter how long it may take to dissolve bulk substances in benzyl alc. completely, we do not recommend the use of a sonicator in sample prepn. for the detn. of residual solvents in pharmaceutical bulks. - 40.
Abend, A. M.; Chung, L.; Bibart, R. T.; Brooks, M.; McCollum, D. G. J. Pharm. Biomed. Anal. 2004, 34, 957
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Abend, Andreas M.; Chung, Le; Bibart, Richard Todd; Brooks, Marvin; McCollum, David G.Journal of Pharmaceutical and Biomedical Analysis (2004),An impurity in benzyl alc. was identified as benzaldehyde dibenzyl acetal (BDBA). The component BDBA is reversibly formed by the reaction of benzyl alc. with benzaldehyde, an oxidative degrdn. product of benzyl alc. Whereas, BDBA is a known chem. entity, it is not typically controlled in com. benzyl alc. since it cannot be formed in the absence of benzaldehyde, which is itself generally controlled. However, once com. benzyl alc. is exposed to the atm., formation of BDBA is possible. The synthesis and characterization of BDBA is reported. The ability of BDBA to react with alcs. to form other types of acetals, and the impact of low levels of BDBA on the quant. anal. of pharmaceutical products, are considered. - 41.
Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752
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Lovering, Frank; Bikker, Jack; Humblet, ChristineJournal of Medicinal Chemistry (2009),The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.
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Tong LiuYuewen LiLifang LaiJiang ChengJiangtao SunJie WuOrganic Letters 2018 Article ASAP
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