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. 2019 Oct 22;10(11):1512–1517. doi: 10.1021/acsmedchemlett.9b00409

Escaping from Flatland: [2 + 2] Photocycloaddition; Conformationally Constrained sp3-rich Scaffolds for Lead Generation

Brian Cox †,‡,*, Kevin I Booker-Milburn §,#, Luke D Elliott §, Michael Robertson-Ralph #, Victor Zdorichenko ‡
PMCID: PMC6862337  PMID: 31749903

Abstract

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Pressure on researchers to deliver new medicines to the patient continues to grow. Attrition rates in the research and development process present a significant challenge to the viability of the current model of drug discovery. Analysis shows that increasing the three-dimensionality of potential drug candidates decreases the risk of attrition, and it is for this reason many workers have taken a new look at the power of photochemistry, in particular photocycloadditions, as a means to generate novel sp3-rich scaffolds for use in drug discovery programs. The viability of carrying out photochemical reactions on scale is also being addressed by the introduction of new technical developments.

Keywords: Drug discovery, photocycloaddition, sp3-rich scaffolds, hit and lead generation

For medicinal chemists, the consideration of calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors in compound design has become a part of everyday life. In their seminal paper entitled “Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success”, Lovering et al. hypothesized that the shift to high-throughput synthetic practices had resulted in more achiral, aromatic compounds.1 They proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp3 (Fsp3) where Fsp3 = (number of sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. They went on to demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs (see Figure 1). They further demonstrated that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting.1

Figure 1.

Figure 1

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Mean Fsp3 for compounds in different stages of development. **P value <0.001. Reprinted from ref (1). Copyright 2009, American Chemical Society.

In a later paper, Lovering described how increasing complexity (Fsp3 and chiral carbon count) reduces promiscuity and Cyp450 inhibition. Increased promiscuity has been linked to toxicity and candidate failure.2 It is also worthy of note that over the past 20 years there have been a number of excellent papers published advancing computational methods for defining “3D shape”.3−5

Interestingly, Walters et al. analyzed the types of molecules that had been made by medicinal chemists over the 50 years preceding 2009 (Figure 2). It showed quite conclusively the dramatic rise in the proportion of molecules containing sp2–sp2 couplings. The authors attributed this trend away from sp3 character to the introduction of new methods for sp2–sp2 couplings and the adaptation of these methods to high-throughput synthesis, utilized widely in optimization programs and in archive “enrichment” campaigns.6

Figure 2.

Figure 2

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Influence of sp2–sp2 coupling chemistries on the molecules published in the Journal of Medicinal Chemistry between 1959 and 2009. Data are shown as the fraction of molecules published in each 5-year period containing at least one acyclic–aromatic carbon–carbon bond. Reprinted from ref (6). Copyright 2011, American Chemical Society.

The realization that “complexity” in the form of greater sp3 character and the presence of chiral centers prompted us and a number of other workers (referenced in the forthcoming text) to look to photochemistry as a source of desirable starting points for medicinal chemistry, in the form of building blocks and for fragment and diversity libraries. The activation of molecules through the absorption of light can provide access to complex molecular structures that are difficult to obtain using ground-state chemistry approaches. Another driver for the exploration of the chemical universe accessible through photochemistry is the growing problem of crowded intellectual property space associated with drug candidates prepared by conventional methods.

It cannot be said that the recent focus on photochemistry for the generation of desirable sp3-rich frameworks is novel; for example, in 1908 Ciamician and Silber published an intramolecular enone [2 + 2] cycloaddition of carvone 1, producing carvone camphor 2. This ground-breaking work ushered in the era of photochemical synthesis, although was only achieved upon prolonged exposure of 1 to Italian sunlight for over 1 year (Figure 3).7 What is different now is the impact of recent advances in technologies that enable the simple and reliable scaling of photochemical reactions both in a medicinal chemistry and potentially in a production setting. A number of flow devices have been reported8−11 including the recent development of a parallel tube flow reactor (PTFR) shown in Figure 4. The reactor consists of a succession of quartz tubes connected together in series and arranged axially around a variable power mercury lamp and is capable of producing multikilogram quantities of product over a 24-h continuous operation period.12

Figure 3.

Figure 3

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Photoinitiated [2 + 2] enone cycloaddition of carvone in sunlight.

Figure 4.

Figure 4

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Parallel tube flow reactor (PTFR). Reprinted from (12). Copyright 2016, American Chemical Society.

There are a multitude of excited state photochemical reactions known13 historically, but the areas that have received the most attention recently as potential providers of desirable sp3-rich frameworks for medicinal chemistry involve photocycloadditions.

Photocycloaddition Chemistry

This area is dominated by [2 + 2] reactions used in the synthesis of cyclobutanes by olefin photocycloaddition reactions14 and the synthesis of oxetanes by [2 + 2] photocycloaddition of carbonyl compounds and alkenes (the Paternò–Büchi reaction).15

Intermolecular [2 + 2] Olefin Photocycloaddition

A large number of intermolecular examples have been reported yielding desirable building blocks for medicinal chemistry. Maleimide 3 has proven to be a very useful chromophore in intermolecular [2 + 2] reactions8,16 and can be considered as a masked pyrrolidine unit; for example, reaction with homopropargylic alcohol 4 provides intermediate 5, which can be modified further into interesting products 6 and 7.17 Its N-benzyl analogue 8 has also been employed in reactions with a variety of functionalized alkenes, the amide 9, for example, being modified to the diamine 10, a useful synthon for two-dimensional parallel synthesis.18 Maleic anhydride and its derivatives behave similarly in intermolecular [2 + 2] photocycloaddition reactions, although as a chromophore the parent maleic anhydride has much poorer productivity than substituted derivatives. Tetrahydrophthalic anhydride 11 reacts with propargyl alcohol 12; alcoholysis of the product followed by thermolysis of the bicyclo[4.2.0]cyclooctene 13 provided the bicyclic lactone 14 by a electrocyclic ring-opening/lactonization sequence.19 Another example of initial intermolecular [2 + 2] photocycloaddition followed by further reactions was the irradiation of cyclo-2-penteneone 15 in the presence of excess cyclopentene 16. Irradiation at 350 nm provided the expected product 17, but irradiation at 300 nm produced an unprecedented 4:4:4 oxetane 18 via a proposed triple cascade process.20 Isoquinolone 19 and its analogues have been extensively used in intermolecular [2 + 2] photocycloaddition reactions with a variety of olefins.21 Interestingly, its reaction with electron withdrawing olefins such as t-butyl acrylate 20 in the presence of the chiral template 22 achieved enantioselectivities exceeding 90% ee.22 These and other results by Bach are notable as traditionally it has been very difficult to obtain stereoselection in photochemistry without substrate control. Chiral auxiliaries have also been employed in enantioselective intermolecular [2 + 2] photocycloaddition, an excellent example is the reaction of an ester of 2-cyclohexenone 23 with isobutene 24, achieving a sole regioisomer 25 in very high % ee.23

Intermolecular [2 + 2] Photocycloaddition of Carbonyl Compounds and Alkenes (Paternò–Büchi Reaction)15

This reaction possesses particular interest for its ability to produce substituted oxetanes, increasingly desirable in medicinal chemistry programs24 that are more difficult to synthesize by ground state methods, and it also offers advantages in the control of relative stereochemistry. Furans and 2,3-dihydrofurans are excellent substrates in the Paternò–Büchi reaction providing a number of very interesting bicyclic templates. Benzaldehyde 26 and 2,3-dihydrofuran 27 react to produce the bicyclic oxetanes 28 and 29 with a high endo selectivity.25 Benzaldehyde 26 also reacts with enamines such as 30 to produce 3-aminooxetanes 31 and 32 in very good cis diastereoselectivity (Figure 5).26

Figure 5.

Figure 5

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Intermolecular [2 + 2] photocycloadditions.

Intramolecular [2 + 2] Olefin Photocycloaddition Reactions

This area has received enormous attention, particularly over the past 10 years, as the potential for intramolecular reactions to generate complex multiple ring systems has been realized. It can also serve as a means to control the regioselectivity of the photocycloaddition by tethering of the reactive functions.14 One medicinally significant molecule that has been the subject of considerable attention is 2,4-methanoproline 34 and its analogues. 2,4-Methanoproline 34 (as its HCl salt) is prepared in a simple sequence of reactions from serine 33.27 The utility and conformational properties of 2,4-methanoproline 34 as a replacement for d- or l-proline has been studied, its N-acetyl methyl ester was found to show a large prevalence for a trans-amide conformation more akin to primary amino acids than to d- or l-proline.28 This makes it a potentially interesting amino acid for inclusion in therapeutic peptides. A number of 4-substituted analogues of 2,4-methanoproline had also been reported. The preparation of “conformationally locked” analogues of neurotransmitters is a common strategy in studying structure–activity relationships, for this reason the 4-caboxylic acid analogue of 2,4-methanoproline 35 was prepared as a conformationally locked analogue of glutamate and shown to be an effective blocker of 3H-d-aspartate uptake in rat brain synaptosomes.29 Due to the common use of pyrrolidine as a structural unit in medicinal chemistry, the synthesis of 2,4-methanopyrrolidine analogues has been reported by a number of groups, for example, the preparation of the 2,4-methanopyrrolidine version 36 of N-methylepibatidine.30 Other workers have used 2,4-methanoproline 34 as a substrate for the preparation of a large number of different 2-substituted 2,4-methanopyrrolidines31 and also prepared analogues of 2,3-ethanoproline 37 also using photochemistry.32 Derivatives of 2-phenyl-2,4-methanopyrrolidine 39, prepared up to kilogram scale using flow photochemistry from simple amino styrenes 38, have been shown to be labile under acidic conditions. This inherent reactivity has been exploited by inducing a complexity generating Diels–Alder cascade sequence with maleic anhydride to isoindoline derivatives 40 with multiple points of diversity.33 A rare example of a cross [2 + 2] cycloaddition to generate a six-membered ring has recently been reported.34 Styrene derivatives 41 undergo a triplet-sensitized intramolecular cycloaddition to conformationally restricted α-tetralone derivatives 42, which can be derivatized to biologically active compound 43.

Alkenes tethered to a chromophoric species by a chain length of three atoms more typically undergo straight [2 + 2] cycloadditions to give 5,4-ring systems. An early example of a triplet-sensitized intramolecular cycloaddition of styrene 44 to give azabicyclo[3.2.0]heptane 45(35) has been used to synthesize a D4/5-HT2A receptor antagonist 46.36 Other examples of potentially useful building blocks that have been prepared are typified in the synthesis of tricyclic compound 48 from a relatively simple oxazolidinone starting material 47(37) or compounds similar to those described above in Figure 5 by the intramolecular cyclization of amides such as 49 followed by further steps to provide useful compounds like 51.38 Cyclohexenones and 2,3-dihydropyridin-4(1H)-ones have also be shown to be excellent substrates for photochemistry by workers. For example, the cyclization of the two enaminones 52 and 53 yielded valuable tricyclic building blocks 54, 55 and 56.39,40 Enaminone 57 produced the aza-De Mayo product 58.41 Use of a chiral Lewis acid, oxazaborolidine-AlBr3 complex 59, with the 2,3-dihydropyridin-4(1H)-one 60 produced the 4-piperidone 61 with high enantioselectivity,42 and the 5,6-dihydropyridin-2(1H)-one 62 provided the 2-piperidone 63 in the presence of (−)-22 as a chiral template.43 Indoles have been utilized in [2 + 2] photocycloaddition reactions, the tethered allene 64 producing the cis-fused indoline 65 and a small amount of the alkyne 66 via 1,5-hydrogen transfer of the biradical intermediate.44 A powerful example of complex structure formation is the [2 + 2] photocyclization and accompanying photo-Fries rearrangement of the indole 67 prepared from a chiral-pool-derived sugar moiety to a highly functionalized product 68 as a single enantiomer.45 A well-known and quite unique product of intramolecular [2 + 2] photocycloaddition is pentacycl[5.4.0.02,6.05,9]undecane-8,11-dione 72, otherwise known as Cookson’s diketone.46 It is prepared by the irradiation of the Diels–Alder cycloaddition adduct 71 of 1,4-benzoquinone 69 and cyclopentadiene 70. The caged structure of Cookson’s diketone 72 has attracted attention for its resemblance to adamantane, which is known to have a variety of biological activities. A variety of amine derivatives (73, NGP-01 (74), and 75) have been prepared (as racemates) from Cookson’s diketone 71 and have been shown to possess potential neuroprotective activity.47−50 NGP-01 74 has also been shown to be a chemosensitizer and to reverse chloroquine 76 resistance in Plasmodium falciparum screens.50 The combination of features of NGP-01 74 with chloroquine 76 produced a compound 77 with activity against a nonchloroquine resistant strain equal to that of chloroquine but five times more active than chloroquine against a chloroquine resistant strain (Figure 6).

Figure 6.

Figure 6

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Intramolecular [2 + 2] photocycloadditions.

Conclusion

Over the coming 5–10 years, the predicted positive impact of researchers “escaping from flatland” with the synthesis and use of higher Fsp3 compounds in medicinal chemistry programs will become apparent. Photocycloaddition reactions stand to play a significant part in generating highly desirable templates of which only a small sample have been covered here. A vision of the future could therefore be marketed medicines not only discovered from photochemically derived libraries, but ultimately manufactured using photochemical flow reactors.

Acknowledgments

We are grateful to the Universities of Sussex and Bristol.

Glossary

ABBREVIATIONS

DCM

dichloromethane

DMF

dimethylformamide

ITX

isopropylthioxanthone

THF

tetrahydrofuran

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

We gratefully acknowledge support for Luke Elliott from the Engineering and Physical Sciences Research Council (EP/P013341/1).

The authors declare no competing financial interest.

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