Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

Abstract

The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential "late-stage functionalization" exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C-H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C-C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

Figure 1

(A) Selected natural products that present substantial challenges for site-selective functionalizations.^– (B) Challenges associated with the site-selective modificaiton of a natural product, such as the monoacylation of polyol 1.

Figure 2

(A) Energy profiles of a desymmetrization reaction, where both potentially reacting alcohols are chemically equivalent. A catalyst that can selectively lower the activation barrier ( pathway, ) will result in high enantioselectivities, (B) Energy profiles of a site-selective transformation, where reactive groups are nonequivalent. Depending on the inherent energy profiles of the functional groups ( versus pathways, ), catalytic reduction of an energy barrier may not result in high observed selectivities ( pathway, ). The achievement of highly selective functionalizations may require substantially more selective catalysts ( pathway, ). (C) This problem is compounded by the addition of more reactive groups and (D) the ability for substrates to undergo multiple derivatization events.

Figure 3

Protein kinases selectively phosphorylate protein hydroxyl groups. Among their many roles is serving in signal transduction pathways to turn the enzyme’s function “on” or “off”.^–

Figure 4

(A) Pmh-catalyzed acyl transfer. The imidazole (or other N-heterocycles) serves as a nucleophilic catalyst, decomposing the acid anhydride and delivering the acyl group to a substrate hydroxyl. Other functionality on the peptide can bind to the substrate and enforce selectivity. (B) The acetamide of 5 serves as a directing group for peptide 7, resulting in high levels of selectivity for this kinetic resolution by acylation. (C) Peptide-based phosphorylation can be accomplished on more complex substrates, such as 8. (D) Peptides utilized in this figure.

Figure 5

Selective acylation of erythromycin (13). Under NMI-catalyzed conditions, the C2′ and C4″ alcohols are the first and second most reactive functional groups (15 being isolated after methanol-induced cleavage of C2′–OAc). However, utilization of peptide 17 reveals a new product, 16.

Figure 6

(A) Expansion of the scope of acylation of erythromycin (13) results in continued selectivity for C2″–OH acylation. (B) Upon isolation of diacylated product 19, the C4″–OH can be selectively phophorylated.

Figure 7

(A) The selective deoxygenation of 14 can be carried out at the C4″–OH via selective phosphitylation of this positon, followed by radical cleavage. (B) The selective deoxygnation of the C4″–OH of 13 can be carried out through the use of catalyst 26, as phenyl tetrazole in this case yields a complex mixture of phosphite products. The C2′–OH can be targeted for elimination through thiocarbonyl intermediate 28.

Figure 8

(A) Acylation of apoptolidin A (30) with DMAP resulted information of 31 and 32. When using peptide ent-17 as catalyst, 31 was the primary acylation product. (B) Further acylated products 33 and 34 were observed in the presence of an excess of acylating agent.

Figure 9

(A) Deoxygenation of protected vancoymcin derivative 36 via site-selective acylation using a variety of Pmh-containing peptides. Reactivity is centered on the G₆ and Z₆ positions to yield 39 and 40 respectively. (B) Radical cleavage of the phenylthiocarbonyl intermediates results in deoxygenation products 47 and 48. (C) Pmh-containing peptide catalysts utilized in this study.

Figure 10

(A) Crystal structure of vancomycin (71, gray) binding to Ac-Lys(Ac)-^DAla-^DAla-O⁻ (yellow), a mimic of 71’s native binding target. (B) Proposed binding strategy of catalyst 80 to deliver the phenyloxythiocarbonyl to the G₆-hydroxyl selectively. Reproduced with permission from ref . Copyright 2012 American Chemical Society.

Figure 11

(A) Site-selective phosphorylation of protected teicoplanin A₂-2 (50) reveals preferences for reaction at the three primary alcohols on the three sugars of 50. Three peptides were shown to selectively favor functionalization of each of these glycosides (B) Catalysts applied in these reactions.

Figure 12

Crystal structure of teicoplanin A₂-2 (50, C-atoms in gray) binding to Pmh-^DPro-Aib-^DAla-^DAla, showing the Pmh residue is pointed directly towards the green sugar. Reproduced with permission from ref . Copyright 2014 American Chemical Society.

Figure 13

(A) Site-selective lipidation of protected vancomycin 36 results in functionalization of G₄, G₆, or Z₆ alcohols. Three different peptide sequences are able to achieve selective lipidation at these three positions.(B) Numerous lipidated analogues of vancomycin display heightened biological activity, especially important against VanA and VanB, which are vancomycin resistant.

Figure 14

(A) Site-selective acylation of the C4–OH of monosaccharides using 4-pyrrolidinopyridine catalyst 73. DMAP provides an unselective mixture of multiple products. (B) Proposed transition state. The catalyst’s amide carbonyl hydrogen bonds to the C6 primary alcohol, orienting C4–OH for selective acylation. (C) Scope of selective acylation reactions. (D) Scope of acylating agents utilized.^–

Figure 15

Total synthesis of strictinin (78) involving a key site-selective acylation, catalyzed by 4-pyrrolidinopyridine catalyst 73, site-selective esterification, and oxidative phenol coupling.

Figure 16

Selective acylation of digitoxin (86). Only one product is observed when using 4-pyrrolidinopyridine catalyst 73.

Figure 17

Site-selective acylation of lanatoside C (89). While DMAP offers selectivity for the 3‴′ secondary alcohol, catalyst 73 favors reactivity at C4‴′–OH. Variation of the chirality of catalyst 73 or 93 leads to different selectivity patterns, implying while the Trp-stereochemistry is not as important to observed trends, the chirality at the pyrrolidine ring is essntial for matched interactions between the catalyst and substrate. ^a20 °C, 48 h. ^b−20 °C, 96 h. ^cDMF

Figure 18

Selective acylation of avermectin B_2a (95).

Figure 19

Selective acylation of 10-Deacetylbaccatin III (99). Catalyst 73 enhances the inherent selectivity for 101 over 100 as afforded by DMAP. Functionalization of C10–H to yield 100 can be accessed by using (CCl₃CO)₂O as the anhydride source. ^a5.0 equiv. Bz₂O. ^b3.0 equiv (CCl₃CO)₂O.

Figure 20

(A) Site-selective mesylation of rhamnose (104). The catalyst is selective for cis-1,2-diols. (B) Imidazole-2-methoxyoxazolidine catalysts. (C) Selectivity patterns for the mesylation of 104 with various catalysts. (D) A proposed intermediate that forms upon addition of one of the cis-1,2-alcohols into the oxazolidine. The imidazole will next deliver the mesylate via to the free alcohol. (E) Site-selective mesylation of mupirocin methyl ester (108). (F) Site-selective modification of digoxin (111).

Figure 21

(A) Site-selective acylation of protected amphotericin B (114). (B) The more sterically hindered the acyl transfer reagent, the higher the C2′-selectivity. (C) The more electron-rich the benzoyl chloride, the less reactive the reagent is and more C2′ selectivity is observed. (D) Tuning of acid anhydrides results in two additional site-selective reactions. (E) Optimized acylating agent. p-tertbutylbenzoyl chloride.

Figure 22

(A) Aqueous site-selective glycosylation of sucrose with Ca(OTf)₂ and trimethyl amine. (B) Expansion of scope of glycosylation to extremely complex substrates. Lactosyl fructofuranoside is the starting oligosaccharide for 121, stachyose for 122.

Figure 23

Site-selective glycosylation of digitoxin (87) in the presence of diphenylborinic acid catalyst 124, which proceeds via a cis-1,2-diol coordinating to the borinic acid.

Figure 24

Diazo esters are nucleophilic at the α-position. Upon rhodim carbenoid formation, the now electrophilic the α-position is susceptible to nucleophilic attack (e.g. alcohols or C–H bonds).^–

Figure 25

(A) Site selective O–H insertion of 126 with Rh₂(OAc)₄. 4-bromophenyl-substituted diazo esters were found to give the best selectivity for mono O–H insertion. (B) Expansion of complex molecule substrate scope for site-selective O–H insertion. All compounds give one mono insertion product, with the exception of 147, which gives primarly diether 149. Note: numbers in parantheses represent %RSM. (C) Alteration of dirhodium catalyst perturbs the ratio of the two mono insertion products. Abbrev: HBPA: 5-hexynyl-(α-4-bromophenyl)acetate.

Figure 26

(A) Site-selective O–H insertion of 126 with α-trifluoroethyl-substituted diazo esters. Various dirhodium catalysts gave different ratios of mono and difunctionalized products. (B) Expansion of scope for site-selective O–H insertion.

Figure 27

Biosynthesis of paclitaxel. After initial cyclization, a number of enzymes of the P450 family catalyze the site- and stereoselective oxidations to yield 141.

Figure 28

Site-selective tether-assisted oxidation of steroids. A shorter tether length forces oxidation at C15, while a longer tether allows the benzophenone oxidant to reach C17–H.^–

Figure 29

(A) Interplay between hyperconjugative stabilization of intermediates from native substrate functionality and steric hinderance. 3° and 2° C–H bonds are often competitive for oxidation, 1° C–H bonds are disfavored. (B) Given the near equivalence of most C–H bonds, remote EWGs can have large effects.^,, (C) α-Hyperconjugative donation from oxygen lone pairs to the C-H antibonding orbital greatly enhances the nucleophilicity of these bonds.^, (D) Oftentimes, the mechanism of C–H oxidation involves full or partial planarization of targeted bonds. C–H bonds where this deviation from ideal bond angles is accompanied with strain release are favored for oxidation. (E) Directing groups can outcompete other considersations.^–

Figure 30

(A–J) Assorted site- and stereoselective C–H oxidations using a variety of stoichiometric or catalytic oxidations. Selectivity is miainly governed by substrate bias. , , and orbs represent dominance of electronic, steric, and stereoelectronic factors respectively.^,,–

Figure 31

(A) Hartwig’s Ir-catalyzed C–H silylation/oxidation pathway favors formation of 1,3-diols. (B) The oxidation of 184 results in a primary alcohol at the C23 position. The previous state of the art to access oxidized derivatives at the position was a 10 step synthesis. (C) After Ru-catalyzed silylation of the C3 alcohol, a similar Ir-catalyzed rearrangement/oxidation yields C23 oxidized 188.

Figure 32

(A) Pyridyl-appended imines can function as directing groups for Cu-catalyzed aerobic oxidations of C12–H in steroids. This method tolerates both alcohols and alkenes. (B) The proposed mechanism proceeds via bimetallic activation of O₂ to activate the C12–H bond.

Figure 33

Site-selective C–H oxidation of the allylic positions of a variety of natural products.

Figure 34

(A) Oxidation of betulin derivatives 199 and 200 with TFDO and PIDA to selectively target the C16 and C12 positions. C16–H is the most electron rich and sterically accessible secondary C–H bond in the molecule. C12-oxidation is achieved via direction from the C20 alcohol or peroxide. (B) Directed oxidation of betulin derivative 204 with Pb(OAc)₄ followed by treatment with AgOAc reveals a C13 oxidized product that has undergone skeletal rearrangement via a 1,2-shift. (C) The Hartwig [Ir]-catalyzed 1,3-diol oxidation protocol was utilized to target the C23–H, directed by the C3 alcohol. (D) Summary of all oxidation methods used to target different positions of betulin (197) and betulinic acid (198).

Figure 35

(A–C) The use of cyclodextrin-containing porphyrin catalysts (D) and receptor-containing substrates to achieve site-selective oxidations of steroids. (E) The cyclodextrin units of the catalyst bind to two (A) or three (B) of the receptor arms, positioning the steroid ring and a specific C–H bond directing over the Mn-active site.^–

Figure 36

(A) Fe-PDP catalysts. (B) Summary of iron-catalyzed, 3°-selective C–H oxidations on small molecule substrates. (C) The oxidation of (+)-artemisinin (215) with 214a favors the most electron rich C10–H bond. (D) The presence of a free carboxylate at C6 replaces the AcOH ligands, overiding the inherent selectivity and favoring lactone formation at C15–H instead. (E) 219 is too sterically encumbered to oxidize C12–H. The remaining C–H bonds are too electronically deactivated by the lactones and epoxide to be oxidized.

Figure 37

(A) The conversion of 220 to 222 is known to proceed by a prescedented radical rearrangement and oxidation, supporting the hypothesis that catalyst 214 operates via a H-atom abstraction and radical based mechanism. (B) Proposed general radical mechanism. (C) Oxidation of picrotoxinin derivative 225 reveals two lactone products.

Figure 38

(A) With a methyl ester, the innate substrate reactivity for C1–H atom abstraction followed by rearrangement and oxidation predominates. (B) The free carboxylate directs oxidation to C2–H.

Figure 39

(A) Secondary C2–H bonds are favored due to strain release of C2 due to the axial methyl groups at C4 and C6, while the tertiary C–H bonds are deactivated via sterics and electronics. (B) Secondary C2–H bonds are more electron rich due to hyperconjugative activation from an adjacent cyclopropane. (C) Iterative oxidation of 237. The first oxidation is driven by the electron-richness of C–H bonds adjacent to ethers and the second by strain release. (D) Oxidation C7-H relieves strain in the starting material. The tertiary C–H bonds are deactivated via steric and electronics. Intriguingly, the unprotected primary alcohol at C22 is not oxidixed. (E) Examples of π-rich cyclopropane’s hyperconjugation with adjacent C–H bonds and of hyperconjugation from oxygen lone pairs to adjacent C–H bonds.

Figure 40

The inclusion of bulimy groups on the pyridine 5 and 5′ position reduces the cone angle, making the catalyst even more susceptible to minor steric effects.

Figure 41

(A) Oxidation of (−)-247 reveals preference for C6 and C7. (B) The substrate was analyzed with computations, comparing the C–H atoms’ relative electronic and steric parameters in order to predict reactivity. Catalyst 246 is better abie to respond to minor steric effects and yields substantaily higher selectivity than 214b. Predicted results correlated well with experimental findings. (C) The electron withdrawing lactone and acetates, along with the sterically hindered concave side of the molecule favor the C6 and C7 atoms for oxidation.

Figure 42

(A) Artemisinin was subjected to oxidation with both 214a and 246a, revealing that tertiary C10–H is too hindered for oxidation by 246a, which instead favors C9–H. Predicted results from paramaterization correlate well with observed results. (B) Catalyst 214a favors tertiary C11–H while more hindered catalyst 246a favors C10–H.

Figure 43

(A) Oxidation of dextrometliorphan derivative (+)-254 revealed preferences for oxidation of the C6–H and one of the C7–H bonds, the most distal groups from the protonated piperazine ring. (B) Oxidation of abiraterone acetate analogue (+)-257 shows preference for the C6–H bond, which is distant from the EWGs on the A and D rings. This is aided by the strain release that is afforded in the planarization of C6 from the axial methyl group at C10. The catalyst is also able to select for C6–H against tertiary C–H bonds at C5, C8, and C14. (C) Cycloheximine derivative (+)-260 is oxidized at C19–H, which is furthest away from the multiple EWGs of the molecule.

Figure 44

(A) Catalyst derivatives with X-type ligands, removing the need for counterions, modification of the aliphatic chiral diamine, and substitution of the pyridine rings with chiral bulky (+)-pinene. (B) Oxidation of (−)-ambroxide (237) reveals a strong preferene for C–H bond adjacent to the cyclic ether due to strong hyperconjugative activation. Increased yields are observed at lower catalytic loading with novel catalysts. Oxidation of (+)-cedryl acetate (266) favors the tertiary C–H bond distal from the electron withdrawing acetate. Yields are substantial lower, though catalyst modification increases the yields. (C) Oxidation of (+)-sclareolide (238) reveals a mixture of three predominant oxidation products. Alteration of the catalysts is shown to substantially alter product ratios, revealing conditions that favor all three substrates in moderate yields.

Figure 45

The total syntheses of two highly oxidized taxanes. Inspired by nature’s use of distinct cylcase and oxidase phases, the synthetic strategy features a number of selective oxidation reactions.

Figure 46

(A) Chlorination of 5α-cholestane (283) with Mn-porphyrin 282 results in the selective formation of 284 and 285. (B) Chlorination of sclareolide (238) results in preferential formation of the equatorial C2-chlorination product (286). (C) Proposed mechanism for the Mn-porphyrin catalyzed chlorinations. (D) Fluorination of 5α-androstan-17-one (288) results in preferential formation of 289 and 290. (E) Fluorination of sclareolide (238) with Mn-porphyrin 282 results in the selective formation of 291 and 292. (F) Proposed mechanism for the Mn-porphyrin catalyzed fluorination. (G) Structure of Mn(TMP)CI 284. Abrev. TMP: tetramesityporphyrin.^,

Figure 47

(A) Bromination of 238 by N-chloroamide (293) under visible light irradiation conditions revealed preference for C2-equatorial bromination (294). (B) This C2-equatorial selectivity is also observed for chlorination to yield 297, which is further utilized in the total synthesis of 295.^,

Figure 48

Site-selective iodination of a number of natural products. ^aDMF as used as solvent. ^bTfOH (0.1 equiv) w/as added. ^cNo ln(OTf)₃ was utilized.

Figure 49

(A) NBS-mediated selective bromination of H_A of 313. (B) NBS-mediated bromination of H_A and the alkene of 314. The incipient brominum intermediate undergoes EAS. (C) Substrate and reagent controlled bromination. While most brominating sources functionalize H_A, treatment of 317 with BDSB results in bromination of H_B. (D) Brominating agents. Abrev. NBS: N-bromosuccinimide; NBSac: N-bromosaccharin; TBCO: tetrabromocyclohexadienone; NBA: N-bromoacetamide; TCCA: trichlorocyanuric acid; BDSB: Bromodiethylsulphide bromopentachloroantimonate.

Figure 50

(A) Model of vancomycin (35) binding to a ^DAla-^DAla containing peptide. The Asn side chain may then deliver a bromine atom to the 7-ring. (B) The bromination of vancomycin (35) with no catalyst or in the presence of a achiral promoter offer no selectivity for either 322 or 323. Hit catalyst 321 preferentially favors bromination to 322 under various conditions. (C) Guanidine is able to reverse selectivity for 322 and favor bromination to 323. Catalyst 325 can deliver tribromide 326 with good selectivity.

Figure 51

(A) Site-selective bromination of teicoplanin (49). The inherent reactivity reveals a preference for 333, while use of either catalyst 328 or 329 favors bromination of ring 3. (B) Derivatization of the aryl bromides and aryl chlorides of the teicoplanin derivatives via Suzuki cross-couplings. The 2_CCl reacts faster than the 7_fBr and 3_CBr. (C) Screening of teicoplanin derivatives against bacterial strains. Compounds 334, 337, 339, and 340 are particularly effective against vancomycin resistant VanA.

Figure 52

(A) Selective removal of the 3_CCl of 35. (B) Selective cross-coupleavariety of boronic acids on the 6_C position.

Figure 53

Biosynthesis of cholesterol from squalene, featuring a site-selective epoxidation.^,

Figure 54

(A) Site-selective epoxidation of famesol (353). Peptides that yielded 2,3-epoxide (354) and 6,7-epoxide (355) were discovered. (B) Mechanism of Asp-catalyzed epoxidation. (C) Proposed mechanistic models for 2,3- and 6,7-peptide catalyzed epoxidation.^,,

Figure 55

Site-selective amination of sclareolide (238) using dirhodium catalyst 359. The C2 position (362) is favored due to strain release in the transition state of the amination.

Figure 56

3°C–H selective amination of cycloheximide derivative 363.

Figure 57

(A) Competition between aziridination and C–H amination of aikene-containing substrates. (B) Common conditions for amination reactions. (C) Representative aminations of natural products. Benzylic and allylic amination, in addition to aziridination are the common reaction pathways. (D) Rearrangement pathway for aziridination product 126.

Figure 58

Mn-porphyrin-catalyzed azidation of aliphatic C–H bonds. Selective reactions on sclareolide, estrone, and artemisinin derivatives have been achieved.

Figure 59

Selective azidation of natural products using Fe(OAc)₂ and a chiral ligand source.^,

Figure 60

Allylicazidation versus diazidation.

Figure 61

Selective trifluoromethylation-azidation reactions.

Figure 62

Divergent selectivity in the derivatization of the scaffold of cholesterol derivative 420.

Figure 63

Examples of ineffective substrates for Fe-catalyzed azidation

Figure 64

Method for the site-selective C–H xanthylation of aliphatic C–H bonds, including on a number of natural products. Xanthates can be further derivatized into a variety of different functional groups.

Figure 65

(A) Trifluoromethylthiolation of C–H bonds c an be accomplished via visible-light promoted and Ir-catalyzed photoredox catalysis.(B) Structure of Ir-photoredox catalyst.(C) Natural products targeted by this method. The most electron rich and sterically accessible 3° C–H bonds are functionalized here. (D) Proposed mechanism. After excitation of the Ir-photocatalyst can be coupled to oxidation of the benzoate co-catalyst, which facilitates the C–H abstraction on the substrate. This c an be trapped with the trifluoromethylthiolating agent. Abrev. HAT=hydrogen atom transfer; SET=single electron transfer.

Figure 66

Site-selective deoxyfluorination of natural products. Using 447 asasource of nucleophilic fluorine, the least sterically hindered alcohols are displaced onarange of complex molecules.

Figure 67

(A) Three different dirhodium catalysts reveal three different selective functionalizations of 454. (B) Application of these rhodium carbenoid reactions towards other natural products results in similar observed selectivitles.

Figure 68

(A) Site-selective bromotrifluoromethyoxylation of taxol derivative 478. (B) Selective reactions on other natural products. (C) The structure of (DHQD)₂PHAL (476). (D) Proposed mechanism for the bromotrifluoromethoxylation. ^aUsing 2.0 equiv DBDMH

Figure 69

Site-selective cyclopropanation of alkene-containing natural products. Diazo esters derived Rh-carbenoids selectively react with electron rich olefins, while alkynyl sulfonium ylides prefer to add to electron-deficient alkenes.

Figure 70

Site-, regio-, and stereoselective nitroso Diels-Aider cycioaddition of rapamycin.

Figure 71

Molecules that have been the target for catalyst-controlled selective group transfer and oxidation chemistry.