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Aliphatic C—H Oxidations for Late-Stage Functionalization M. Christina White, and Jinpeng Zhao J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05195 • Publication Date (Web): 05 Sep 2018 Downloaded from http://pubs.acs.org on September 5, 2018
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Journal of the American Chemical Society
Aliphatic C—H Oxidations for Late-Stage Functionalization M. Christina White*, Jinpeng Zhao Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana—Champaign, Urbana, Illinois 61801, United States ABSTRACT: The atomistic change of C(sp3)—H to C(sp3)—O can have a profound impact on the physical and biological properties of small molecules. Traditionally, chemical synthesis has relied on pre-existing functionality to install new functionality, and directed approaches to C—H oxidation are an extension of this logic. The impact of developing undirected C—H oxidation reactions with controlled siteselectivity is that scientists gain the ability to diversify complex structures at sites remote from existing functionality, without having to carry out individual de novo syntheses. This perspective offers a historical view of why as recently as 2007, it was thought that the differences between aliphatic C—H bonds of the same bond type (for example, 2o aliphatic) were not large enough to distinguish them preparatively with small molecule catalysis in the absence of directing groups or molecular recognition elements. We give an account of the discovery of Fe(PDP)-catalyzed non-directed aliphatic C—H hydroxylations and how the electronic, steric, and stereoelectronic rules for predicting siteselectivity that emerged have affected a shift in how the chemical community views the reactivity among these bonds. The discovery that siteselectivity could be altered by tuning the catalyst [i.e. Fe(CF3-PDP)] with no changes to the substrate or reaction now gives scientists the ability to exert control on the site of oxidation on a range of functionally and topologically diverse compounds. Collectively, these findings have made possible the emerging area of late-stage C—H functionalizations for streamlining synthesis and derivatizing complex molecules.
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Introduction The impact of developing non-directed aliphatic C—H oxidation reactions analogous to those found in nature is substantial. Chemists gain the ability to diversify complex structures at sites remote from existing functionality for the purpose of changing physical and/or biological properties, without carrying out individual de novo syntheses. Prior to 20071, 2, the chemical community mindset was that the physical differences between aliphatic C—H bonds of the same bond type (for example, 2o C—H bonds) was too small to distinguish between them preparatively without a directing group or molecular recognition approach, vide infra. In 2018, there has been a paradigm shift and it is widely accepted that the electronic, steric, and stereoelectronic differences between aliphatic C—H bonds in complex molecule settings makes them susceptible to siteselective oxidations. The power of such late-stage functionalizations to rapidly change the properties of drugs is being recognized by programs in the pharmaceutical industry. This perspective will provide an accurate historical account on how the literature on C— H oxidations prior to 2007 shaped the mindset that such bonds were indistinguishable and our view on what led to the paradigm shift in thinking by 2018. Adding hydroxyl groups is a fast track to function. The atomistic change of transforming aliphatic C(sp3)—H bonds to C(sp3)—O can have a profound impact on the properties of molecules. The introduction of oxygen functionality into molecules alters their physical properties (solubility, polarity) and can significantly impact on their interactions with biomolecular targets. The precise positioning of oxidized functionality acting as hydrogen bond donors and acceptors in three-dimensional space enables small molecules to interact with specific protein sites and effect varying physiological responses. Several examples are shown in
Figure 1. A. Odor and taste H
H
H O
O [O]
[O]
H muguet terpene (odorless)
OH Lyral® (floral scent)
B. Pharmacology terpenes Bz
O
OH
O
Ph
(+)-valencene (orange taste)
N OH HO
HO
OH
O O H 2 OAc OBz
OH HO
Taxol® antiproliferative nonribosomal peptide OH OH HO
O
HO HN HO
O
O O
OH
H
CO2H ibuprofen drug
CYP2C9 cilofungin (echinocandin) OH antifungal
= oxygen functionality critical for biological activity installed by C—H oxidation via heme or non-heme iron enzymes.
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OH OCH3
OH N
HO
O
C. Metabolism
NH
O
N H
O O O
O
NHC(O)Ar O
6
O
erythromycin A antibacterial
NH
N
β-nootkatone (grapefruit taste)
polyketides O AcO
NH
O
H
HO
CO2H 2-hydroxyl ibuprofen rapidly cleared
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Figure 2. A. Directed versus non-directed approaches HO Me Me α Me Me
H
98 kcal/mol pKa ~ 50
LDA; MoO5(pyr)HMPA
O O
H Me
O
H
78%
H
96 kcal/mol pKa ~ 25 H Me O Me
Me
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Fe(PDP) H2O2, AcOH
O
Me
46%
H (1 equiv.)
Me
H Me
O O
H
Me H (+)-2-oxo-sclareolide
H (+)-sclareolide
B. Catalyst-controlled site-selectivity (R,R)-Fe(PDP) (2007) (SbF6)2 N N N
O
H
FeII
Approach Trajectories NCMe Cone = 145º
NCMe
O O
H
OH
H 10
Fe(PDP)
H
O
O
O O
H2O2, AcOH
Fe(CF3-PDP)
H
O
O
54% yield
(1 equiv.) (+)-artemisinin
O
9
N
H
O
H 93 kcal/mol
O
O O
N N
O
O Me
H
OR
52% yield
O
HO
O
R = C(O)CH2Cl OH Me
6
7
H
NMe
N Ns
H N O
N
NCMe Approach
Trajectories
NCMe Cone = 76º
F3C
TfO NH
FeII
CF3
CF3
C. Late-stage oxidation of natural product derivatives (yield based on 1 equiv. substrate) steroids terpenes HO N O O Me O 11 O O H O 12 10 Me OAc H O Me O HO 2 H H H H 3 H O H AcO Me O H H OH (-)-terpenoid (-)-manool nectaryl (+)-abiraterone derivative (-)-dihydropleuromutilone derivative derivative derivative 45% yield 81% yielda 62% yieldc 42% yieldd 66% yieldb alkaloids peptides amides O
(SbF6)2
F3C
H
H2O2, AcOH
O
N H
(R,R)-Fe(CF3-PDP) (2013)
96 kcal/mol H H 98 kcal/mol H
Me
O N H
H O
O
N H Me
AcO
OH
H O
O
O OAc
(-)-triacetoxytricalysiolide B 61% yield HO O S Me
H N
O
H
CO2Me
AcO
N
Me O O
HO (+)-sulbactam (+)-finasteride tripeptide Ns-P-L-A-OMe derivative derivative derivative 55% yield 32% yield over 3 steps 54% yield (gram scale) (68% yield per step) a2:1 C2:C3 ratio. b6:1 C10/12:C11 ratio. c2:1 alcohol:ketone ratio. d6:1 alcohol:ketone ratio. e2.5:1 C7 ketone:C6alcohol ratio. Panel A sclareolide α-oxidation: ref 53c. (+)-streptovitacin A derivative 50% yield
(+)-dextromethorphan derviative 45% yielde
Figure 1 where installation of a ketone or hydroxyl moiety can change the smell or taste of a small molecule.3 In the pharmaceutical realm, oxygen moieties in drugs can be essential for the physiological response. For example, in the drugs paclitaxel (Taxol®), erythromycin A, cilofungin, and ritonavir, removal of the benzoate or key hydroxyl moieties results in either complete or partial loss of the desired biological activity.4 Introduction of hydroxyl moieties is also critical in metabolic processes that clear drugs from our bodies.5 Aliphatic C—H hydroxylation: nature’s way. Carbon-oxygen is a versatile functionality: it may be elaborated into other common functional groups (N, S, C) or further derivatized (e.g. sugars, phosphates). Traditional synthetic approaches rely on pre-existing functional groups on molecules to install new functionality. What strategic advantages exist in installing oxygen via C—H hydroxylation? Nature has evolved C—H hydroxylation reactions using heme and non-heme iron enzymes [e.g. cytochrome P-450 (CYP), a-ketoglutarate dependent oxygenases] that install oxygen functionality independently and remotely from existing functionality. In
the biosynthesis of the natural product drugs, such enzymes are used to install key hydroxyl groups for biological activity in the final structure (Figure 1B). In echinocandin B, non-heme and heme iron enzymes (Ecd-G, Ecd-H) perform aliphatic C—H oxidations in both free L-homotyrosine and the assembled macrocyclic peptide (at ornithine).6 In the biosynthesis of erythromycin, the C-6 hydroxyl moiety, key for medicinal potency, is installed onto the 6deoxyerythronolide B (6-dEB) core via a designated P-450 (EryF) at late stages of the synthetic sequence.7 In the metabolism of ibuprofen, a liver CYP2C9 mediates C—H hydroxylation at C2 that leads to its rapid clearance from the body.5 Non-directed aliphatic C—H oxidation. The strength and ubiquity of aliphatic C—H bonds (pKa ~ 50, BDE ~96-101 kcal/mol8) in complex molecules renders them among the most challenging bonds to selectively oxidize. Despite sporadic use prior to 2007, C—H oxidation reactions and their strategic use in chemical synthesis was largely overlooked by the synthetic community. Although we and others had begun to delineate the strategy of latestage oxidation for streamlining and diversifying chemical synthe-
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Journal of the American Chemical Society
sis,9 preparative and selective aliphatic C—H oxidation reactions did not exist to fully demonstrate the power of this strategy. In support of this, C—H oxidation and the associated streamlining logic does not appear in prominent textbooks10 on total synthesis prior to 2007. The majority of 20th century examples were of TFDO oxidations at tertiary sites on steroids (vide infra, Figures 4). The lack of substrate structural diversity, the operational difficulty of the oxidant, and paucity of rationale for site-selectivities in part explains why prominent reviews in 2007 and 2006 stated that differences between aliphatic C—H bonds was not large enough to achieve useful levels of site-selectivity: "…there is very little differ-
ence in reactivity between the various C—H bonds in alkanes, so targeting a specific C—H bond is difficult”1 and “Selective targeting of internal isolated sp3 C—H bonds in complex targets has hitherto been limited to enzymatic or biomimetic systems equipped with a recognition element capable of arranging the C— H bond of interest and the reactive center in proximal and favorable orientation. At present, it seems that the reactivity differences between isolated alkyl C—H bonds (e.g., two adjacent methylenes in the middle of a long alkyl group) are very small to tackle this problem in the absence of a molecular recognition element.”2 A report came in 2007 from our group of [Fe(PDP)] catalysis capable of predictable, site-selective aliphatic C(sp3 )—H oxidations among 3o C—H bonds remote from existing functionality in complex natural products.11 This was followed by a report in 2009/2010 demonstrating that even the most challenging secondary C(sp3 )—H bonds can similarly be site-selectively oxidized.12 A third report in 2013 showed that the site of oxidation can be rationally altered by modifying the catalyst.13 Through these studies, we elucidated that C—H bonds can be predictably differentiated by catalysts based on their electronic, steric, and stereoelectronic properties. This fundamental insight led to a quantitative model that enables the site of oxidation to be predicted in complex settings as a function of the catalyst.13 Fe(PDP) catalysis has now been demonstrated to effect preparative, predictable late-stage oxidations in a range of complex molecules derived from nature- terpenes, steroids, alkaloids,14 peptides,15 lactams16 - at strong aliphatic C—H bonds remote from functionality (Figure 2). Whereas it was known that site-selectivity could be achieved between different C—H bond types (for example, 3o versus 2o, 1o versus 2o /3o, vide infra, Figures 4, 5, 21), the Fe(PDP) work caused a shift in the community’s thinking on the ability to achieve selectivity among the same type of aliphatic C—H bond.17 Additionally, Fe(PDP)-oxidations first demonstrated that such siteselectivities can furnish preparative amounts of mono-oxidized products and follow easy rules that predict the oxidation site in complex molecules. These aspects of Fe(PDP) catalysis contrasted prior reactions run with large excesses of substrate, furnishing
