Adding Aliphatic C-H Bond Oxidations to Synthesis

Author(s): M. Christina White

Source: Science , 17 February 2012, New Series, Vol. 335, No. 6070 (17 February 2012),
pp. 807-809
Published by: American Association for the Advancement of Science

Stable URL: https://www.jstor.org/stable/41487270

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 PERSPECTIVES I

them from increasing to high frequencies.
Furthermore, some have already been asso-
ciated with severe human diseases, support-
ing the less-is-less hypothesis. Other LoF
variants, which can reach higher population
frequencies, fall into poorly evolutionarily
conserved genes or belong to multigene fam-
ilies displaying high paralogous sequence
genetic variants (and the epistatic interac- 7. K. Pela к et al., PLoS Genet. 6, elOOllll (2010).
tions among them) and environmental vari- 8. S. В. Montgomery, E. T. Dermitzakis, Nat. Rev. Genet. 12,
277 (2011).
ables to variation in organismal traits (see 9. S. В. Montgomery et al., Nature 464, 773 (2010).
the figure). 10. ]. К. Pickrell et al., Nature 464, 768 (2010).
11. A. S. Dimas et al., Science 325, 1246 (2009).
References 12. ]. E. Powell et al., Genome Res.; lO.llOl/gr.126540.111
(2011).
1. The 1000 Genomes Project Consortium, Nature 467,
13. L. B. Barreiro et al., Proc. Natl. Acad. Sci. U.S.A. 109,
1061 (2010).
2. C. Stewart et al., PLoS Genet 7, el002236 (2011).
1204 (2012).

identity. This suggests that the functions of 3. P. H. Sudmant et al., Science 330, 641 (2010). 14. E. Choy et al., PLoS Genet. 4, el000287 (2008).
15. ]. C. Maranville et al., PLoS Genet. 7, el002162 (2011).
the corresponding genes are highly redun- 4. D. G. MacArthur et al., Science 335, 823 (2012).
5. M. V. Olson, Am. J. Hum. Genet. 64, 18 (1999).
dant, explaining their greater tolerance for
6. P. C. Ng et al., PLoS Genet. 4, el000160 (2008). 10.1126/science.l219299
LoF variants and supporting a less-is-noth-
ing scenario. Also, although no substantial
enrichment in positive selection signals was
CHEMISTRY
observed among LoF variants at the genome-
wide level, 20 of them fell into regions dis-
playing signatures of positive selection, as
predicted by the less-is-more hypothesis, Adding Aliphatic C-H Bond
suggesting that they may have conferred a
selective advantage in human evolution.
The key question is whether LoF vari-
Oxidations to Synthesis
ants and other variants located both in cod- M. Christina White
ing and noncoding regions of the genome
have a true impact on human phenotypes. Oxidations of aliphatic C-H bonds, known since the 1800s, have only recently been consid
The study of the relationship betweenuse in organic synthesis.
genetic variation and intermediate molecu-
lar phenotypes, such as expression quantita- strate (generally solvent quantities), gener-
tive trait loci, offers new functional insights least reactive in organic chemis- ated <1% oxidized products, and showed
into the etiology of complex human traits Aliphatic try, least yet try, reactive
yet enzymesenzymes C-Hthatbonds in have organic are evolved among chemis- that the
have evolved unexplained and/or inconsistent site selec-
and diseases ( 8 ). Genetic variants located not only oxidize them, but can discriminate tivity trends (see the figure, panels A and
in regulatory regions across the genome between individual tertiary (3°) and second- B). For example, C-H hydroxylations with
control gene expression (9, 70), but theirary (2°) C-H bonds in complex molecules. iron porphyrin catalysts like 1 showed poor
effects are not straightforward ( 8 ). Indeed,Chemists considered reactivity differences yields and minor, unexplained site selectivi-
their impact on gene expression can differbetween these inert bonds too minor for a ties for oxidizing the most distal sites from
between cell types and tissues ( 8 , 77, 72).small-molecule catalyst to discriminate (7); the electron-withdrawing group on sub-
Even in the same cell type, genetic variantsbio-inspired catalysts with intricate binding strates (6). Stoichiometric organic oxidants
can modulate gene expression differentlypockets were thought to be the only viable such as methyl(trifluoromethyl)dioxirane
depending on the presence or absence ofsolution (2). This view pervaded because the (TFDO) (8) oxidized 3° C-H bonds in select
external stimuli, such as drugs or infectiousreported examples of selective aliphatic C-Hsubstrates, such as steroids, in good yields
agents (13-15). Mac Arthur et al. provideoxidations [halogenations (3), alkylations ( 4 ), (see the figure, panel F). However, the oper-
a glimpse of this by studying how a frac-animations (5), hydroxylations (6), and dehy- ational difficulty of generating stoichiomet-
tion of LoF variants affect gene expression,drogenations (7)] were not sufficiently high inric amounts of perfluorinated reagents -
and show that a minority are associated withyield or predictable in site selectivity to be use- and, in the case of TFDO, rapid decomposi-
reduced expression of the correspondingful in synthesis, except in some special casestion under ambient conditions (temperatures
gene. The intricate relationships observedsuch as steroids (see below). In the past severalabove -20°C and visible light) to reactive
between genetic variation and gene expres-years, however, aliphatic C-H oxidations and free radicals (to form -CH3 and *CF3) - lim-
sion emphasize the complex ways in whichsimple rules for predicting their selectivities ited their reproducibility and use (9).
genotypic variation may underlie pheno-have been emerging prominently in synthetic In certain cases, higher reactivity and
typic consequences at the physiological or planning. Powerful small-molecule catalystscontrol of site selectivity were obtained
pathological levels. have been invented that furnish high enough for intramolecular reactions (see the fig-
Whole-genome sequencing data from yields (>50%) to be preparatively useful andure, panel C). Substrate tethers that gener-
diverse human populations exposed to dif-can predictably discriminate between aliphaticated carbene or nitrene species upon react-
ferent environments and presenting differ-C-H bonds even within complex moleculesing with oxidant and rhodium (Rh) catalysts
ent life-styles will provide a realistic pic-that have many possible sites of oxidation. led to powerful reactions in synthesis for
ture of the extent of human genetic varia- In contrast to these newest methods, theC-H alkylations (70, 77) and aminations
tion, including low-frequency and popula-majority of earlier intermolecular transfor- (72). Substrate-directed metalations with
tion-specific variants. Such information,mations were run with large excesses of sub- palladium furnished reactions for acetoxyl-
combined with epigenomics, transcrip- ation and iodinations (13, 14). For carbene
tomics, and proteomics data from the sameDepartment of Chemistry, Roger Adams Laboratory, Univer- and nitrene insertion reactions, the rank
individuals and from different cell types,sity of Illinois, Urbana, IL 61801, USA. E-mail: white@scs.order of reactivity between different C-H
will help to determine the contribution of uiuc.edu
bond types (for example, 2° versus 3° ali-

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PERSPECTIVES

a stable organocatalyst 3 was also reported

that used AcOH and H202 for the preparative
hydroxylation of 3° aliphatic C-H bonds (18).
Rules that reliably predict site selectivi-
ties of oxidation are crucial for such reactions
to be adopted into late-stage synthetic plan-
ning, where C-H oxidations are most strate-
gically powerful (19). With preparative utility
achieved under Fe(PDP) catalysis, systematic
studies could now be performed on simple
substrates designed to test individually the
effects of electron-withdrawing groups, steri-
cally bulky groups, and stereoelectronic acti-
vating groups on the site selectivity of oxi-
dation among C-H bonds of the same rela-
tive bond strengths [2° or 3° ( see the figure,
panel E)]. Using the highly electrophilic,
bulky oxidant generated with Fe(PDP) and
H202, electron-withdrawing functionality on
the substrate could effectively prevent oxida-
tion even at remote sites (up to four carbons
away), and steric bulk on the substrate could
shield proximal sites from oxidation. Addi-
tionally, Fe(PDP) could be directed to oxidize
sites that were activated through stereoelec-
tronic effects, such as hyperconjugative acti-
vation and relief of 1,3-diaxial interactions
and torsional strain.
Perhaps the most important finding with
Fe(PDP) was that the same selectivity rules
Aliphatic C-H bonds as a new functional group in synthesis. The emergence of reactions with preparative
that
utility and rules for predictable selectivity in aliphatic C-H bond oxidations is illustrated. Unless otherwise govern the differential reactivity of 'tra-
noted,
one equivalent of substrate is used, and the C-H functionalization site is shown with a yellow circle. (A ditional"
and B) functional groups (i.e., electronics,
sterics,
Intermodular aliphatic C-H bond reactivities and site selectivities for (A) hydroxylations [Ac = acetyl, Fe(TPP)Cl and stereoelectronics) also govern
the reactivity
1 = iron tetraphenylporphyrin chloride; selectivities using FePPIX-DME = ferriprotoporphyrin(IX) dimethylester] of relatively inert C-H bonds
and (B) alkylations (Et = ethyl); yields are based on gas chromatography (GO. (0 Intramolecular alkylation with
(15-17). The generality of these predictable
improved reactivity and different site selectivity (Me = methyl). (D) Newer examples of intermolecular aliphatic
selectivity rules for other electrophilic, bulky
C-H hydroxylations that achieve high yields, site selectivity, and stereoretention (Piv = pivaloyl). (E) Examples
oxidants has now begun to emerge (18, 20).
of how selectivity rules predict reaction sites in hydroxylations with Fe(PDP) (EWG = electron-withdrawing group;
Many of the earlier examples of selectivity
ř-Bu = tert- butyl). (F) A 20th-century example of C-H oxidation in a steroid substrate. (G) New catalysts enable
selective intramolecular C-H aminations [using Rh2(HNCOCF3)J and alkylations for synthesis of complex alka-
can now be easily, retrospectively, rational-
loids such as tetrodotoxin (bonds formed shown in red). For example, in the alkylation, "complex mixtures" ized with these rules (21).
resulted with Rh2(OAc)4 catalyst, whereas only desired product was seen with Rh2(HNCOCPh3)4 (Ph = phenyl).It(H)
was uncertain whether the reactivity and
selectivity
Intermodular hydroxylations of complex terpenes made possible with Fe(PDP); the 3° case is artemisinin and the observed with simple substrates
2° case is dihydropleuromutilone (C-7 oxidation: 42% hydroxyl, 20% ketone). would translate over a range of complex-
molecule settings. In addition to many more
phatic) was delineated for intramoleculardations would diminish their site selectivity. possible sites of C-H oxidation for inter-
reactions; however, factors governing selec- Preparatively useful intermolecular reac- molecular reactions, the presence of dense
tivities among one bond type (for example, functionality and topological complexity
tions are still lacking for many types of ali-
2° aliphatic) were unclear. Moreover, these phatic C-H oxidations. However, in 2007,on it a substrate can markedly retard reaction
"bond type" selectivities were often incon- was shown that a nonheme, nitrogen-coordi- rates and erode selectivities. The majority of
nated iron catalyst, Fe(PDP) 2, enabled pre-
sistent. For example, selectivities for inter- 20th-century examples of intra- and inter-
molecular Rh-carbene insertion into the parative hydroxylations of aliphatic 3° C-H molecular aliphatic C-H oxidations in com-
less sterically hindered 2° versus 3° C-H bonds (75). One equivalent of substrate couldplex-molecule settings were limited to ste-
bond conflict with those reported for an be reacted with Fe(PDP), acetic acid (AcOH), roids (see the figure, panel F). For example,
analogous intramolecular reaction (see the and hydrogen peroxide (H202) under ambi- with weaker organic oxidants such as TFDO,
figure, panels В and C) ( 4 , 11). The lack ent conditions to furnish >50% isolated yields
where competing 2° oxidation is not an issue,
of systematic studies on selectivity effects of mono-oxidized products (see the figure, intermolecular reactions showed a striking
suggested that examples of site selectivity panel D). Fe(PDP) was later shown to cata- preference for oxidation at the C-25 3° C-H
were anomalous, rather than a general reac- lyze preparative oxidations of 2° aliphatic bond of the C- and D-ring side chain across a
tivity trend. Moreover, it was thought that C-H bonds, arguably the most difficult C-H range of A and В rings (8). However, the priv-
attempts to boost yields in the remarkable bonds to oxidize selectively because of theirileged nature of the steroid core (highly rigid
cases of intermolecular aliphatic C-H oxi- and sparsely functionalized) and conflicting
bond strength and ubiquity ( 16 , 1 7). In 2009,

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 PERSPECTIVES I

rationales given for selectivities (sterics and In essence, C-H bonds have emerged as 7. R. H. Crabtree et al.,;. Am. Chem. Soc. 101, 7738 (1979).
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Newer methods have provided extraordi- for reactivity in a synthetic sequence. Many J. Am. Chem. Soc. 113, 7654 (1991).
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(1986).
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of the alkaloid tetrodotoxin, selective intra- ence of more electron-rich functional groups Organic Reactions (Wiley-VCH, Weinheim, Germany,
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17. M. S. Chen, M. C. White, Science 327, 566 (2010).
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one equivalent of substrate could be used to Soc. Chim. Belg. 93, 945 (1984). 21. T. Newhouse, P. S. Baran , Angew. Chem. Int. Ed. 50, 3362
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EVOLUTION

Contemplating the First Plantae What characterized the first photosynthetic

eukaryotes?
Frederick W.Spiegel

rium, the chimera is said to be the product of mera became the sole ancestor to the eukary-
otes such as plants and algae contain primary endosymbiosis. If the colonizer was a otic supergroup Plantae (or Archaeplastida),
The organelles, otes cells such
organelles, calledofplastids
as calledor chloro-
photosynthetic plants plastids and algae or eukary- contain chloro- photosynthetic eukaryote, the chimera is the which contains the glaucophytes, red algae,
plasts, responsible for photosynthesis. Plas- product of secondary or higher-order endo- and land plants and green algae. Alterna-
tids contain some DNA, a vestige of their ori- symbiosis (2, 3). Because of their complex tive "non-Plantae" hypotheses suggest that
gin from free-living cyanobacteria. On page genetic histories, the relationships among chi- the cyanobacterium that was ancestral to the
843 of this issue, Price et al. (7) use compara- meric organisms can be difficult to interpret plastids of glaucophytes, red algae, and land
tive genomics with the obscure algal protist, (3). It can also be challenging to infer relation- plants and green algae must have colonized
Cyanophora paradoxa , to propose a reso- ships between photosynthetic eukaryotes and different protists more than once (4-7).
lution to the question of how plastids have their closest relatives that never had plastids. Acceptance of the Plantae hypothesis
spread through the eukaryotes. By under- Phylogenetic data suggest that all plastids requires that Plantae be monophyletic and
standing the implications of their results, we in today's photosynthetic eukaryotes can be that it cannot include any secondarily photo-
may be able to picture the overall characteris- traced back to just two different cyanobac- synthetic algae or any primitively plastid-fřee
tics of the very first alga. terial colonizers (3). One of these coloniz- eukaryotes. In other words, a well-supported
In recent decades, it has become clear that ers led to the primary plastids in the photo- phylogeny must show that only the glauco-
photosynthetic eukaryotes rose through endo- synthetic amoeba Paulinella (3), but this is phytes, red algae, and land plants and green
symbiosis (2, 3). In this process, a eukaryotic not the focus of Price et al ., who investigate algae evolved from one chimeric ancestor.
cell becomes inhabited by a photosynthetic primary endosymbiotic events thought to To test this hypothesis, Price et al. com-
cell. A complex set of events ensues, includ- have occurred more than a billion years ago. pare genomes from the most complete set of
ing transfer of genes from the colonizer's Today's Glaucophyta (-13 species, includ- photosynthetic eukaryotes to date. They pro-
genome to the host's nuclear genome. This is ing C. paradoxa ), red algae (~6000 spe- vide a number of independent lines of evi-
followed by the evolution of mechanisms that cies), and green algae and land plants (over dence, including data about genes that are
allow proteins encoded by these transferred 300,000 species) all have primary plastids independent of the plastids. All their data
genes back into the colonizer so that it can descended from one cyanobacterial ances- strongly support the Plantae hypothesis.
still photosynthesize. The result is a chimeric tor (7, 2). All other eukaryotic algae have The glaucophytes are the most species-
organism in which the colonizer has become secondary or higher-order plastids derived poor Plantae. Many phylogenies show them
the plastid. If the colonizer was a cyanobacte- from either red or green algae (7-5). The data branching most basally in Plantae, that is,
have been equivocal as to how many times diverging before the separation of the reds
Department of Biological Sciences, SCEN 601, 1 Uni-
that cyanobacterium colonized eukaryotic and the greens (2). In such cases, we often
versity of Arkansas, Fayetteville, AR 72701, USA. E-mail: hosts. According to the Plantae hypothesis, have a careless tendency to think of the
fspiegel@uark.edu it entered only one protist; the resulting chi- species-poor branch as "primitive" in all

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