A general catalytic β-C-H carbonylation of aliphatic amines to β-lactams

Article abstract of DOI:10.1126/science.aaf9621

Methods for the synthesis and functionalization of amines are intrinsically important to a variety of chemical applications. We present a general carbon-hydrogen bond activation process that combines readily available aliphatic amines and the feedstock gas carbon monoxide to form synthetically versatile value-added amide products. The operationally straightforward palladium-catalyzed process exploits a distinct reaction pathway, wherein a sterically hindered carboxylate ligand orchestrates an amine attack on a palladium anhydride to transform aliphatic amines into β-lactams. The reaction is successful with a wide range of secondary amines and can be used as a late-stage functionalization tactic to deliver advanced, highly functionalized amine products of utility for pharmaceutical research and other areas.

Full text of DOI:10.1126/science.aaf9621

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ized and synthetically versatile small-molecule
lactam building blocks; second, by obviating
the need for nitrogen-protecting or auxiliary
groups, the number of synthetic steps required
to access functional amines is greatly reduced;
third, C–H carbonylation directed by free-NH
amine motifs in pharmaceutical agents or natural
products could be used as a potentially powerful
late-stage functionalization approach to analog
synthesis.
ORGANIC CHEMISTRY
A general catalytic b-C–H
carbonylation of aliphatic amines
to b-lactams
Carbon monoxide (CO) is an abundant chemical
feedstock, and metal-catalyzed carbonylation
reactions are integral to the laboratory- and
manufacturing-scale synthesis of chemical products.
Most of these processes involve CO binding to a
metal to form a metal-carbonyl complex with
well-established reactivity (28). Recently, our
group described a sterically controlled C–H ac-
tivation strategy for carbonylation of free-NH
aliphatic amines (26). Highly hindered amines,
displaying fully substituted carbon atoms on
either side of the nitrogen motif, underwent C–H
carbonylation to yield b-lactams (Fig. 2A). A
key factor in the success of this strategy was
the sterically induced destabilization of the
readily formed bis(amine)-Pd(II) complex, re-
sulting from a clash between the two highly
hindered amines, which shifts the equilibrium
toward a mono(amine)-Pd(II) species required
for C–H activation. The anticipated pathway for
these amine-directed reactions had been based
on seminal studies by Fujiwara and colleagues
(29), who outlined a mechanistic blueprint that
has underpinned most subsequent directed C–H
carbonylation reactions with Pd(II) catalysts:
In our case, amine-directed cyclopalladation of
the C–H bond formed a four-membered ring
complex and was followed by coordination of
CO, 1,1-migratory insertion to an acyl-Pd spe-
cies, and reductive elimination to generate the
carbonyl product. However, when the same re-
action concept was applied to more commonly
encountered, less hindered amines, the reaction
failed or was low-yielding and resulted in oxida-
tive degradation and acetylated amine products
(Fig. 2A). Furthermore, we were not able to ob-
serve any trace of the corresponding four-
membered-ring cyclopalladation complex, in
contrast to the case for reactions with the hin-
dered amine counterparts. Indeed, we calculated
that a transition state for four-membered-ring
cyclopalladation on these less hindered amines
was too high to be a realistic pathway (30). On
the basis of these observations, we reconsid-
ered the classical mechanism for C–H carbon-
ylation. CO is a strongly binding ligand, and it
is perhaps surprising that it does not interact
with the Pd catalyst before C–H activation. More-
over, Pd(OAc)2 (Ac, acetate group) and CO display
contrasting redox properties, and their com-
bination predictably leads to catalyst reduction,
which can complicate a catalytic process. In-
trigued by the apparent paradox of the redox
properties of the reagents, we became inter-
ested in the mechanism of CO-mediated reduc-
tion of Pd(OAc)2, outlined in Fig. 2B. Although
little is known about this pathway, studies by
Darren Willcox,* Ben G. N. Chappell,* Kirsten F. Hogg, Jonas Calleja,
Adam P. Smalley, Matthew J. Gaunt†
Methods for the synthesis and functionalization of amines are intrinsically important to
a variety of chemical applications. We present a general carbon-hydrogen bond activation
process that combines readily available aliphatic amines and the feedstock gas carbon
monoxide to form synthetically versatile value-added amide products. The operationally
straightforward palladium-catalyzed process exploits a distinct reaction pathway, wherein
a sterically hindered carboxylate ligand orchestrates an amine attack on a palladium
anhydride to transform aliphatic amines into b-lactams. The reaction is successful with a
wide range of secondary amines and can be used as a late-stage functionalization tactic to
deliver advanced, highly functionalized amine products of utility for pharmaceutical
research and other areas.
he preparation and functionalization of
amines is fundamental to a variety of chem-
ical applications, such as the synthesis of
medicinal agents, biologically active mole-
cules, and functional materials (1). The best-
polar functional groups such as carboxylic acids
(16, 17), heteroarenes (18), and hydroxyl func-
tionalities (19); aliphatic hydrocarbons containing
the free-NH amino group, however, continue to
cause problems that restrict wider application (20).
A number of factors can be identified that im-
pede the development of free-NH aliphatic amine–
directed C–H activation with catalysts such as
Pd(II) salts (Fig. 1B): The high affinity of a free-NH
amine for Pd(II) salts leads to the formation of
stable bis(amine)-Pd complexes and can preclude
catalysis; b-hydride elimination pathways often
lead to oxidative degradation of the amine and
catalyst reduction; and other polar functional
groups can compete with the amine for coordi-
nation to the Pd catalyst, leading to poorly re-
active or unselective systems. As a result, successful
aliphatic amine–directed C–H activation typically
requires the nucleophilicity of the nitrogen atom
to be modulated by strongly electron-withdrawing
protecting groups (21), directing auxiliaries (22–25),
or an intensified steric environment around the
NH motif (26, 27). Despite the success of these
methods, the additional functional and structural
features that need to be incorporated into the
amine framework for successful C–H activation
can sometimes preclude downstream operations.
Taken together, the limitations of current meth-
ods give weight to the appeal of a free-NH ali-
phatic amine–directed C–H activation process
(Fig. 1A). Here we report the development of a
general process for the catalytic C–H carbonyla-
tion of aliphatic amines, wherein readily available
unprotected amines are combined with carbon
monoxide to generate b-lactams. The design of
a reaction pathway for C–H carbonylation con-
trolled by a sterically hindered carboxylate ligand
was crucial in overcoming the incompatibility of
free-NH aliphatic amines and Pd(II) catalysts.
There are a number of specific advantages of this
method: First, readily available aliphatic amines
can be directly converted into highly functional-
T
established methods for amine synthesis involve
carbon-nitrogen bond–forming processes based
on alkylation (2), carbonyl reductive amination
(3), and cross-coupling (4–6). Although recent
advances in olefin hydroamination (7, 8) and
biocatalysis (9, 10) have further expanded the
toolbox of available transformations, the need
for functional amines keeps the development
of increasingly general catalytic reactions for
amine synthesis at the forefront of synthetic
organic chemistry. Inspired by the efficacy with
which these well-established methods produce
amines, we recognized the potential utility of a
general catalytic process capable of directly in-
troducing new functionality onto the framework
of readily accessible and simple amines. In par-
ticular, we envisioned that their union with car-
bon monoxide through a selective amine-directed
C–H carbonylation would produce a b-lactam fea-
ture, the versatile reactivity and biological rele-
vance of which would make the method valuable
to practitioners of synthetic and medicinal chem-
istry (Fig. 1A).
Transition metal catalysts capable of C–H
activation have inspired intense research ef-
forts within the synthetic chemistry commu-
nity (11–14). Although many advances have been
made in the field of aromatic sp2-hybridized
C–H [C(sp2)–H] bond activation, functionaliza-
tion of less reactive C(sp3)–H bonds in aliphatic
molecules continues to present a challenge (15).
Because of the lower reactivity of C(sp3)–H bonds,
their activation often relies on the proximity to
Department of Chemistry, University of Cambridge, Lensfield
Road, Cambridge CB2 1EW, UK.
*These authors contributed equally to this work. †Corresponding
author. Email: mjg32@cam.ac.uk
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Moiseev and colleagues (31) provided clues that
led us to propose a simplified model that we
supported through computation. Two mole-
cules of CO coordinate to monomeric Pd(OAc)2
(int-I) and a calculated Pd–C–O angle of 153.7°,
along with a bond distance between the car-
boxylate and CO of 2.06 Å, suggested an inter-
action between the two ligands. An attack on
one of these CO ligands by a neighboring car-
boxylate was energetically favorable, leading
to a Pd anhydride–type species, int-II. The tran-
sition state for this step (int-I to int-II) was
calculated to be +11.50 kcal mol−1 relative to
int-I. Coordination of a further CO (int-III)
could trigger an intermolecular attack of the
k1-bound acetate onto the distal carbonyl group
of the anhydride, causing the release of CO2,
acetic anhydride, and Pd(0). Motivated by the
potential reactivity of the putative Pd anhy-
dride int-II, we postulated that attack by an
amine on the proximal carbonyl would lead to a
carbamoyl-Pd species (Fig. 2C), from which C–H
activation would be possible. This unorthodox
cyclopalladation pathway would lead to C–H
activation two carbon atoms away from the
nitrogen group—distinct from classical cyclo-
palladation processes that usually result in ac-
tivation three carbons from the directing motif.
action was capricious and accompanied by the
formation of acetylated amine and oxidative deg-
radation products (entry 1). On the basis of our
mechanistic blueprint, we expected that the at-
tack on the Pd anhydride species at position a
would lead to CO2 release, reduction of the Pd
catalyst, and an acetylated amine side product
(Fig. 2B). We speculated that a larger carboxylate
would generate a sterically biased Pd anhydride,
steering the amine attack to position b to form
the carbamoyl-Pd species and precluding the de-
leterious reduction pathway. Accordingly, addition
of adamantanoic acid (AdCO2H) to the standard
reaction resulted in an increase in yield to 32%
(entry 2). A similar improvement was observed
when the original reaction was conducted in the
presence of benzoquinone (BQ) (entry 3) (34).
We found that the addition of both AdCO2H and
BQ resulted in a dramatic increase in yield, with
the b-lactam isolated in 65% yield (entry 4). The
addition of nitrogen-containing ligands, such as
quinoline 3a or quinuclidine 3b, enabled us to
lower the amounts of the other reagents (entries
6, 7, and 9) (35). We also found that other hin-
dered carboxylic acids were effective in the re-
action (entry 8). An optimized procedure thus
involved stirring a 0.1 M solution of amine 1a in
toluene with 10 mole (mol) % Pd(OAc)2, 10 mol %
Cu(OAc)2, 100 mol % BQ, 25 mol % adamanta-
noic acid, and 10 mol % 3a at 120°C under an
atmosphere of CO; this gave an 83% yield of b-
lactam 2a after isolation. To probe the nature of
the C–H activation step, we synthesized a deriv-
ative (4) of the proposed carbamoyl-Pd species
(Fig. 2E). Under conditions that would create a
similar chemical environment to the reaction (see
Fig. 2D, entry 10, where PPh3 is used as an addi-
tive), we showed that the b-lactam 2b could be
formed, albeit in low yield, supporting our hy-
pothesis that C–H activation can occur through
this carbamoyl-Pd intermediate (36).
A number of further preliminary mechanistic
experiments were conducted to ascertain the role
of the distinctive components of this C–H carbonyl-
ation process. First, we confirmed the importance
of the sterically bulky carboxylate by comparing
the reaction of the acetate- and adamantanoate-
derived bis(amine)-Pd(II) carboxylate complexes
(5a and 5b in Fig. 3A) in the presence of BQ
under a CO atmosphere; the yield of b-lactam from
the acetate complex (5a) was 25%, compared
with 89% from the adamantanoate complex (5b),
supporting our hypothesis of a sterically con-
trolled attack on the putative Pd anhydride
species (Fig. 3A). Second, we identified BQ as
essential for the high-yielding formation of 2a
from 5b: In its absence, the yield drops from 89
to 26%, suggesting that BQ may play a mech-
anistic role in the pathway beyond that of an
oxidant (35). Third, we deduced that although
quinoline 3a and quinuclidine 3b additives
increase the yield of b- lactam, they do not sub-
stantively affect the rate of the catalytic reaction.
Last, we observed a kinetic isotope effect of 1.14
from parallel reaction of 1a and d6-1a, suggesting
that C–H activation is not the rate-determining
step (Fig. 3B). A close inspection of the reaction
of d6-1a, using nuclear magnetic resonance (NMR),
revealed that hydrogen-deuterium scrambling
had occurred in the lactam product 2a at the
Reaction development and
mechanistic studies
To test our hypothesis, we reacted amine 1a un-
der anticipated conditions for C–H carbonyla-
tion (Fig. 2D) (32, 33). Although we observed the
desired product (b-lactam 2a) in low yield, the re-
Fig. 1. A strategy for the catalytic synthesis of functionalized aliphatic amines. (A) Hypothesis: Combining well-established amine synthesis with metal-
catalyzed C–H functionalization will lead to the rapid synthesis of functionalized amides. (B) Pd-catalyzed C(sp3)–H carbonylation of free-NH amines. A blue
circle or R denotes a general organic group. (C) The importance of b-lactams.
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methyl group and at the position adjacent to
the carbonyl of the amide. However, no hydrogen-
deuterium scrambling was observed in the re-
covered starting material d6-1a. These observations
indicate that C–H activation is reversible and
takes place after an irreversible step.
Taken together, these observations suggest a
catalytic cycle for this C–H carbonylation reaction
(30), which we have supported with a computa-
tional study of a simplified system using diisopro-
pylamine 1b and pivalic acid and without the
involvement of 3a or 3b (Fig. 3C). The process
begins with carboxylate exchange on Pd(OAc)2:
Coordination of the sterically hindered acid (RCO2H)
(R, t-butyl group) forms Pd(O2CR)2 or a mixed
carboxylate complex. Next, amine coordination
forms the mono(amine)-Pd(II) complex int-IV,
which is in equilibrium with the off-cycle bis(amine)-
Pd(II) complex (int-V); we deemed int-V, as the
catalyst resting state, to be the energetic ref-
erence point. CO binding then forms int-VI, from
which a viable transition state (TS1) to the Pd
anhydride complex int-VII was determined. On
the basis of our kinetic isotope effect and com-
putational studies, we suggest that the attack of
the amine at the internal carbonyl of int-VII (via
TS2) to form carbamoyl-Pd species int-VIII is
irreversible, and from this point, reversible C–H
activation takes place through a concerted metala-
tion deprotonation pathway (TS3) to form a five-
membered-ring cyclopalladation intermediate
int-IX (see also Fig. 2E). Last, BQ-assisted reduc-
tive elimination (via TS4) leads to b-lactam 2b
after decomplexation from Pd(0); oxidation of
the Pd(0) species with Cu(OAc)2 regenerates the
active Pd(II) species. The amine additives 3a and
3b may stabilize the Pd(0) species before oxida-
tion by preventing deactivating aggregation (37).
This effect may be more pronounced toward the
end of the reaction, when the concentration of
the amine substrate 1 is lower, and possibly ex-
plains why 3a and 3b have an effect on yield but
not on the rate of reaction.
Substrate scope with simple amines
Having established optimal reaction conditions
and validated a possible reaction mechanism, we
focused our efforts on establishing the scope of
the C–H carbonylation process. In setting a
benchmark, we targeted a substrate scope that
would encompass all structural classes of ali-
phatic secondary amines with respect to substi-
tution at the carbon atoms directly connected to
the free-NH group. We previously reported a C–H
activation strategy for fully substituted aliphatic
secondary amines that proceeds via four-membered-
ring cyclopalladation—a pathway distinct from
Fig. 2. Toward an activation mode for C–H carbonylation of unhindered
aliphatic amines. (A) Previous work: C–H carbonylation of hindered aliphatic
amines via a four-membered-ring cyclopalladation pathway (left) and poor-
yielding C–H carbonylation of less hindered amines (right). (B) Reduction of
Pd(OAc)2 by CO. (C) Design: A sterically controlled ligand-enabled C–H activation.
(D) Optimization studies. (E) C–H activation from a de novo carbamoyl-Pd com-
plex. Computational studies were conducted using Amsterdam Density Func-
tional software at the ZORA:BLYP-D3/TZ2P level with the COSMO solvation
model (PhMe) (supplementary materials). Ph, phenyl group; Me, methyl group;
Ac, acetate group; BQ, benzoquinone; Ad, adamantyl group; MesCO2H, 2,4,6-
trimethylbenzoic acid; DG, change in Gibbs free energy; TS, transition state; int,
intermediate; h, hours; equiv, equivalent.
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this process (26). However, the majority of amines
in everyday use are represented by less substi-
tuted variants. Each class of these amine starting
materials can be prepared by classical methods
of C–N bond formation, thereby linking the C–H
activation process to well-established prepara-
tive methods and reliable chemical feedstocks.
Figure 4 shows the wide breadth of the substrate
scope for this aliphatic amine C–H activation
process. We began by assessing amines with five
substituents around the nitrogen motif and found
that these hindered secondary amines were com-
patible with the reaction conditions and could be
efficiently converted into the corresponding b-
lactams in good yields (2c to 2i). In the case of
2d, classical amine-directed five-membered-ring
cyclopalladation could potentially lead to a g-
lactam product; however, only the product formed
via the new carbonylation pathway was observed.
Amines with an unsymmetrical arrangement
of four substituents around the NH motif also
worked very well in the C–H activation process
(2j to 2s). A variety of useful functional groups
were amenable to the reaction conditions, produc-
ing the b-lactam products in good yields. The
reaction with amines containing two substituents
on either side of the free-NH amine motif (2a, 2b,
and 2t to 2af) tolerated the incorporation of
protected hydroxyl motifs (2u and 2af), carbon-
yls (2w), and amine motifs (2ab, 2ad, and 2ae)
into the b-lactam products, providing opportu-
nities for downstream synthetic manipulations of
these valuable products. Pyridines (2y and 2z) and
thioethers (2ac) were tolerated as well, with no
adverse effects on regioselectivity or catalyst poi-
soning (38). The reaction of an N-aryl amine (to
2ag), however, was unsuccessful under these con-
ditions, and the starting material was returned
unchanged (39).
Having demonstrated that the reaction works
well on heavily substituted secondary amines, we
next sought to investigate the process with less
hindered substrates. These types of amines would
be expected to form stable bis(amine)-Pd(II) com-
plexes (compare with int-V, Fig. 3C), and their
high nucleophilicity suggested that selective at-
tack on the putative Pd anhydride complex might
be difficult to control. Additionally, each substrate
contains up to four C–H bonds that can readily
undergo b-hydride–elimination side reactions.
Despite these potential pitfalls, we found that a
range of amines with three substituents worked
very well in the C–H carbonylation (2ah to 2aq)
when the reaction was conducted using phenyl-
benzoquinone, a hindered variant of BQ that
prevents deleterious oxidative amination of the
quinone scaffold. A substrate with only unfunc-
tionalized alkyl groups worked well (2ah), demon-
strating that the success of the reaction is not
the result of remote functionality influencing
the reactivity. A variety of functional groups on
the amine substituents were tolerated, includ-
ing sulfones (2aj), esters (2ak), aromatic hetero-
cycles (2al), and alkenes (2an), producing the
b-lactams in high yields. Aliphatic heterocycles
were also competent substrates for this reac-
tion (2aq), thereby providing a simple method
by which to functionalize readily available
amine building blocks suitable for complex
molecule synthesis. Our C–H carbonylation even
produced unsubstituted b-lactam products from
unbranched secondary amines, albeit in lower
Fig. 3. Mechanistic evaluation of the C–H carbonylation reaction. (A) Stoichiometric studies. (B) Kinetic isotope effect (KIE) studies. (C) Proposed mech-
anism for C–H carbonylation of aliphatic amines. In the insets, blue is nitrogen, teal is palladium, red is oxygen, and light gray is carbon. Dotted lines indicate
breaking and forming bonds. Computational studies were conducted as in Fig. 2.
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yields (due in part to by-products formed from
N-acylation and b-hydride elimination) com-
pared with those from the other amine types
(2ar to 2as). As a whole, our scope studies
demonstrate that the C–H carbonylation reac-
tion tolerates a wide range of synthetic ver-
satile functional groups spanning more than 40
examples, highlighting the generality of this
transformation.
Therefore, a major benefit of our aliphatic amine
C–H carbonylation process is its potential amena-
bility to mid- and late-stage functionalization
applications (41). In more complex molecules, the
competition between numerous Lewis basic func-
tionalities capable of steering C–H activation
could cause deactivation or selectivity issues.
Application to complex molecules
Aliphatic amine motifs are present in at least 30%
of small-molecule pharmaceutical agents and are
heavily represented in preclinical candidates (40).
Fig. 4. The scope of the aliphatic amine C–H carbonylation. Yields of isolated products are shown. All compounds are racemic. Piv, pivaloyl group; Et, ethyl
group; Phth, phthalimido group; Cbz, carbobenzyloxy group.
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To test this, we prepared an amine (1at) with
three possible sites of C–H activation and found
that C–H carbonylation was directed by the ali-
phatic amine motif (to form 2at) without any
trace of the competitive pyridine-directed C–H
activation product (Fig. 5A). To further the
potential for late-stage functionalization, we sub-
jected a selection of pharmaceutical derivatives
and biologically active molecules to our C–H car-
bonylation protocol (Fig. 5B). Salbutamol and
propranolol are b2-adrenergic receptor agonists
and are representative of a huge range of mar-
keted pharmaceutical agents with a distinctive
secondary amino alcohol. Simple derivatives of
these molecules (6a and 6b) effectively underwent
C–H carbonylation to form b-lactams (7a and 7b)
in synthetically useful yields. A derivative of the
acute heart failure drug dobutamine (6c) reacted
smoothly to afford b-lactam in 72% yield (7c).
Fenfluramine (6d), part of an anti-obesity treat-
ment, was successfully carbonylated to yield a
separable mixture of regioisomeric b-lactams
(7d, 2.5:1), highlighting a moderate selectivity for
the branched methyl group. Last, C–H carbonyl-
ation on the aza-sterol 6e, an inhibitor of the
hedgehog-activating transmembrane protein
Smoothened (42), formed the b- lactam 7e in
useful yield, providing access to valuable analogs
of this molecule that would be difficult to obtain
by other means. A successful late-stage function-
alization program would require the delivery of
multiple analogs to get the maximum benefit from
the strategy; b-lactams support a rich array of
chemistry that can transform the amide func-
tion into pharmaceutically relevant motifs (43).
Removal of the hydroxyl-protecting group from
b-lactam 7b yielded alcohol 8, reductive ring open-
ing afforded b-amino alcohol 9, and esterification
yielded b-amino ester 10 (Fig. 5C). Under certain
reductive conditions, the b-lactam could be trans-
formed into azetidine 11, an important structural
feature that is common in many drug develop-
ment programs (Fig. 5C), underlining the diver-
sity of structural motifs readily available from
this aliphatic C–H activation tactic.
Outlook
We expect this general C–H carbonylation pro-
cess for aliphatic secondary amines to find broad
application among practitioners of synthetic and
pharmaceutical chemistry. In addition to the util-
ity of this protocol, we anticipate that the dis-
tinct reactivity of free-NH aliphatic amines in
combination with Pd catalysts will inspire further
advances in a range of C–H activation processes.
Moreover, this C–H carbonylation pathway is
conceptually distinct from classical cyclopalladation-
related approaches and may lead to opportunities
for C–H activation reactions in other classes of
functionalized aliphatic and aromatic molecules.
Fig. 5. Application to complex substrates. (A) Regioselective C–H activation in the presence of competing directing groups. (B) Late-stage C–H func-
tionalization on biologically active molecules. (C) Derivatizations of the b-lactam framework. TIPS, triisopropylsilyl; WHO, World Health Organization; Smo,
Smoothened (protein); TBAF, tetrabutylammonium fluoride; THF, tetrahydrofuran; dr, diastereoisomeric ratio; rr, regioisomeric ratio; rt, room temperature.
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REFERENCES AND NOTES
Council (EPSRC) (to D.W., K.F.H., A.P.S., and M.J.G.), the Herchel
Smith Trust (to B.G.N.C.), the Marie Curie Foundation (to J.C.), and
the Royal Society (Wolfson Merit Award to M.J.G.). Mass
spectrometry data were acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University. Computational
work was performed with the Darwin Supercomputer of the
University of Cambridge High Performance Computing Service
(http://www.hpc.cam.ac.uk/), provided by Dell, using Strategic
Research Infrastructure Funding from the Higher Education
Funding Council for England. The supplementary materials contain
1H and 13C NMR spectra and computational details. Crystallographic
data are available free of charge from the Cambridge
Crystallographic Data Centre under reference numbers
CCDC-1508626 to CCDC-1508631.
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ccording to detailed forecasts of future glo-
bal food demand, current rates of increase
in crop yields per hectare of land are in-
adequate. Prior model predictions have
suggested that the efficiency of the photo-
the photosystem II (PSII) antenna complex can be
harmlessly dissipated as heat, which is observable
as a process named nonphotochemical quenching
of chlorophyll fluorescence (NPQ) (3). Changes
in NPQ can be fast but are not instantaneous and
therefore lag behind fluctuations in absorbed
irradiance. In particular, the rate of NPQ relax-
ation is slower than the rate of induction, and
this asymmetry is exacerbated by prolonged or
repeated exposure to excessive light conditions
(4). This slow rate of recovery of PSII antennae
from the quenched to the unquenched state im-
plies that the photosynthetic quantum yield of
CO2 fixation is transiently depressed by NPQ
upon a transition from high to low light inten-
sity (Fig. 1). When this hypothesis was tested in
model simulations and integrated for a crop
canopy over a diurnal course, corresponding losses
of CO2 fixation were estimated to range between
7.5 and 30% (5–7). On the basis of these com-
putations, increasing the relaxation rate of NPQ
appeared to be a very promising strategy for im-
proving crop photosynthetic efficiency and in
turn yield (8).
A
synthetic process and thereby crop yield could
be improved (1). Here, we show improvement
of photosynthetic efficiency and crop productivity
through genetic manipulation of photoprotection.
Light in plant canopies is very dynamic, and
leaves routinely experience sharp fluctuations
in levels of absorbed irradiance. When light in-
tensity is too high or increases too fast for pho-
tochemistry to use the absorbed energy, several
photoprotective mechanisms are induced to pro-
tect the photosynthetic antenna complexes from
overexcitation (2). Excess excitation energy in
1Carl R. Woese Institute for Genomic Biology, University of
Illinois, 1206 West Gregory Drive, Urbana, IL 61801, USA.
2Institute of Plant Genetics, Polish Academy of Sciences,
Ulica Strzeszyńska 34, 60-479 Poznań, Poland. 3Howard
Hughes Medical Institute, Department of Plant and Microbial
Biology, 111 Koshland Hall, University of California Berkeley,
Berkeley, CA 94720-3102, USA. 4Molecular Biophysics and
Integrated Bioimaging Division, Lawrence Berkeley National
Laboratory, Berkeley, CA 94720, USA. 5Lancaster Environment
Centre, University of Lancaster, Lancaster, LA1 1YX, UK.
*These authors contributed equally to this work. †Corresponding
author. Email: niyogi@berkeley.edu (K.K.N.); slong@illinois.edu
(S.P.L.)
Although the exact NPQ quenching site and
nature of the quenching mechanisms involved
are still debated (9), it is clear that for NPQ to
occur, PSII-associated antennae need to undergo
a conformational change to the quenched state,
ACKNOWLEDGMENTS
We gratefully acknowledge funding from the European Research
Council and the UK Engineering and Physical Sciences Research
SCIENCE sciencemag.org
18 NOVEMBER 2016 • VOL 354 ISSUE 6314 857

A general catalytic β-C−H carbonylation of aliphatic amines to β
-lactams
Darren Willcox, Ben G. N. Chappell, Kirsten F. Hogg, Jonas
Calleja, Adam P. Smalley and Matthew J. Gaunt (November 17,
2016)
Science 354 (6314), 851-857. [doi: 10.1126/science.aaf9621]
Editor's Summary
CO takes the lead to make β-lactam rings
Strained β-lactam rings are a key feature of penicillin and some other drugs. Willcox et al.
designed a versatile route to these four-membered ring motifs through the palladiumcatalyzed coupling
of carbon monoxide with secondary amines. The bulky carboxylate ligand appears to facilitate
preliminary CO incorporation into a Pd anhydride, which is then attacked by the amine to set up ring
closure via C−H activation. This approach broadens the substrate scope compared with a previous
scheme in which C−H activation preceded CO insertion.
Science, this issue p. 851
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