Organic chemistry: Strain-release amination

Article abstract of DOI:10.1126/science.aad6252

To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.

Full text of DOI:10.1126/science.aad6252

RESEARCH
◥
synthesis of the parent amine 2, followed by
amide formation (11) or substitution chemis-
try (12), limiting the retrosynthetic analysis
of lead compounds such as 3 (13). The goal of
this work was to solve both of these issues by
(i) the invention of a process-friendly synthe-
sis of amine 2; and (ii) development of a route
to 1 that does not even require the intermedi-
acy of 2, bypassing conventional retrosynthetic
logic. Our strategy to address these challenges
was to embrace the innate reactivity of the
most strained C–C bond present in propellane
A (~60 kcal/mol are stored in this bond) (14)
by engaging it directly with an amine. This
concept was then extended to other systems
containing “spring-loaded” bonds (15, 16) as a
general tool to append small, cyclic bioisoteric
motifs (4 → 5–7, Fig. 1B). We describe the pre-
paration and use of convenient “strain-release
reagents” (such as A to C) to expand chemical
space for drug discovery: Specifically, the intro-
duction of motifs such as bicyclo[1.1.1.]pentanes,
azetidines, and cyclobutanes is delineated. The
exquisite chemoselectivity of this approach has
also been established, and initial applications
to the areas of peptide labeling and bioconju-
gation are reported (see below). This work lays
a foundation for the synthesis of new chemi-
cal entities, probe molecules, and clicklike
RESEARCH ARTICLE
ORGANIC CHEMISTRY
Strain-release amination
Ryan Gianatassio,1* Justin M. Lopchuk,1* Jie Wang,1 Chung-Mao Pan,1 Lara R. Malins,1
Liher Prieto,1 Thomas A. Brandt,2 Michael R. Collins,3 Gary M. Gallego,3
Neal W. Sach,3 Jillian E. Spangler,3 Huichin Zhu,3 Jinjiang Zhu,3 Phil S. Baran1†
To optimize drug candidates, modern medicinal chemists are increasingly
turning to an unconventional structural motif: small, strained ring systems. However,
the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines,
or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold
itself. Thus, there is an urgent need for general methods to rapidly and directly
append such groups onto core scaffolds. Here we report a general strategy to
harness the embedded potential energy of effectively spring-loaded C–C and C–N
bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry,
amines. Strain-release amination can diversify a range of substrates with a
multitude of desirable bioisosteres at both the early and late stages of a synthesis.
The technique has also been applied to peptide labeling and bioconjugation.
ystematic structural tuning of drug can-
didates, or leads, is an essential feature of
medicinal chemistry research. Exchang-
ing substituents that exhibit similar yet
distinct properties in biological environ-
house approach unsustainable (10). More glob-
ally, conventional preparations of substituted
bicyclo[1.1.1]pentan-1-amine 1 have required the
S
ments, termed “bioisosteres,” can address a myr-
iad of structural liabilities, circumventing issues
such as unwanted metabolic clearance. Such
structures also serve to combat the continued
challenge of narrowing intellectual property
space (1). These motifs can be rather unusual in
that they are often not found in natural products:
Fluoroalkyl groups (2, 3) and strained ring sys-
tems that include small spirocycles and bi-
cycles are examples (4). Interest in the latter
area was fueled by an ongoing program at
Pfizer (5), where difficulties in the synthesis of
bicyclo[1.1.1]pentan-1-amine (2, Fig. 1A) led
to the abandonment of a lead oncology clin-
ical candidate (6). Developments in the syn-
thesis of this strained motif date back to 1970
with Wiberg’s classic synthesis of 2 from
bicyclo[1.1.1]pentane in four steps via the in-
termediacy of bicyclo[1.1.1]pentan-1-carboxylic
acid (see fig. S1) (7). Although this pioneering
work allowed synthetic access to 2 and subse-
quent studies pointed to the counterintuitive
stability of A, many improvements were carried
out over the ensuing 46 years (8–10). All of these
reports required ≥3 steps to form amine 2 be-
cause of the need for multiple functional group
interconversions, rendering Pfizer’s current in-
1Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2Chemical Research and Development, Pfizer Worldwide
Research and Development, Eastern Point Road, Groton, CT
06340, USA. 3Department of Chemistry, La Jolla
Laboratories, Pfizer Inc., 10770 Science Center Drive, San
Diego, CA 92121, USA.
Fig. 1. Synthetic methods for incorporating small, strained ring systems. (A) Revisiting the
retrosynthetic disconnection of an important scaffold in medicinal chemistry, bicyclo[1.1.1]pentan-
1-amine. (B) Strain-release amination: “any-stage” functionalization of lead compounds in drug
discovery.
*These authors contributed equally to this work.
†Corresponding author. E-mail: pbaran@scripps.edu
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connections that rely on the native activation of
strained C–C bonds.
ing 9 in ~20% yield. The key breakthrough
was the finding that the corresponding turbo-
amide (20) (Bn2NMgCl•LiCl) led to clean for-
mation of 9 even on a >100 g scale. The use of
PhLi leads to reproducible, scalable, and clean
formation of propellane A. The dibenzyl group
was then easily removed, and the HCl salt of
2 was precipitated (30 g scale). This protocol
was successfully scaled up at an outsourcing
vendor and can now be used in a process set-
ting to deliver bicyclo[1.1.1]pentan-1-amine–
containing clinical candidates economically
on scale.
solution is stable for weeks to months at –20°C
or –78°C, respectively), the scope of this direct
“propellerization” was explored (Fig. 2B). Strain-
release amination of A using a variety of in
situ–derived turbo amides delivered a wide
range of tertiary amines containing the valu-
able bicyclo[1.1.1]pentane bioisosteric motif.
Figure 2 illustrates 29 different amines vary-
ing in complexity that can be easily accessed.
In cases when the reaction did not go to com-
pletion, the starting amine could be recovered
(e.g., 16, 24, 38). The method tolerates a
variety of functional groups, including acetals
(16), benzyl ethers (17), ketals (23), and Lewis-
basic groups (21, 22, 27, 28, 30–32, 37, 38).
Application of propellane
strain-release amination
As mentioned above, efforts in this area were
initiated on account of the practical difficul-
ties encountered at Pfizer in procuring large
quantities of bicyclo[1.1.1]pentan-1-amine 2
(Fig. 2A). The tendency of propellane A to
react with strong nucleophiles such as t-BuLi
and aryl Grignard reagents inspired our ap-
proach (17, 18). Extensive exploration (see table
S1) identified Davies-type amine nucleophiles
(Bn2N-Li) (19) as a good starting point, furnish-
With a reliable route to stock solutions of
propellane A (after codistillation with Et2O,
Fig. 2. “Propellerization” of amine-containing substrates. Isolated yields are reported. (A) An improved synthesis of the known bicyclo[1.1.1]pentan-1-
amine. (B) A general “propellerization” of amines enabled by strain-release reagents. (C) Substrate scope of amine-containing substrates.
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Late-stage incorporation of this challenging
bioisostere onto six different commercial drugs
(Fig. 2C, 33-38) obviated otherwise laborious
multistep sequences to access these analogs.
The use of turbo-amides is key to enabling the
“any-stage” functionalization of both simple
and complex amines with A. We anticipate that
the path to these bioisosteres will find imme-
diate and widespread use in medicinal chem-
istry. Indeed, this chemistry has already been
field-tested at Pfizer (for example, compounds
14, 15, 17, 19, 21, and 30 were prepared at
Pfizer for use in ongoing programs).
to azetidinylated products (42–59) that are
subsequently trapped with a variety of acylat-
ing agents to simplify isolation and handling
(free azetidines can be generated if desired).
Using this protocol, azetidines were directly
appended to 18 different amines varying in
complexity, including three pharmaceutical
agents.
butanes at 140°C (28, 29). In seeking a reagent
that would allow for more mild reaction con-
ditions and the use of the amine as a limiting
reagent, we synthesized a variety of substituted
phenylsulfonylated bicyclobutanes (C2 to C7,
Fig. 4) and evaluated them in a strain-release
amination with amine 39. Not surprisingly,
aryl sulfones containing electron-withdrawing
substituents were the most reactive, and the
addition of LiCl further accelerated the amina-
tion. Removal of the arylsulfonyl group could
be easily achieved in the same pot under mild
reductive conditions (Mg, MeOH). This proto-
col was applied to 16 diverse amines with the
use of reagent C7, including four commercial
drugs, to append the cyclobutyl group (Fig.
4B). The reaction of C7 is chemoselective for
amines in the presence of free hydroxyl groups;
71 could be prepared from 4-hydroxypiperidine
in 43% yield over three steps (see supplemen-
tary materials for details). The arylsulfonyl
group could also be used as a handle to gen-
erate other useful cyclobutane building blocks
containing deuterium (77), alkyl (78), fluo-
rine (79), and olefin (80) substituents. Strain-
release amination is not limited to the three
ring systems described here, as illustrated in
Fig. 4D, wherein cyclopentane (30) could be
easily appended to 1,2,3,4-tetrahydroisoquinoline
(81 → 83) and N-benzylpiperazine (84 → 85).
Given these collective findings, we antici-
pate that a wide range of strained C–C bonds
Introduction of cyclobutane via
strain release
Given the variety of medicinal contexts in which
cyclobutane derivatives have been enlisted (23),
we next explored a strain-release approach for
this motif. The goal was to generate a stable re-
agent that would enable both rapid and mild
“cyclobutylation” of amines but also permit fur-
ther functionalization of intermediate adducts.
Bicyclobutane and its substituted derivatives,
since their first preparation in 1959 (24), have
been the subject of many synthetic studies, most
of which either engaged the strained system
as a nucleophile or cleaved the center bond via
a transition metal–mediated process (25, 26).
Rather than pursuing the parent bicyclobu-
tane (a gas at room temperature) (27), we ap-
pended an arylsulfonyl group as a means to
both activate the strained C–C bond and ren-
der the reagent bench stable. Encouragingly,
a few examples have been reported wherein
benzylamine, when employed as a solvent, could
be added to phenylsulfonyl-substituted bicyclo-
Introduction of azetidine via
strain release
The documented use of azetidines as a tactic to
both rigidify amine backbones and serve as
phenyl bioisosteres inspired the evaluation of a
similar approach (1, 20). Like the propellane sys-
tems, access to amino-azetidines is largely limited
to a building-block approach that relies on the
multistep synthesis of protected azetidinones
(21). Strain-release amination of B was there-
fore evaluated as a means to simplify the pre-
paration of such compounds. Isolated examples
of the addition of nucleophiles to B are known
but require superstoichiometric amounts of Lewis
acids and only work with dibenzyl amine, ani-
lines, and thiols (22). As depicted in Fig. 3, the
addition of in situ–generated turbo-amides to
a solution of in situ–generated B leads cleanly
Fig. 3. “Azetidinylation” of amine-containing substrates. (A) A general “azetidinylation” of amines enabled by strain-release reagents. (B) Scope of
amine-containing substrates.
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Fig. 4. “Cyclobutylation”of amine-containing substrates. (A) A general “cyclobutylation”of amines with C7 enabled by strain-release reagents. (B) Substrate
scope of amine-containing substrates. (C) Diversification of intermediate cyclobutylsulfone 76. (D) Installation of cyclopentane onto primary and secondary
amines by strain-release amination.
will be amenable to amination and further
functionalization.
tide 87, no background reaction was observed
(Fig. 5C) after 24 hours. In marked contrast, the
commonly employed maleimide electrophile led
to multiple adducts with 87 after only 1 hour of
exposure. The complete chemoselectivity ob-
served for cysteine shows promise for the use
of strain-release functionalization in a variety
of contexts, such as site-selective bioconjuga-
tion (31–34) and peptide stapling (35–38). The
efficient tagging of other thiols, including glu-
tathione and cysteine methyl ester, attests to the
generality of the approach (see supplementary
materials for details). Further, by modifying the
electronic character of the aryl sulfone group,
we could adjust the temporal parameters of the
functionalization (Fig. 5D). This tunable click
reaction may facilitate the strategic design of
electrophilic covalent warheads for enzyme in-
hibition and activity-based protein profiling.
Applications to peptide labeling
Outlook
The “spring-loaded” electrophiles described herein
exhibit a broad substrate scope for amination
and inspired exploration of this platform in a
more biologically relevant context. A model pep-
tide (86, Fig. 5) was therefore prepared contain-
ing an assortment of proteinogenic nucleophilic
functional groups and exposed to strain-release
reagent C7 in a mixed organic/aqueous solvent
system. Remarkably, complete selectivity was ob-
served for labeling of the cysteine thiol [91%
isolated yield of 88 after 5 hours; see HPLC
(high-performance liquid chromatography) trace
in Fig. 5B]. In the presence of cysteine-free pep-
The operational simplicity, mild reaction conditions,
inexpensive preparation, and chemoselectivity
exhibited by strain-release reagents A to C will
facilitate their rapid adoption. More globally, an
enormous variety of reagents based on this con-
cept can be envisaged. For the task of procuring a
specific target, this approach to bond formation
will enable practitioners to refocus on the chal-
lenge of synthesizing a molecular scaffold rather
than on the difficulty posed by small ring systems.
We anticipate that this approach will also enable
formation of distinct connections in the materials,
polymer, and bioconjugation arenas.
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Fig. 5. Use of reagent C as a che-
moselective cysteine tag for pep-
tide and protein labeling.
(A) Reaction of C7 with functionalized
peptides 86 and 87. (B) HPLC
chromatogram depicting rapid and
clean conversion of 86 to cysteine-
labeled product 88 after 1 hour.
(C) Superior chemoselectivity of
reagent C7 relative to maleimide 89 in
the presence of cysteine-free peptide
87. (D) Reaction kinetics demonstrat-
ing the tunable functionalization of 86
with substituted arylsulfonyl bicyclo-
butane reagents.
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SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/351/6270/241/suppl/DC1
Materials and Methods
Figs. S1 to S68
Tables S1 to S6
References (39–68)
Institutes of Health provided a postdoctoral fellowship to J.M.L.; the
Shanghai Institute of Organic Chemistry, Zhejiang Medicine Co., and
Pharmaron provided a postdoctoral fellowship to J.W.; and the
University of the Basque Country provided a predoctoral fellowship
to L.P. We thank Y. Ishihara for assistance with the initial preparation
of the manuscript. We are grateful to D.-H. Huang and L. Pasternack
(The Scripps Research Institute) for assistance with nuclear magnetic
resonance (NMR) spectroscopy and A. L. Rheingold and C. E. Moore
NMR Spectra
21 October 2015; accepted 2 December 2015
10.1126/science.aad6252
◥
logram digitally encodes the Fourier transform
of a desired optical filter function (multiple
reflection resonances within the gain bandwidth
of the laser), enabling photonic DOS manipula-
tion at precise filter frequencies. In real space, a
typical hologram lattice contains a multitude of
phase shifts; the locations and sizes of scattering
sites and defects are set such that via coherent
backscattering the device enters a slow light re-
gime. Transfer matrix method (TMM) calculations
of the group delay transfer function (which is in-
trinsically linked to the photonic DOS) of an
ADFB microcavity under the influence of gain
reveal infinite-gain singularities [fig. S4; see (26)
for further details]. These singularities represent
the frequency and gain values at which self-
oscillation occurs. The ADFB microcavity can pro-
duce coherent amplification of the cavity photons
via stimulated emission processes because of the
build-up of phase coherence at the singularities (20).
ADFB structures were realized in THz quan-
tum cascade lasers (QCLs)—extremely long wave-
length semiconductor lasers with active regions
based on precisely engineered inter-subband tran-
sitions (27). Such ADFB THz QCLs provide an
ideal proving ground for graphene-controlled
gain modulation because they use SP-based wave-
guides (at a metal-semiconductor interface, Fig. 1A)
(28). The first crucial step is to excite two-dimensional
(2D) plasmons in an integrated, atomically thin
graphene sheet to take full leverage of the computer-
generated hologram principle. Hologram pixels
are introduced to the QCL waveguide as plas-
monic scattering sites along the longitudinal axis
of the laser ridge (Fig. 1B). By depositing an elec-
trically gateable graphene film onto these devices,
our goal is to switch the THz SP at each pixel “on”
or “off” by tuning ns, thereby altering the photonic
DOS and the degree to which the THz inter-
subband gain spectra follows the hologram re-
sponse. For example, by modulating the hologram
pixel scattering strength we approach the DOS
singularities, resulting in a dramatic increase of
light-matter interaction within the QCL gain me-
dia (20). Photon lifetimes (and hence modal gain
values) are thereby enhanced, leading to selective
enhancement of competing laser modes and a
concomitant suppression of others.
REPORTS
APPLIED OPTICS
Gain modulation by graphene
plasmons in aperiodic lattice lasers
S. Chakraborty,1* O. P. Marshall,1,2 T. G. Folland,1 Y.-J. Kim,2
A. N. Grigorenko,2 K. S. Novoselov2*
Two-dimensional graphene plasmon-based technologies will enable the development of fast,
compact, and inexpensive active photonic elements because, unlike plasmons in other
materials, graphene plasmons can be tuned via the doping level. Such tuning is harnessed
within terahertz quantum cascade lasers to reversibly alter their emission. This is achieved in
two key steps: first, by exciting graphene plasmons within an aperiodic lattice laser and,
second, by engineering photon lifetimes, linking graphene’s Fermi energy with the round-trip
gain. Modal gain and hence laser spectra are highly sensitive to the doping of an integrated,
electrically controllable, graphene layer. Demonstration of the integrated graphene plasmon
laser principle lays the foundation for a new generation of active, programmable plasmonic
metamaterials with major implications across photonics, material sciences, and nanotechnology.
mong the many intriguing properties of
graphene, its plasmonic characteristics are
some of the most fascinating and potentially
useful (1, 2). Long-lived, tunable intrinsic
graphene surface plasmons (SPs) have
(3, 17), giving rise to the possibility of compact
electrically controllable THz optical components
(18). We incorporated graphene into a plasmonic
THz laser microcavity to dynamically modulate
round-trip modal gain values and therefore laser
emission via EF. In this way, gated graphene be-
comes a powerful tool with which to control the
fundamental properties of a laser—a tool that is
potentially extremely fast and all electrical in na-
ture, with negligible electrical power requirements.
The interaction between light and matter can
be altered by manipulating the electromagnetic
density of states (DOS) using a microresonator
(19, 20). By incorporating a photonic lattice or
plasmonic structure into a laser, one can control
the frequency and amplification of resonant modes
and hence manipulate the properties of lasing
emission (21–23). Furthermore, by breaking the
regularity of these structures it is possible to mod-
ulate the photon DOS and hence light-matter
interaction at several frequencies simulta-
neously. This technique was used recently to de-
velop an aperiodic distributed feedback (ADFB)
cavity laser with a lattice that is in essence a
computer-generated hologram (24, 25). The ho-
A
already been demonstrated in a number of ex-
periments (3–9), including optical modulators
(10, 11), providing the potential for applications
(12, 13). In contrast to the noble metals that are
usually used in SP devices (13, 14), graphene’s
Fermi energy, EF, and carrier concentration, ns
(and therefore its conductivity and SP mode
properties), can be altered, for example, by elec-
trical gating and surface doping (3, 15, 16). Con-
sequently, the behavior of graphene SP-based
structures can be modified in situ, without the
need for structural device changes. In particular,
graphene’s optical and plasmonic properties are
tunable in the terahertz (THz) spectral region
1School of Electrical and Electronic Engineering, University of
Manchester, Manchester M13 9PL, UK. 2School of Physics and
Astronomy, University of Manchester, Manchester M13 9PL, UK.
*Corresponding author. E-mail: s.chakraborty@manchester.ac.uk
(S.C.); kostya@manchester.ac.uk (K.S.N.)
A hologram with relatively weak feedback was
chosen so that any subtle influence of graphene
plasmons on laser emission was not hidden by
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