Kinetically controlled E-selective catalytic olefin metathesis

Article abstract of DOI:10.1126/science.aaf4622

A major shortcoming in olefin metathesis, a chemical process that is central to research in several branches of chemistry, is the lack of efficient methods that kinetically favor E isomers in the product distribution. Here we show that kinetically E-selective cross-metathesis reactions may be designed to generate thermodynamically disfavored alkenyl chlorides and fluorides in high yield and with exceptional stereoselectivity.With 1.0 to 5.0 mole % of a molybdenum-based catalyst, which may be delivered in the form of air- and moisture-stable paraffin pellets, reactions typically proceed to completion within 4 hours at ambient temperature. Many isomerically pure E-alkenyl chlorides, applicable to catalytic cross-coupling transformations and found in biologically active entities, thus become easily and directly accessible. Similarly, E-alkenyl fluorides can be synthesized from simpler compounds or more complex molecules.

Full text of DOI:10.1126/science.aaf4622

RESEARCH
| REPORTS
a lower abundance of two species from the family
Rikenellaceae, Alistipes finegoldii, and Alistipes
senegalensis, whereas blood lipids were associated
with two other species, Alistipes shahii and Alistipes
putredinis (table S11). Notably, these species were
also associated to certain dietary factors and drugs.
For instance, a high level of A. shahii, which was
associated to low triglyceride (TG) levels, was linked
to higher fruit intake (q = 0.00027). Individuals
with a higher abundance of A. shahii had a higher
23. E. Le Chatelier et al., Nature 500, 541–546 (2013).
Research, and KU Leuven. S.V.-S. and M.J. are supported by
postdoctoral fellowships from FWO. T.V., M.S., and R.J.X. are
supported by NIH, JDRF, and CCFA. A.Z., C.W., and J.F. designed
the study. A.Z., E.F.T., L.F., and C.W. initiated the cohort and
collected cohort data. A.Z., E.F.T., Z.M., S.A.J., M.C.C., and D.G.
generated data. A.Z., A.K., M.J.B., E.F.T., M.S., T.V., A.V.V., G.F.,
S.V.-S., J.W., F.I., P.D., M.A.S., C.H., R.J.X., and J.F. analyzed data.
G.F, S.V.-S., J.W., E.B., M.J., R.K.W., E.J.M.F., M.G.N., D.G., D.J.,
L.F., Y.S.A., C.H., J.R., R.J.X., and M.H.H. participated in integral
discussions. A.Z., A.K., M.J.B., R.J.X., C.W., and J.F. wrote the
manuscript. The authors have no conflicts of interest to report.
The raw sequence data for both MGS and 16S rRNA gene
sequencing data sets, and age and gender information per sample
are available from the European genome-phenome archive
24. G. D. Wu et al., Science 334, 105–108 (2011).
25. K. Korpela et al., Nat. Commun. 7, 10410 (2016).
26. A. Poullis, R. Foster, M. A. Mendall, D. Shreeve, K. Wiener, Eur.
J. Gastroenterol. Hepatol. 15, 573–574 (2003).
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(
28. F. Cabreiro et al., Cell 153, 228–239 (2013).
29. K. Forslund et al., Nature 528, 262–266 (2015).
30. J. Fu et al., Circ. Res. 117, 817–824 (2015).
ACKNOWLEDGMENTS
We thank the LifeLines-DEEP participants and the Groningen
LifeLines staff for their collaboration. We thank J. Dekens,
M. Platteel, and A. Maatman for management and technical
support. We thank J. Senior and K. McIntyre for editing the
manuscript. This project was funded by grants from the Top
Institute Food and Nutrition, Wageningen, to C.W. (TiFN GH001);
the Netherlands Organization for Scientific Research to
J.F. (NWO-VIDI 864.13.013), L.F. (ZonMW-VIDI 917.14.374),
and R.K.W. (ZonMW-VIDI 016.136.308); and CardioVasculair
Onderzoek Nederland to M.H.H. and A.Z. (CVON 2012-03). A.Z.
holds a Rosalind Franklin Fellowship (University of Groningen), and
M.C.C. holds a postdoctoral fellowship from the Fundación
Alfonso Martín Escudero. This research received funding from
the European Research Council (ERC) under the European
Union’s Seventh Framework Program: C.W. is supported by
FP7/2007-2013)/ERC advanced Grant Agreement no. 2012-322698.
M.G.N. is supported by an ERC Consolidator Grant (no. 310372).
L.F. is supported by FP7/2007–2013, grant agreement 259867,
and by an ERC Starting Grant, grant agreement 637640
(ImmRisk). J.R. and G.F. are supported by FP7 METACARDIS
HEALTH-F4-2012-305312, VIB, FWO, IWT (Agency for Innovation
by Science and Technology), the Rega institute for Medical
number of different species in the gut (species rich-
ness) (Spearman r = 0.2, adjusted P = 3.96x10−11),
(https://www.ebi.ac.uk/ega/) at accession number EGAS00001001704.
suggesting a beneficial effect on the microbial
ecosystem (table S18). Correlations with the num-
ber of different species were also found for other
bacteria, including Roseburia hominis, Coprococ-
cus catus, and Barnesiella intestinihominis and
unclassified species from genus Anaerotruncus
that also showed correlation both with fruit, veg-
etable, and nut consumption and with intrinsic
phenotypes like HDL, triglycerides, and quality
of life. On the basis of these data, it would be
interesting to explore the potential to modulate
disease-associated species through medication
or diet, although we still need to address the
causality and underlying mechanism.
Our study revealed significant associations be-
tween the gut microbiome and various intrinsic,
environmental, dietary and medication parame-
ters, and disease phenotypes, with a high replica-
tion rate between MGS and 16S rRNA gene
sequencing data from the same individuals. More-
over, our study provides many new intrinsic and
exogenous factors that correlate with shifts in
the microbiome composition and functionality
that potentially can be manipulated to improve
Other phenotypic data can be requested from the LifeLines
cohort study (https://lifelines.nl/lifelines-research/access-to-lifelines)
following the standard protocol for data access. The study was
approved by the institutional review board of UMCG, ref.M12.
113965. D.J. has additional funding from EU FP7/ no. 305564 and
EU FP7/ no. 305479. C.H. is on the Scientific Advisory Board for
Seres Therapeutics. Y.S.A. is a director and co-owner of
PolyOmica, which provides services in statistical (gen)omics.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/352/6285/565/suppl/DC1
Materials and Methods
Figs. S1 to S13
Tables S1 to S19
References (31–54)
1 September 2015; accepted 11 March 2016
10.1126/science.aad3369
ORGANIC CHEMISTRY
Kinetically controlled E-selective
microbiome-related health, and we hope our re- catalytic olefin metathesis
sults will inspire further experiments to explore
the biological relevance of associated factors. Al-
though most of the factors that we assessed exerted
a very modest effect, fecal levels of CgA showed a
high potential as a biomarker for gut health.
1
1
1
1
Thach T. Nguyen, Ming Joo Koh, Xiao Shen, Filippo Romiti,
2
1
Richard R. Schrock, Amir H. Hoveyda *
A major shortcoming in olefin metathesis, a chemical process that is central to research
in several branches of chemistry, is the lack of efficient methods that kinetically favor E
isomers in the product distribution. Here we show that kinetically E-selective cross-metathesis
reactions may be designed to generate thermodynamically disfavored alkenyl chlorides
and fluorides in high yield and with exceptional stereoselectivity. With 1.0 to 5.0 mole %
of a molybdenum-based catalyst, which may be delivered in the form of air- and
moisture-stable paraffin pellets, reactions typically proceed to completion within 4 hours at
ambient temperature. Many isomerically pure E-alkenyl chlorides, applicable to catalytic
cross-coupling transformations and found in biologically active entities, thus become easily
and directly accessible. Similarly, E-alkenyl fluorides can be synthesized from simpler
compounds or more complex molecules.
REFERENCES AND NOTES
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lefin metathesis is an enormously enabling
chemical process for which well-defined
catalysts were discovered nearly three
decades ago (1, 2). Kinetically controlled
Z-selective reactions were introduced in
Although E-selective cross-metathesis (CM) re-
actions involving Ru catechothiolate complexes
(4) were reported very recently in 2016, only
the thermodynamically preferred E isomers of
simple (unfunctionalized) 1,2-disubstituted ali-
phatic alkenes could be obtained in 3 to 31% yield
(5). E alkenes are often lower in energy and thus
generated preferentially; nonetheless, olefin me-
tathesis strategies that furnish them are needed
for several reasons: The energy gap between the
geometric forms is often too small to ensure
high selectivity; E olefin isomers are not always
thermodynamically preferred; and, in many cases,
13. T. Lee et al., Acta Paediatr. 95, 935–939 (2006).
14. L. Öhman, M. Stridsberg, S. Isaksson, P. Jerlstad, M. Simrén,
Am. J. Gastroenterol. 107, 440–447 (2012).
O
15. V. Sciola et al., Inflamm. Bowel Dis. 15, 867–871 (2009).
16. M. Wagner et al., Inflammation 36, 855–861 (2013).
17. R. Aslam et al., Curr. Med. Chem. 19, 4115–4123 (2012).
18. A. Bartolomucci et al., Endocr. Rev. 32, 755–797 (2011).
19. M. I. Queipo-Ortuño et al., Am. J. Clin. Nutr. 95, 1323–1334 (2012).
2
009 (3), but there are no corresponding transfor-
mations that are broadly applicable and through
which E isomers can be synthesized in high yield.
1
2
0. A. Duda-Chodak, T. Tarko, P. Satora, P. Sroka, Eur. J. Nutr. 54,
Department of Chemistry, Merkert Chemistry Center, Boston
2
325–341 (2015).
College, Chestnut Hill, MA 02467, USA. Department of
2
2
1. C. E. Mills et al., Br. J. Nutr. 113, 1220–1227 (2015).
2. H. Sokol et al., Proc. Natl. Acad. Sci. U.S.A. 105, 16731–16736
Chemistry, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA.
*Corresponding author. Email: amir.hoveyda@bc.edu
(2008).
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E and Z alkene isomers cannot be easily sepa-
rated. Perhaps the most notable instance relates
to acyclic alkenyl halides, where hyperconjuga-
tive donation of electron density from a filled sC–H
into a low-lying vacant s*C–halogen orbital causes
stabilization of the Z isomers (6). Herein, we
disclose the design of efficient and kinetically
E-selective CM reactions through which E-alkenyl
chlorides and fluorides can be obtained in good
yield and with exceptional stereoselectivity.
E-1,2-Disubstituted chloroalkenes can be used
in catalytic cross-coupling, one of the most influ-
ential transformations in modern chemistry (7).
These isomers are found in biologically active
molecules as well (8); two examples are pitinoic
acid B, a potent anti-inflammatory agent (9), and
kimbeamide A, a natural product with notable
antitumor activity (10) (Fig. 1A). E-Alkenyl fluo-
rides are of interest because of the substantial
value of organofluorines in medicine (11) and
agrochemicals (12). A biologically active fluoro-
alkenyl entity that inhibits Bacillus subtilis S-
ribosyl-homocysteinase (LuxS) (13) is presented
in Fig. 1A; only an E/Z mixture of this compound
has been evaluated, due to the difficulties associated
with accessing a stereoisomerically pure alkenyl
fluoride. Functionalization of a stereochemically
defined fluoro-substituted olefin would facilitate
preparation of other desirable F-containing mol-
ecules (14).
ing chlorides (21), which may alternatively be syn-
thesized by treatment of an aldehyde with excess
chromium chloride and chloroform (22). A small
number of procedures furnish E-alkenyl fluorides
from aldehydes (23) or alkynes (24, 25), but none
are catalytic and several require stoichiometric
amounts of strongly basic [e.g., tert-butyllithium
(t-BuLi)] and/or toxic reagents (e.g., hexame-
thylphosphoramide). In another case, a stereo-
chemically defined fluorine-substituted alkenyl
tosylate must first be secured by the use of n-
Equally important, by conversion of an alkene to
an E-alkenyl fluoride through catalytic and stereo-
selective CM, a hydrogen may be substituted with
a fluorine atom within a complex molecule, such as
the methyl ester of the potassium channel activator
isopimaric acid (Fig. 1A) (15). Such modification
can result in the alteration and/or enhancement
of the molecule’s biological activity (16, 17).
E-1,2-Disubstituted alkenyl chlorides can be
prepared in a number of ways (see the supple-
mentary materials for comprehensive bibliogra-
phy). Terminal alkynes may be transformed to
nucleophilic E-alkenylmetal intermediates that
are then treated with an electrophilic halogen
source (18–20). E-Alkenyl boronic acids, prepared
from a terminal alkyne by a two-step procedure
(such as hydroboration followed by hydrolysis),
can be converted by a third step to the correspond-
4
BuLi and LiAlH before it is subjected to a cross-
coupling reaction (26). Efficient and E-selective
catalytic CM strategies that deliver alkenyl chlo-
rides and fluorides (Fig. 1B)—involving robust,
abundant, and less costly alkenes (versus alde-
hydes or alkynes)—would complement the afore-
mentioned methods, offering a more direct and
economical approach on most occasions.
We recently demonstrated that molybdenum-
based monoaryloxide pyrrolide (MAP) complexes
possess the distinctive ability to promote efficient
Z-selective CM reactions that afford alkenyl halides
(27). These transformations probably proceed
Fig. 1. Kinetically E-selective CM: potential effect and challenges. (A) Examples of biologically active organic molecules that contain an E alkenyl chloride
or fluoride. (B) Challenges in designing a kinetically E-selective CM route to prepare alkenyl halides. (C) Analysis of stereochemical models that suggest a
strategy for the design of kinetically E-selective olefin metathesis processes. pent, pentane; Me, methyl; Ln, ligand. G and R denote functional groups.
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via olefin-derived alkylidenes that then react
with a halo-olefin reagent. Reactions with wide-
ly used complexes (e.g., dichloro-Ru carbenes)
are either inefficient and/or nonstereoselective
E-1,2-dichloroethene via III, would metallacycle
IV or its corresponding diastereomer V be fa-
vored? In IV, the eclipsing interactions between
In search of more clues, we examined the crystal
structure of an unsubstituted molybdacyclobutane
derived from a MAP complex (29), noting that
a a b
C –G or C –Cl and C –H bonds in a structurally
b
the molybdenum–C distance is longer than the
(
27). Designing a kinetically E-selective variant,
flat (29) molybdacyclobutane (nonpuckered due
to the longer C–Mo bonds) would be less severe
metal–C bond length (2.33 versus 2.05 Å) (Fig.
a
however, poses several distinct challenges. Not
only was there no blueprint for high-yielding and
kinetically controlled E-selective olefin meta-
thesis when these studies were initiated, but
the desired products would also be thermo-
dynamically less favored: The Z-haloalkenes are
the more preferred isomers, as indicated by the
relative energies shown in Fig. 1B (6).
In contemplating a strategy for achieving
kinetic E selectivity, we evaluated the stereo-
chemical model proposed for the corresponding
Z-selective CM reactions (28), realizing an im-
plicit principle. Reaction via metallacyclobutane
I is preferred versus reaction via II (Fig. 1C) be-
cause the eclipsing interaction between the C–R
and C–G bonds in I is less destabilizing than the
steric repulsion between the C–R unit and the
larger catalyst ligand in II. The question then be-
came: If an alkylidene complex were to react with
1C). This observation suggested that there might
be less steric repulsion between the halogen and
the larger aryloxide ligand in IV (versus in V),
which could translate to an E-selective process.
However, the above analysis pointed to another pos-
sible complication: The vinyl chloride by-product
might cause a diminution in selectivity by re-
action via metallacyclobutane I, affording the
thermodynamically favored Z-alkenyl halide. The
use of vacuum (28) would not be an option:
Although the volatility of E-1,2-dichloroethene
allows it to be easily handled and readily re-
moved (boiling point: 48°C), a substantial amount
(if not all) would be lost under even mildly re-
duced pressure.
compared with those involving the C
–Cl bonds of V (the C –C distance is ~2.75 Å).
Whereas in IV, which would release an E-alkene,
the C –Cl bond is oriented toward the more size-
able ligand, in V it would be a C –Cl unit that is so
a
–G and
C
b
a
a
b
a
disposed. Moreover, collapse of IV would yield a
presumably lower-energy syn-alkylidene (Cl point-
ing toward the imido ligand) (30). The resulting
highly active (27) chloro-substituted syn-alkylidene
(syn-i) would then react with the olefin substrate
via the lower-energy a,a′-disubstituted metalla-
cyclobutane ii (minimal eclipsing interaction or
steric repulsion with the aryloxide ligand, with G
and Cl oriented toward the smaller imido unit) to
generate complex iii, which could be converted
to III. It was unclear which of the latter pathways
would be dominant and how high the stereo-
selectivity would be.
The above reasoning implied that an entirely
distinct catalyst construct would not be needed
for achieving high kinetic E selectivity and could
be validated experimentally: CM of alkene 1 and
Fig. 2. Kinetically controlled E-selective CM reactions that generate alkenyl chlorides. (A) Model studies involving commercially available and easy-to-
handle E-dichloroethene (2a) indicated that structural adjustment of the catalyst’s aryloxide ligand is needed for maximal efficiency and stereoselectivity. b.p.,
boiling point; ND, not determined. (B) A range of alkyl-, aryl-, and heteroaryl-substituted E-alkenyl chlorides can be obtained in up to >98/2 E/Z selectivity. Yields
are for purified products. TBS, tert-butyldimethylsilyl; Et, ethyl; G, functional group; Ac, acetyl; pin, pinacolato; Boc, tert-butoxycarbonyl. See the supplementary
materials for details.
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E-1,2-dichloroethene 2a with 5.0 mol % Mo-1a
Fig. 2A) affords E-alkenyl chloride 3a with an
0/20 E/Z ratio. Equally encouraging was that
the products were obtained in 70% yield after
purification, without resorting to long reaction
times or elevated temperatures (2 hours, 22°C).
We envisioned that removing the ortho aryl sub-
stituents within the aryloxide ligand (highlighted
in Mo-1a and Mo-1b, Fig. 2A) might alleviate
(30). To retain high selectivity without efficiency
loss, we evaluated the performance of Mo-1c and
Mo-1d and established that either complex can
produce 3a with appreciable efficiency in ~90% E
selectivity (Fig. 2A). With Mo-1d and 20 equiv-
alents (equiv.) of 2a, selectivity improved to 93%
E, probably due to diminished competitiveness
of nonselective CM involving the vinyl chloride
by-product (via I, Fig. 1C). Excess 2a was easily
removed in vacuo.
An array of E-alkenyl chlorides was accessed
by reaction between a terminal olefin and com-
mercially available 2a, which was used as re-
ceived (no purification). Transformations may
be performed with sterically congested alkenes:
cyclohexyl-substituted 3b was obtained in 80%
yield and 92/8 E/Z selectivity. CM with various
aryl (4a to 4g) and heteroaryl a-olefins (4h to
4k) generated the products in 54 to 85% yield
after 4 hours at room temperature. The differ-
ence between the conversion and yield is largely
due to the formation of homocoupling products.
We did not detect the Z isomer in any reaction [by
(
8
1
analysis of 400-MHz H nuclear magnetic reso-
nance (NMR) spectra of the unpurified product
mixtures]. Product 4a was obtained from the re-
action with E-b-methyl styrene. Aryl halides 4c
and 4d and arylboronate 4g are noteworthy be-
cause their synthesis through cross-coupling could
pose chemoselectivity issues (31, 32).
b
steric repulsion with the C chlorine atom, favoring
reaction via IV. We therefore prepared and exam-
ined the selectivity of the CM reaction with Mo-1b,
which led to substantially improved stereoselec-
tivity (91/9 E/Z) but lower efficiency (41% versus
72% conversion with Mo-1a), probably due to com-
Preparation of E-1,2-disubstituted alkenyl chlo-
rides with unhindered aliphatic alkenes (versus
petitive bimolecular alkylidene decomposition
Fig. 3. Synthesis of unhindered
E-alkenyl chlorides by catalytic
and stereoselective substituent
swapping. (A) With unhindered
aliphatic a-olefins, catalytic
CM with 2a is efficient but
moderately E-selective. This
may be attributed to the rapid
formation of an E/Z mixture of
1,2-disubstituted alkenes,
formed by homocoupling, that
reacts with 2a. Thus, readily
available E-1,2-disubstituted
alkenes may be used instead
(
G = Ph). (B) Through the
use of easily accessible b-alkyl
styrenes, a number of biologically
active compounds can be
readily prepared. (C) The catalytic
method, in combination with
catalytic cross-coupling, may be
used to access a variety of
potentially valuable derivatives.
An air- and moisture-resistant
paraffin tablet containing a Mo
MAP complex can easily be used.
Yields are for purified products.TES,
triethylsilyl; thf, tetrahydrofuran;
Tf, trifluoromethanesulfonyl;
DIAD, di(iso-propyl)azodicarboxylate;
Phth, phthalyl; Ph, phenyl; cod,
cyclooctadiene; HMDS, hexa-
methyldisilazide; i-Pr, iso-propyl;
SPhos, 2-dicyclohexylphosphino-
2′,6′-dimethoxybiphenyl. See
the supplementary materials
for details.
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those with an allylic substituent as in 3a and 3b)
presented another complication (Fig. 3A). CM was
efficient with olefin 5, affording chloroalkene 3c
in 78% yield, but selectivity was moderate (74%
E isomer). Other than the possibility of a more
facile post-metathesis isomerization of the rela-
tively uncongested olefin, this discrepancy might
originate from a more competitive and moderately
selective generation of homocoupling products,
which can then react with 2a to afford isomeric
mixtures. Further, the finding that CM with E-1,2-
disubstituted olefin 6 produced 3d and 3e with
similar selectivity (~70/30 E/Z) implies that 1,2-
dialkyl olefins might undergo rapid nonstereo-
selective isomerization by self-metathesis before
reaction with 2a.
specific group exchange. The ideal substituent
would be easily and efficiently accessible and
would be sufficiently large to discourage self-
metathesis and adventitious E-to-Z isomeriza-
tion, but not so large as to inhibit CM with 2a.
We selected E-b-substituted styrenes because
these comparatively robust compounds can be
prepared by various methods, as showcased by
the findings in Fig. 3, B and C.
The first example (Fig. 3B) is a concise syn-
thesis of the amine segment of kimbeamide A
(compare with Fig. 1A). The substrate (12) was
synthesized from commercially available (racemic
or as either enantiomeric form) propargyl alcohol
The above data show that alkylidenes derived
from Mo-1d can catalyze CM between 1,2-
disubstituted alkenes with E-dichloroethene 2a:
Within 4 hours at room temperature, 3d was
obtained in 84% yield despite its volatility, and
3e was isolated in >98% yield. Such high activ-
ity indicated the need for a strategy for access-
ing alkenyl chlorides with better stereocontrol.
We surmised that with an appropriate E-1,2-
disubstituted olefin, chloro-olefins might become
accessible with kinetic E selectivity by what
amounts to an efficient catalytic and stereo-
Fig. 4. Preparation of E-alkenyl fluorides by catalytic CM. (A) Mechanistic analysis that serves as the basis for the development of the catalytic
processes. (B) Examination of a model process and identification of an effective complex. (C) With Mo-1a and commercially available E-1-chloro-2-
fluoroethene 2b, an assortment of E-1,2-alkenyl fluorides can be synthesized efficiently and with E/Z ratios that are typically >98/2. Yields are for purified
products. G, functional group; Bn, benzyl; PMP, para-methoxyphenyl; imid., imido. See the supplementary materials for details.
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(
7) and carboxylic acid (8). Partial hydrogenation
cially available, economically far more viable,
and easier to use (boiling point: –4°C). The is-
sue was whether with 2b the transformations
would be appreciably product-selective (alkenyl
fluoride versus chloride), as CM can proceed via
four distinct metallacyclobutane isomers (VII
to X, Fig. 4A), only one of which would produce
the desired E-fluoroalkene (VII). We posited that
CM might be preferentially channeled via VII
for several reasons: (i) Overall, there should be
less steric strain in VII and IX versus VIII and
X, respectively. There are no severe eclipsing
interactions in VII and IX, and steric repulsion
between a halogen atom and the larger aryloxide
2a was used, CM between E-b-alkyl styrenes and
2b led to substantial amounts of b-fluorostyrene
and aliphatic chloroalkene products. Formation
of 22 (>98% fluoro product, 59% yield, >98% E)
shows that acid-sensitive moieties, such as a para-
methoxyphenyl acetal, are tolerated. The transfor-
mation leading to fluorine-tagged isopimaric acid
methyl ester (23) involves a particularly congested
alkene. A precursor to the aforementioned LuxS
inhibitor, alkenyl-fluoride 25, was prepared in
three steps from 24 in 51% overall yield with >98%
E selectivity. The present approach affords the
E-fluoroalkene in its stereoisomerically pure form
and is substantially more efficient than the pre-
viously reported route (7% overall yield from
24) (13).
Thus, we have devised strategies that allow for
olefin metathesis processes to proceed with high
efficiency and kinetic E selectivity, delivering a
valuable set of organic halides where Z isomers
are thermodynamically favored. The possibility
of using easy-to-handle paraffin tablets, soon to
be commercially available, further enhances the
potential effect of this approach (35). The strat-
egies delineated above are expected to lead to
the development of other efficient, practical, and
kinetically E-selective olefin metathesis transfor-
mations; this is especially relevant to cases
where there is minimal energy difference be-
tween the two stereoisomeric forms and/or the
Z-alkene is preferentially generated with the
more commonly used catalysts (e.g., alkenyl sul-
fides, alkenyl nitriles, or enynes) (36).
of enyne 11, followed by a Mitsunobu reaction,
afforded diene 12 (>98% E-b-alkylstyrene, >98%
Z allylic amine; 69% overall yield). Subsequent
treatment with 3.0 mol % Mo-1d and 2a gen-
erated 3f in 95% yield and >98/2 E/Z selectivity
after 1 hour at room temperature. The Z-alkene
was left untouched in the course of CM (>98% Z
at the allylic amine site), highlighting exceptional
chemoselectivity. Another case corresponds to
pitinoic acid B (Fig. 3B); here, catalytic cross-
coupling of commercially available and enantio-
merically pure alkyl chloride 13 and trifluoroborate
1
4 afforded 15 (33) directly in 47% yield. E-b-
Substituted styrene 15 was then converted to
E-alkenyl chloride 3g, which has been formerly
transformed to the anti-inflammatory agent (9).
Other than facilitating synthesis of biological-
ly active compounds, the approach offers a con-
venient route for their modification—two cases
are shown in Fig. 3C. We were able to convert
a
ligand would be more costly at the C position
(as compared with VIII and X, respectively). (ii)
Matching polarity of the Mo=C and C=C bonds
of the dihaloethene, as indicated by the distinct
1
chemical shifts in the H NMR spectrum of the
latter [d 6.90 and 6.15 parts per million for CH(F)
and CH(Cl), respectively, in CDCl ], as well as
3
0
.74 g of cinnarizine, a potent anticonvulsant
the smaller size of a fluorine atom (0.42 Å atomic
radius versus 0.79 Å for Cl), should favor VII over
IX. In the event (Fig. 4B), CM between aryl alkene
18 and 2b (solution in toluene) with 5.0 mol %
Mo-1d favored the formation of alkenyl fluo-
ride 19a over the chloro-substituted alkene 4l
(77/23). Both products were generated with
>98% E selectivity.
While contemplating how we could improve
the ratio of fluoroalkenes to chloroalkenes, we
noted that because 19a and 4l are formed with
>98% E selectivity, reaction via IX is probably
the major competing pathway. If so, reverting to
the original MAP complex Mo-1a, containing
agent, to E-alkenyl chloride 3h in 94% yield and
with >98% E selectivity (5.0 mol % Mo-1d, 10
equiv. 2a, toluene, 22°C, 4 hours). Importantly,
the Mo MAP complexes can be delivered in the
form of air- and moisture-resistant paraffin pellets.
For example, with a pellet containing Mo-1d (Fig.
3
C) (~5 mg in ~95 mg of paraffin wax; 5.0 mol %
loading), reaction of cinnarizine with 2a cleanly
afforded 3h in 95% yield (>98% E isomer). To
ensure complete release of the MAP species, the
transformation was performed at 50°C in toluene
under nitrogen atmosphere (Fig. 3C). After 4 hours,
the resulting mixture was purified by routine
silica gel chromatography (see the supplemen-
tary materials for further details). The entire
procedure was carried out in a fume hood.
Compounds such as 3h are a convenient en-
try to analogs that cannot be accessed efficiently
or with high E selectivity by alternative methods,
including direct CM; the three examples shown
in Fig. 3C (16a to 16c), obtained by catalytic cross-
coupling with commercially available boronic
acids or pinacol esters (34), are illustrative. In
another case, a persilylated derivative of the anti-
depressant rosavin was converted to E-alkenyl
chloride 3i in 90% yield and >98% E selectivity.
As with cinnarizine-derived 3h, analogs may be
easily synthesized via 3i or its deprotected form
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2
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(
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rectly accessed (Fig. 4C); 2b was used without
purification, and reactions generated up to >98/2
fluoroalkene/chloroalkene selectivity. As with
19a, pure alkenyl fluorides could easily be ob-
tained in most cases (54 to 78% yield). In only one
instance (20) did we detect any of the Z-alkene.
Different styrenes, including those with versatile
functional groups (e.g., 19b and 19d), were effec-
tive cross partners. Several examples involving
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are presented in Fig. 4C. Similar to the cases in
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substituted olefins were less E-selective (com-
pare 20 versus 21). Unlike when symmetrical
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ACKNOWLEDGMENTS
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This research was financially supported by the NIH (grant
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NMR Spectra
11 February 2016; accepted 30 March 2016
10.1126/science.aaf4622
acid; Fig. 1A, shown in black). These Aib foldamers
show a strong preference for helical conforma-
tions (9) and therefore have two principal con-
formational states, in which the helix adopts a
global left- or right-handed screw sense. Fur-
thermore, helical Aib-rich peptides have a known
tendency to insert into phospholipid bilayers
because they occur naturally in the form of
membrane-disrupting fungal antibiotics known
as peptaibols (10).
CHEMISTRY
Conformational photoswitching of a
synthetic peptide foldamer bound
within a phospholipid bilayer
1
1
1
2
A chiral amino acid residue was covalently
Matteo De Poli, Wojciech Zawodny, Ophélie Quinonero, Mark Lorch,
Simon J. Webb, Jonathan Clayden *
1
,3
4
linked to the N terminus of an (Aib)
and then N-acylated by an azobenzene motif
Fig. 1A, shown in red) to enable photochemical
n
foldamer
(
The dynamic properties of foldamers, synthetic molecules that mimic folded biomolecules,
have mainly been explored in free solution. We report on the design, synthesis, and
conformational behavior of photoresponsive foldamers bound in a phospholipid bilayer
akin to a biological membrane phase. These molecules contain a chromophore, which
can be switched between two configurations by different wavelengths of light, attached
to a helical synthetic peptide that both promotes membrane insertion and communicates
conformational change along its length. Light-induced structural changes in the
chromophore are translated into global conformational changes, which are detected
induction of conformational change (11). This
motif manifests well-understood photochemical
interconversion between E and Z configurations
and thus offers a reversible light-driven means
of initiating conformational reorganization from
the terminus of the oligomer. The influence of
azobenzene geometry on the relative population
19
of conformational states of the (Aib)
was first explored in solution using foldamers
(Fig. 1A) that carry a C-terminal glycinamide as
n
helix
by monitoring the solid-state F nuclear magnetic resonance signals of a remote
fluorine-containing residue located 1 to 2 nanometers away. The behavior of the foldamers
in the membrane phase is similar to that of analogous compounds in organic solvents.
1
1
a solution-state H nuclear magnetic resonance
(NMR)–compatible reporter of helical conforma-
n the field of synthetic biology, substantial
progress has been made in the use of light
to control biological function by custom-
ization of membrane-bound proteins with
artificial chromophores (1). In parallel, syn-
photoswitchable proteins such as rhodopsin (4),
could ultimately provide opportunities for con-
trolling chemical processes within membrane-
defined compartments.
tion (12). An unequal conformational population
can result when the first turn of a helical Aib-
containing foldamer incorporates a single chiral
tertiary amino acid residue, and the magnitude
of this bias depends on the detailed structure of
the first (N-terminal) b-turn of the helix (12).
H NMR spectra of valine-containing foldamers
1a to 1d were acquired in deuterated methanol
3
(CD OD) solution as their thermally equilibrated
mixtures of E (major) and Z (minor) geometrical
isomers (analogous behavior in phenylalanine-
containing foldamers is reported in table S1).
Methanol has a polarity similar to that of the
interfacial region of the phospholipid bilayer
and prevents aggregation of the foldamers in so-
lution (13, 14). Because the left- and right-handed
I
A detailed understanding of how the phos-
pholipid bilayer affects long-range conforma-
tional changes in membrane-bound molecules
is impeded by the difficulty of directly observing
conformational changes in the membrane phase
and by a lack of examples of biomolecules that
adopt well-defined structures both in the mem-
brane phase and in solution (5–7). A simplified
yet functional synthetic analog of the membrane-
spanning domains of natural proteins, contain-
ing in-built spectroscopic handles that are diag-
nostic of conformation, would be a powerful tool.
Dynamic conformational changes in a membrane-
bound molecule could then be explored, free of the
complexities of protein structure, and compared
with analogous changes in isotropic solution.
Given the requirement for a synthetic structure
with a tendency to embed into membranes and
with well-understood conformational dynamics,
we chose to explore the membrane insertion of
foldamers [synthetic polymeric molecules with well-
defined conformations (8)] built from oligomers
of the achiral amino acid Aib (2-aminoisobutyric
thetic molecular photoswitches have been used
to control chemical processes such as ligand
binding and catalysis in isotropic solution (2, 3).
Here, we report the design and synthesis of a
fully synthetic photoresponsive helical molecule
that can insert into a phospholipid bilayer. We
show that light-induced switching between con-
figurational isomers can be used to induce global
conformational change that propagates over sev-
eral nanometers in a synthetic molecule within
a membrane environment. Membrane-bound
artificial photoswitchable synthetic structures
capable of translating photochemical informa-
tion into extended conformational changes, in a
manner reminiscent of the operation of natural
1
n
conformational states of an (Aib) helix inter-
convert on a submillisecond time scale at am-
1
bient temperature, the H NMR spectrum that
is observed results from a weighted average of
both conformational states, reflecting their rel-
ative population. The diagnostic feature in the
averaged spectra of foldamers 1 is the signal
or signals due to the methylene protons of the
C-terminal glycinamide residue. A single signal
indicates equal populations of the two states; a
pair of signals indicates unequally populated
1
School of Chemistry, University of Manchester, Manchester
2
M13 9PL, UK. Department of Chemistry, University of Hull,
3
Hull HU6 7RX, UK. Manchester Institute of Biotechnology,
4
University of Manchester, Manchester M1 7DN, UK. School
of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Corresponding author. E-mail: j.clayden@bristol.ac.uk
*
SCIENCE sciencemag.org
29 APRIL 2016 • VOL 352 ISSUE 6285 575

Kinetically controlled E-selective catalytic olefin metathesis
Thach T. Nguyen, Ming Joo Koh, Xiao Shen, Filippo Romiti,
Richard R. Schrock and Amir H. Hoveyda (April 28, 2016)
Science 352 (6285), 569-575. [doi: 10.1126/science.aaf4622]
Editor's Summary
EZ catalyst control in olefin metathesis
A decade has passed since the partner-swapping chemical dance known as olefin metathesis
garnered a Nobel Prize, and distinct routines continue to emerge. In general, olefins are most stable in
an E configuration, with the two largest substituents diametrically opposed. However, chlorine and
fluorine substituents often invert this trend, favoring the alternate Z geometry. Nguyen et al. report a
molybdenum metathesis catalyst with ligands carefully optimized to produce Cl- and F-substituted E
olefins more quickly than the more stable Z isomers.
Science, this issue p. 569
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