Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands

Article abstract of DOI:10.1002/adsc.201900631

Site-selective nitrene transfer to di- and polyene substrates has been achieved using designed peptide-embedded bioxazoline ligands capable of binding copper. In model 1,3-diene substrates, the olefinic position proximal to a directing group was selectively functionalized. Additional studies indicate that this selectivity stems from non-covalent substrate-catalyst interactions. The peptide-mediated nitrene transfer was also applied to polyene natural product retinol and selective proximal functionalization allowed access to a cis-pyrroline modified retinoid. (Figure presented.).

Full text of DOI:10.1002/adsc.201900631

Title: Site-Selective Nitrene Transfer to Conjugated Olefins Directed by
Oxazoline Peptide Ligands
Authors: Golo Storch, Naudin van den Heuvel, and Scott Miller
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10.1002/adsc.201900631
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Site-Selective Nitrene Transfer to Conjugated Olefins Directed
by Oxazoline Peptide Ligands
Golo Storch, Naudin van den Heuvel, and Scott J. Miller*
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
E-mail: scott.miller@yale.edu
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
mediated through hydrogen bonding (Figure 1B,
II).[8]
Abstract. Site-selective nitrene transfer to di- and
polyene substrates has been achieved using designed
peptide-embedded bioxazoline ligands capable of
binding copper. In model 1,3-diene substrates, the
olefinic position proximal to a directing group was
selectively functionalized. Additional studies indicate
that this selectivity stems from non-covalent substrate-
catalyst interactions. The peptide-mediated nitrene
transfer was also applied to polyene natural product
retinol and selective proximal functionalization allowed
access to a cis-pyrroline modified retinoid.
On the basis of precedents for reactions catalyzed by
peptidyl-copper complexes,[9,10] the use of amides as
directing groups in aziridinations,[11] and for
bis(oxazoline) ligands influencing the course of site-
selective reactions,[12] we wondered whether short
peptide sequences could be designed that would act
as ligands for transition metals and thereby allow for
achieving site-selective nitrene transfer as a function
of non-covalent substrate-catalyst interactions. With
the aim of subsequent application in oligo- and
polyene natural product functionalization, we were
especially interested in conjugated olefin substrates
(Figure 1C).
Keywords: peptide ligands • site-selectivity • polyene
natural products • nitrene transfer • aziridination
Chemo- and site-selective functionalization of
complex molecules via incorporation of nitrogen is a
valuable tool for diversifying biologically active
natural products.[1] In this context, nitrene transfer to
olefins—resulting in aziridination[2]—can potentially
be applied to a large variety of natural products since
carbon-carbon double bonds are a prevalent structural
feature. However, selective olefin modification is
challenging as a result of their non-polar properties.
On the other hand, selective nitrene transfer to
polyene natural products[3] (see Figure 1A for
examples) would offer access to derivatives with
potentially altered biological activity[4] and
additionally the vinylaziridine products would allow
for a variety of follow-up chemistry.[5] In most
reports on diene aziridination, site-selectivity, if
observed at all, has been a result of inherent
selectivity.[6] The first studies on catalyst-control in
diene functionalization were reported by Pérez and
coworkers
using
silver
complexes
of
homoscorpionate ligands (Tp*,Br) which allowed for
directing nitrene transfer to the closer olefinic
position, presumably as a result of catalyst
interactions with the OH-group (Figure 1B, I).[7] In a
related study, Schreiner and coworkers successfully
designed a RhII-catalyst for aziridination of the
central olefinic position in a farnesol derivative,
1
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10.1002/adsc.201900631
Advanced Synthesis & Catalysis
Figure 1. Polyene natural products and site-selective
enzymatic mechanism of cyclodehydration is initiated
via nucleophilic attack of the serine OH-group,[16b]
while synthetic strategies include the aza-Wittig
reaction,[17] and (di-ethylamino)sulfur trifluoride
(DAST) mediated dehydration (Figure 2B).[18]
Related to the recently reported and elegant approach
of Meldal and Diness,[19] we hypothesized that double
cyclodehydration of a Ser-Ser sequence would lead to
oxazoline peptides that are structurally related to
bidentate bioxazoline (BiOx) ligands (Figure 2B).
Indeed, treatment of linear peptide 1 with DAST
resulted in clean formation of bioxazoline 2 (Figure
2C). Complexation of 2 to Pd(CH3CN)2Cl2—square
planar d8 configuration analogous to CuIII nitrene
species—was studied in order to probe for transition
metal binding, and clean formation of one single
species was observed via NMR spectroscopy,
presumably the N,N-chelate 3 (Figure 2C, see SI for
details). These results allowed for preparation of
designed bioxazolines embedded in peptide structures.
aziridination
strategies.
TcesNH2:
2,2,2-
Trichloroethoxysulfonamide.
Oxazolines were also chosen as promising metal
coordinating residues due to the analogy to
bisoxazolines and related L2-type ligands[13] that are
highly effective ligands in copper-catalyzed
aziridinations. Furthermore, as a common structural
feature in peptide-based natural products, oxazolines
can be embedded in peptides via cyclodehydration of
serine residues—a post-translational modification
that results in alternation of hydrogen bonding
networks and rigidification of peptide structure.[14]
Naturally occurring oxazoline-containing peptides
have been found to bind transition metals in peptide
siderophores,[15] westiellamides, and patellamides
(Figure 2A).[16] However, to the best of our
knowledge, no catalytic activity for these naturally
occurring complexes has been reported so far. The
Figure 2. Examples of metal complexes of naturally occurring oxazolines and synthesis of oxazoline peptide ligands.
DAST: (diethylamino)sulfur trifluoride.
We began our catalytic studies with unsymmetrical
1,4-diarylbuta-1,3-dienes as model substrates since
we expected these compounds to share similarities
with polyene natural products in terms of reactivity,
while being easier to handle and less prone to
cis/trans isomerization. Also, they have previously
been investigated in terms of their analogy to
retinoids.[20] Non-covalent interaction sites were
installed in the aryl meta-position, since para-
functionalization was anticipated to be too remote
while ortho-modified substrates showed high intrinsic
selectivity as a result of electronic perturbance of the
diene unit. We focused on studying amide interaction
sites, and isovaleryl amide substrate 4, unlike similar
compounds, showed excellent solubility properties
and was therefore chosen for screening. However,
initial studies were hindered by the high reactivity of
the vinylaziridine products, which made their
isolation challenging. We considered this an
opportunity to develop a clean one-pot reaction
sequence for the functionalization of dienes. Using
parent 1,4-diphenyl-1,3-butadiene we were able to
identify and isolate the vinyl aziridine products and
found that a palladium–catalyzed hydrogenation with
2
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10.1002/adsc.201900631
Advanced Synthesis & Catalysis
formic acid[21] resulted in highly selective cleavage of
the allylic C-N bond while leaving the olefinic double
bond intact (Figure 3A, see SI for details). In a
control experiment we observed that 2,5-dimethyl-1-
tosyl-3-pyrrolidine is not converted to the
homoallylic amine under analogous reaction
conditions (see SI for details) and, therefore, the
involvement of pyrroline species stemming from
formal [4+1] addition of the nitrene may be less
likely. Interestingly, this one-pot reaction sequence to
homoallylic amines complements methods for site-
selective hydroamination of dienes.[22]
In order to assess intrinsic selectivity with bidentate
oxazoline ligands, we initially used bioxazoline 7 as a
truncated mimic of our oxazoline peptide ligands.[23]
Almost equal amounts of proximal and distal
products were formed (Figure 3B, entry 1). A quick
screen of commercial ligands revealed that
isopropylidene bisoxazolines performed slightly
better but still only with low site-selectivity (Figure
3B, entry 3). Our study of peptide ligands began with
optimizing the geometry of the chelating binding site
through a screen of serine epimers (Figure 3B, entry
4-6) that revealed superior performance of
homochiral ligands both in terms of yield and site-
selectivity compared to other epimers and also
commercial ligands. Investigation of a large variety
of C- and N-terminal modified peptide ligands
showed optimal results in cases with aromatic amino
acid side chains (Figure 3B, entry 7-12), which led to
the identification of the Boc-Phe-[Ser]-[Ser]-NH-
CHPh2 sequence that resulted in good yield and
selectivity greater than 1 : 5, favouring proximal
functionalization. Notably, high levels of selectivity
were maintained concomitant with only a slight
decrease in yield at lowered catalyst loading (Figure
3B, entry 13).[24] Direct comparison of experiments in
CH2Cl2 and CH3CN (Figure 3B, entry 1,2 & 7,8)
revealed that site-selectivity in the peptide ligand
catalyses is fully depleted when using a polar organic
solvent capable of interfering with defined non-
covalent substrate-catalyst interactions.
In order to gain more detailed insights into the origins
of the site-selectivity enhancement, we expanded our
study to similar meta-substituted 1,4-diaryl-1,3-
butadiene substrates. We were especially curious
whether indications for a hydrogen bond between the
substrate amide NH and the catalyst could be found.
In this context, we studied trifluoroacetamide 10 in
direct comparison to the N-methylated analogue 11
(Figure 4, A). Bn-BiOx, again, resulted in an
unselective reaction with 10, and screening (see SI
for details) of our peptide oxazoline library led to the
identification of a sequence—Boc-Phe-[Ser]-[Ser]-
3,3-Dpa-OBn—with significantly improved site-
selectivity (Figure 4B, Entry 1-2). Intriguingly, none
of this selectivity enhancement was observed in the
case of N-methylated substrate 11, which even
showed a slight inherent selectivity towards the distal
product (Figure 4B, Entry 3-4).
Figure 3. Investigation of unsymmetrical 1,4-diarylbuta-1,3-dienes as polyene model substrates in an aziridination-
hydrogenation sequence. [a]: Average of two catalysis trials. [b]: Determined by NMR versus trimethyl trimesic acid
internal standard. [c]: CH3CN/CH2Cl2 (4:1) instead of CH2Cl2 as solvent. [d]: 10 mol% copper catalyst.
This observation supports involvement of the NH
group in hydrogen bonding interaction between
substrate and catalyst. Additionally, we studied 12
bearing an electron-rich 4-methoxybenzoyl group that
could potentially engage in secondary π-stacking
interactions. Ligand Boc-Phe-[Ser]-[Ser]-NH-CHPh2
(see SI for all data points) resulted in a significant
site-selectivity increase to 1 : 6.4 favouring the
proximal product, which corresponds to almost
fourfold intrinsic selectivity (Figure 4B, Entries 5-6).
On the basis of these results, we turned our attention
towards an application of peptide oxazolines to the
site-selective functionalization of the polyene natural
product retinol, as postulated in Figure 1A. Interest in
derivatives of the latter mainly stems from activity in
dermatology and cancer treatment. In this context,
synthetic derivatives offer the possibility to increase
stability towards cis/trans isomerism as well as
selectivity enhancement for certain types of
receptors.[25] Also, retinol contains a primary alcohol
3
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10.1002/adsc.201900631
Advanced Synthesis & Catalysis
functionality that we hypothesized could act as non-
covalent directing group with the peptide ligands.
Following the general reaction scheme (Figure 5A),
we aimed for functionalization of the proximal, polar
site. Using UPLC-MS analysis, the reaction using
Bn-BOX 8 was found to result in multiple species
each exhibiting MS characteristics consistent with
reaction of retinol with the nitrene source (see SI for
details). However, using Boc-Phe-[Ser]-[Ser]-Phe-
OMe, formation of all but two products was
suppressed, which were identified as cis-13 and
trans-13 (in almost equal amounts), two
diastereomers of proximal functionalization. Most
probably this overall [4+1] cycloaddition occurs via
ring expansion of an initially formed vinyl aziridine
intermediate (Figure 5A, top right).[26,27]
days (Figure 5B).
Figure 5. Site-selective functionalization of retinol. (i)
1.0 equiv. retinol, 1.0 equiv. TsNIPh, 24 mol% ligand, 20
mol% [Cu(CH3CN)4]BF4, 10 equiv. Na2SO4, 33 mM in
CH2Cl2, 0 °C to r.t., overnight, 50%.
In contrast, isolated cis-13 remained unchanged under
analogous
conditions
and
the
increased
thermodynamic stability of cis-13 has been confirmed
by DFT studies on a model pyrroline (see SI for
details). This product epimerization implies that the
peptide-catalyzed version of this reaction overall
results in exclusive formation of cis-13 in 50% yield
(NMR versus internal standard) without using either
retinol or TsNIPh in excess.
In this study, peptide embedded oxazolines were
designed and applied as ligands for site-selective
nitrene transfer reactions with model dienes and—at
the proof-of-concept level—the polyene natural
product retinol. Additional studies strongly point
towards non-covalent interactions between substrate
and catalyst being the origin of highly increased
selectivity for reactive sites close to directing groups
capable of hydrogen-bonding. The successful
selective functionalization of retinol via clean
formation of stable pyrroline products opens up a
variety of possible applications of this catalytic
system, for example nitrene transfer to polyene
antibiotics. Furthermore, this new class of bidentate
oxazoline ligands could be useful in a variety of
different catalytic transformations, with their C1-
symmetry allowing for diverse tuning in the context
of addressing challenges in stereo- and site-selective
transformations.
Figure 4. Study of non-covalent substrate-catalyst
interactions as origin for the increased site-selectivity. The
distal functionalization product of 10 in the solid state[28] is
depicted. [a] Results are the average of two catalytic trials.
[b] 10 mol% catalyst loading, yields and site-selectivity
determined via UPLC-MS versus trimethyl trimesic acid
internal standard. [c] 20 mol% catalyst loading, yields and
site-selectivity determined via NMR versus trimethyl
trimesic acid internal standard. Dpa: 3,3-Diphenylalanine.
Experimental Section
The Supporting Information contains experimental details
for substrate synthesis, characterization of all catalysts and
products, copies of NMR spectra, additional data regarding
the analysis of catalytic experiments and assignments, as
well as details on DFT investigations.
In order to probe for hydrogen bonding interactions,
we also studied CH3CN as a polar solvent, which
fully inhibited the Bn-BOX-mediated reaction while
the peptide variant still showed formation of 13,
albeit with significantly reduced yield and selectivity
(see SI for details). Intriguingly, the isolated pyrroline
retinoid trans-13 underwent reversible ring-opening
in CDCl3 solution resulting in complete, clean
epimerization to cis-13 over the course of several
General procedure for the DAST mediated
cyclodeydration
The serine peptide (1.0 equiv.) was dissolved in CH2Cl2
(anhydrous, 0.1 M) and the solution was cooled to –78 °C.
DAST (3.0 equiv.) was added and the reaction mixture was
stirred for 1 h at –78 °C and then slowly warmed to r.t. in
the cooling bath over additional 3 h (excess dry ice was
removed). The homogeneous, clear solution was then
cooled down to -78 °C again, K2CO3 (anhydrous, 6.0
equiv.) was added, and stirring was continued for 1 h.
Subsequently, the reaction mixture was poured into
NaHCO3 solution (aqueous, saturated, fivefold amount
w.r.t. CH2Cl2) and diluted with CH2Cl2 (fourfold amount
w.r.t. reaction solvent). The organic phase was separated
and the aqueous phase was extracted with CH2Cl2. The
combined organic phases were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude
product was purified via automated reversed phase
chromatography (load in CH3CN; C18 silica;
CH3CN/water; 1 CV: 30%, 10 CV: 30–100%, 1 CV:
100%; product containing fractions were combined,
4
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10.1002/adsc.201900631
Advanced Synthesis & Catalysis
extracted with CH2Cl2, dried over Na2SO4, filtered, and
concentrated under reduced pressure). The pure product
was precipitated from Et2O/npentane, dried in vacuo
overnight, and stored in a glove box to prevent
decomposition.
References
[1] a) J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem.
Res. 2012, 45, 911–922; b) J. M. Alderson, J. R. Corbin,
J. M. Schomaker, Acc. Chem. Res. 2017, 50, 2147–
2158; c) J. R. Clark, K. Feng, A. Sookezian, M. C.
White, Nat. Chem. 2018, 10, 583–591.
General procedure for the aziridination-hydrogenation
sequence
[2] a) S. Minakata, Acc. Chem. Res. 2009, 42, 1172–1182;
b) Y. Zhu, Q. Wang, R. G. Cornwall, Y. Shi, Chem.
Rev. 2014, 114, 8199–8256; c) L. Degennaro, P.
Trinchera, R. Luisi, Chem. Rev. 2014, 114, 7881–7929.
A Schlenk flask loaded with Na2SO4 (anhydrous, 0.50
mmol, 10 equiv.) was heated with a heat gun and
conditioned with N2 while cooling down to room
temperature. Ligand (12 µmol, 24 mol%) and
[Cu(CH3CN)4]BF4 (10.0 µmol, 20 mol%) were added, and
the flask was evacuated and backfilled with N2. Then,
CH2Cl2 (anhydrous, 2.0 mL, 25 mM w.r.t. nitrene source)
was added and the catalyst solution was stirred at room
temperature for 1 h. Subsequently, diene substrate (75.0
µmol, 1.5 equiv.) was added and the solution was cooled to
0 °C (ice bath) followed by addition of TsNIPh (50.0 µmol,
1.0 equiv.). The reaction was stirred at 0 °C for 1 h. While
still in the cooling bath, the reaction mixture was diluted
with THF (anhydrous, 2.0 mL), and DIPEA (anhydrous,
1.50 mmol, 30 equiv.), Pd2(dba)3 (10.0 µmol, 20 mol%),
and formic acid (1.50 mmol, 30 equiv.) were added. The
ice bath was removed and the reaction mixture was stirred
at room temperature for 2 h. Then, it was passed through a
plug of silica (Pasteur pipette, 5 cm, rinsed with 5 CV
hexanes/EtOAc (50:50)) and concentrated under reduced
pressure. The crude products were purified via automated
normal phase chromatography (silica; CH2Cl2/MeOH; 1
CV: 0%, 12 CV: 0–15%; all fractions containing product—
as determined by UPLC–MS analysis—were collected).
Then, 350 µL internal standard solution (trimethyl trimesic
acid in deacidified CDCl3, 47.7 mM, 16.7 µmol, 0.33
equiv.) was added, the sample was diluted with CDCl3, and
analyzed via NMR spectroscopy (10 s relaxation time).
[3] a) S. D. Rychnovsky, Chem. Rev. 1995, 95, 2021–
2040; b) C. Thirsk, A. Whiting, J. Chem. Soc., Perkin
Trans. 1 2002, 999–1023.
[4] F. M. D. Ismail, D. O. Levitsky, V. M. Dembitsky, Eur.
J. Med. Chem. 2009, 44, 3373–3387.
[5] a) J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247–258;
b) I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem.
Res. 2006, 39, 194–206; c) H. Ohno, Chem. Rev. 2014,
114, 7784–7814.
[6] a) J. G. Knight, M. P. Muldowney, Synlett 1995, 949–
951; b) M. Nishimura, S. Minakata, S. Thongchant, I.
Ryu, M. Komatsu, Tetrahedron Lett. 2000, 41, 7089–
7092; c) R. S. Atkinson, C. K. Meades, J. Chem. Soc.,
Perkin Trans. 1 2001, 1518–1527; d) C. Piangiolino, E.
Gallo, A. Caselli, S. Fantauzzi, F. Ragaini, S. Cenini,
Eur. J. Org. Chem. 2007, 743–750; e) D. J. Mack, J. T.
Njardarson, Chem. Sci. 2012, 3, 3321–3325; f) A.
Armstrong, R. D. C. Pullin, C. R. Jenner, J. N. Scutt, J.
Org. Chem. 2010, 75, 3499–3502.
[7] a) J. Llaveria, Á. Beltrán, M. M. Díaz-Requejo, M. I.
Matheu, S. Castillón, P. J. Pérez, Angew. Chem. Int. Ed.
2010, 49, 7092–7095; b) J. Llaveria, Á. Beltrán, W. M.
C. Sameera, A. Locati, M. M. Díaz-Requejo, M. I.
Matheu, S. Castillón, F. Maseras, P. J. Pérez, J. Am.
Chem. Soc. 2014, 136, 5342–5350.
Site-Selective Retinol Functionalization
A Schlenk flask loaded with Na2SO4 (anhydrous, 1.00
mmol, 10 equiv.) was heated with a hot air gun and
conditioned with N2 while cooling down to room
temperature. Ligand (12 µmol, 12 mol%) and
[Cu(CH3CN)4]BF4 (10.0 µmol, 10 mol%) were added, and
the flask was evacuated and backfilled with N2. Then,
CH2Cl2 (anhydrous, 3.0 mL, 33 mM w.r.t. nitrene source)
was added and the catalyst solution was stirred at room
temperature for 1 h. Subsequently, diene substrate
(100 µmol, 1.0 equiv.) was added and the solution was
cooled to 0 °C (ice bath) followed by addition of TsNIPh
(100 µmol, 1.0 equiv.). The reaction mixture was let warm
up in the cooling bath overnight. Subsequently, it was
passed through a plug of silica (Pasteur pipette, 5 cm,
rinsed with 5 CV hexanes/EtOAc (50:50)). See Figure SI-
21 for UPLC-MS analysis. Then, 700 µL internal standard
solution (trimethyl trimesic acid in deacidified CDCl3, 47.7
mM, 33.3 µmol, 0.33 equiv.) were added and the yield was
determined via NMR spectroscopy (10 s relaxation time).
[8]J.-P. Berndt, Y. Radchenko, J. Becker, C. Logemann, D.
R. Bhandari, R. Hrdina, P. R. Schreiner, Chem. Sci.
2019, 10, 3324–3329.
[9] M. K. Brown, S. J. Degrado, A. H. Hoveyda, Angew.
Chem. Int. Ed. 2005, 44, 5306–5310.
[10] a) B. Kim, A. J. Chinn, D. R. Fandrick, C. H.
Senanayake, R. A. Singer, S. J. Miller, J. Am. Chem.
Soc. 2016, 138, 7939–7945; b) A. J. Chinn, B. Kim, Y.
Kwon, S. J. Miller, J. Am. Chem. Soc. 2017, 139,
18107–18114; c) Y. Kwon, A. J. Chinn, B. Kim, S. J.
Miller, Angew. Chem. Int. Ed. 2018, 57, 6251–6255.
[11] F. Zhong, T. Bach, Chem. Eur. J. 2014, 20, 13522–
13526.
Acknowledgements
[12] C. L. Allen, S. J. Miller, Org. Lett. 2013, 15, 6178–
6181.
This work is supported by the National Institutes of Health (NIH
R35-GM132092). GS is also very grateful to the Deutsche For-
schungsgemeinschaft (DFG) for a postdoctoral fellowship (STO
1175/1-1). We also thank Dr. Brandon Q. Mercado for
assistance with X-ray crystallography.
[13] a) Z. Li, K. R. Conser, E. N. Jacobsen, J. Am. Chem.
Soc. 1993, 115, 5326–5327; b) D. A. Evans, M. M.
Faul, M. T. Bilodeau, B. A. Anderson, D. M. Barnes, J.
Am. Chem. Soc. 1993, 115, 5328–5329; c) G. Desimoni,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900631
Advanced Synthesis & Catalysis
G. Faita, K. A. Jørgensen, Chem. Rev. 2011, 111,
PR284–PR437.
[22] a) O. Löber, M. Kawatsura, J. F. Hartwig, J. Am.
Chem. Soc. 2001, 123, 4366–4367; b) J. Pawlas, Y.
Nakao, M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc.
2002, 124, 3669–3679; c) C. Brouwer, C. He, Angew.
Chem. Int. Ed. 2006, 45, 1744–1747; d) L. Huang, M.
Arndt, K. Gooßen, H. Heydt, L. J. Gooßen, Chem. Rev.
2015, 115, 2596–2697; e) X.-H. Yang, V. M. Dong, J.
Am. Chem. Soc. 2017, 139, 1774–1777; f) X.-H. Yang,
A. Lu, V. M. Dong, J. Am. Chem. Soc. 2017, 139,
14049–14052.
[14] a) G. Abbenante, D. P. Fairlie, L. R. Gahan, G. R.
Hanson, G. K. Pierens, A. L. van den Brenk, J. Am.
Chem. Soc. 1996, 118, 10384–10388; b) R. Sinha Roy,
A. M. Gehring, J. C. Milne, P. J. Belshaw, C. T. Walsh,
Nat. Prod. Rep. 1999, 16, 249–263; c) E. M. Nolan, C.
T. Walsh, ChemBioChem 2009, 10, 34–53; d) C. T.
Walsh, S. J. Malcolmson, T. S. Young, ACS Chem.
Biol. 2012, 7, 429–442; e) X. Yang, W. A. van der
Donk, Chem. Eur. J. 2013, 19, 7662–7677.
[23] Although the focus of this present study was on site-
selectivity, enantio-selectivity was also determined.
Proximal product 6 was formed racemic applying
ligand 7, with 35% ee using (S,S)-tBu-BOX, and with
32% ee in the case of Boc-Phe-[Ser]-[Ser]-Phe-OMe.
[15] a) G. A. Snow, Bacteriol. Rev. 1970, 34, 99–125; b)
M. Luo, E. A. Fadeev, J. T. Groves, Nat. Chem. Biol.
2005, 1, 149–153.
[16] a) A. L. van den Brenk, K. A. Byriel, D. P. Fairlie, L.
R. Gahan, G. R. Hanson, C. J. Hawkins, A. Jones, C. H.
L. Kennard, B. Moubaraki, K. S. Murray, Inorg. Chem.
[24] Further lowering of the catalyst loading to 5 mol%
resulted in no significant TON increase.
1994, 33, 3549–3557; b) P. Wipf, S. Venkatraman, C. P. [25] a) J. H. Barnard, J. C. Collings, A. Whiting, S. A.
Miller, S. J. Geib, Angew. Chem. Int. Ed. 1994, 33,
1516–1518.
Przyborski, T. B. Marder, Chem. Eur. J. 2009, 15,
11430–11442; b) R. Álvarez, B. Vaz, H. Gronemeyer,
Á. R. de Lera, Chem. Rev. 2014, 114, 1–125.
[17] M. Riedrich, S. Harkal, H.-D. Arndt, Angew. Chem.
Int. Ed. 2007, 46, 2701–2703.
[26] a) K. Fugami, Y. Morizawa, K. Ishima, H. Nozaki,
Tetrahedron Lett. 1985, 26, 857–860; b) M. Brichacek,
D. Lee, J. T. Njardarson, Org. Lett. 2008, 10, 5023–
5026; c) M. Brichacek, M. Navarro Villalobos, A.
Plichta, J. T. Njardarson, Org. Lett. 2011, 13, 1110–
1113; d) Q. Wu, J. Hu, X. Ren, J. Zhou, Chem. Eur. J.
2011, 17, 11553–11558.
[18] a) A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R.
Williams, Org. Lett. 2000, 2, 1165–1168; b) M.
Brandstätter, F. Roth, N. W. Luedtke, J. Org. Chem.
2015, 80, 40–51.
[19] C. B. Jacobsen, D. S. Nielsen, M. Meldal, F. Diness,
J. Org. Chem. 2019, DOI: 10.1021/acs.joc.9b00732.
[27] It has to be noted that based on the pyrroline product,
initial aziridination of the first or second double bond
could funnel to the same product species.
[20] a) M. T. Allen, D. G. Whitten, Chem. Rev. 1989, 89,
1691–1702; b) L.-y. Yang, R. S. H. Liu, K. J. Boarman,
N. L. Wendt, J. Liu, J. Am. Chem. Soc. 2005, 127,
2404–2405.
[28] CCDC-1943272
contains
the
supplementary
crystallographic data and it can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[21] A. Satake, I. Shimizu, A. Yamamoto, Synlett 1995,
64–68.
6
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10.1002/adsc.201900631
Advanced Synthesis & Catalysis
COMMUNICATION
Site-Selective Nitrene Transfer to Conjugated
Olefins Mediated by Oxazoline Peptide Ligands
TOC Graphic
Adv. Synth. Catal. Year, Volume, Page – Page
Golo Storch, Naudin van den Heuvel, and Scott J.
Miller*
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