Lipidated cyclopropenes via a stable 3-N spirocyclopropene scaffold

Article abstract of DOI:10.1016/j.tetlet.2018.08.010

Lipidated cyclopropenes serve as useful bioorthogonal reagents for imaging cell membranes due to the cyclopropene's small size and ability to ligate with pro-fluorescent tetrazines. Previously, the lipidation of cyclopropenes required modification at the C3 position because methods to append lipids at C1/C2 were not available. Herein, we describe C1/C2 lipidation with the biologically active lipid ceramide and a common phospholipid using a cyclopropene scaffold whose reactivity with 1,2,4,5-tetrazines has been caged.

Full text of DOI:10.1016/j.tetlet.2018.08.010

Accepted Manuscript
Lipidated cyclopropenes via a stable 3-N spirocyclopropene scaffold
Pratik Kumar, Ting Jiang, Omar Zainul, Alyssa N. Preston, Sining Li, Joshua
D. Farr, Pavit Suri, Scott T. Laughlin
PII:
S0040-4039(18)30980-8
https://doi.org/10.1016/j.tetlet.2018.08.010
TETL 50185
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 May 2018
24 July 2018
6 August 2018
Please cite this article as: Kumar, P., Jiang, T., Zainul, O., Preston, A.N., Li, S., Farr, J.D., Suri, P., Laughlin, S.T.,
Lipidated cyclopropenes via a stable 3-N spirocyclopropene scaffold, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.08.010
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spirocyclopropene scaffold
Pratik Kumar, Ting Jiang, Omar Zainul, Alyssa N. Preston, Sining Li, Joshua D. Farr, Pavit Suri and Scott T.
Laughlin

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Lipidated cyclopropenes via a stable 3-N spirocyclopropene scaffold
Pratik Kumara, Ting Jianga, Omar Zainula, Alyssa N. Prestona, Sining Lia, Joshua D. Farra,b, Pavit Suria and
Scott T. Laughlin,a
a Department of Chemistry, Stony Brook University, Stony Brook, NY, 11790, United States
b Current address: Department of Chemistry, Stanford University, Stanford, CA, 94305, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Lipidated cyclopropenes serve as useful bioorthogonal reagents for imaging cell membranes due
to the cyclopropene’s small size and ability to ligate with pro-fluorescent tetrazines. Previously,
the lipidation of cyclopropenes required modification at the C3 position because methods to
append lipids at C1/C2 were not available. Herein, we describe C1/C2 lipidation with the
biologically active lipid ceramide and a common phospholipid using a cyclopropene scaffold
whose reactivity with 1,2,4,5-tetrazines has been caged.
Available online
Keywords:
2018 Elsevier Ltd. All rights reserved.
Cyclopropene tetrazine
Bioorthogonal chemistry
Click chemistry
Lipid
photocage
———

Corresponding author: scott.laughlin@stonybrook.edu, (+1) 631-632-2642

2
Tetrahedron
acid are challenging and rare in the literature.13,20 Alternatively, the
functionalization handle could be installed using a lipid-modified
protected alkyne precursor (R = functional group protected lipid,
Fig. 1), but such functionalized alkyne lipids are commercially
uncommon, expensive and difficult to synthesize (e.g. Avanti®
polar lipids offers four alkyne-modified lipids and the cheapest is
~$150/mg). There are also strategies for cyclopropene
modification at C1/C2 on intact cyclopropenes to obtain secondary
alcohols21–23 but they require challenging conjugation conditions
to attach lipids via an ether or, after a non-trivial oxidation, a
ketone.
Methods for the addition of bulky biomolecules such as lipids
at the C1/2 position of a cyclopropene, instead of C3, would be
desirable for several reasons. For example, C1/C2 derivatization
strategies will expand the accessible cyclopropene chemical space.
Additionally, substituting C1/C2 has been shown to increase the
stability of cyclopropenes.10 As a result, lipidation at C1/C2 could
serve the dual purpose of stabilizing the cyclopropene while
minimizing the size at C3 to limit negative steric effects on the
cyclopropene’s reactivity with 1,2,4,5-tetrazines. Indeed,
modifications of C1/C2 place the substituent orthogonal to the
approach of the tetrazine along the ligation’s reaction coordinate,
resulting in only modest reaction rate deceleration relative to
unmodified cyclopropenes. For example, Ye and co-workers
demonstrated that C1 methylation of a C3-amide-containing
cyclopropene produced only a modest decrease of 9% in the
cyclopropene’s ligation rate.24 Conversely, di-substitutions at C3
cause substantial deceleration or complete inhibition of the
cyclopropene-tetrazine ligation.1,7,25
Figure 2. (A) Photocaged 3-N cyclopropenes allow light-mediated control of
cyclopropene-tetrazine bioorthogonal ligation. Such 3-N cyclopropene
formation requires an EWG to prevent rearrangement to an alkyne or allene.
Installing a linker on the EWG-stabilized 3-N spirocyclopropenes will enable
an alternative to currently available C3 modification for attaching lipids (or
other biomolecules) to cyclopropenes. (B) Lipids can be attached to 3-N
cyclopropenes either at C1/C2 or on the pyrrolidine ring (C) Retrosynthetic
analysis for Cp1 identified aspartic acid as an inexpensive starting point with
the ‘difluorinated intermediate’ as a key scaffold.
Cyclopropenes are popular bioorthogonal reagents for
exploring native biomolecules’ roles in biology.1 They have been
used extensively with sugars,2–4 proteins,5–9 oligonucleotides,10,11
neurotransmitters,12,13 and, to a limited extent, lipids.14,15 The
application of cyclopropenes to lipid biology is particularly
interesting because lipids are one of the few biomolecules with
naturally occurring cyclopropene-containing metabolites,
including sterculynic acid,15 sterculic acid,16 and malvalic acid.17
Produced in plants, these naturally occurring cyclopropene-
bearing lipids have diverse functions, from promoting liver tumor
formation18 to exhibiting anti-parasitic properties, likely through
their inhibition of lipid metabolism.19 Similarly fascinating,
unnatural cyclopropene-modified lipids have found applications in
bioorthogonal chemistry, including, for example, Devaraj and co-
workers’ preparation of a C3 lipidated cyclopropene (see Fig. 1 for
cyclopropene carbon numbering) and demonstration of its use as a
tool for live-cell imaging of mammalian cells.14
Figure 1. Current strategies to append cyclopropene handles onto
biomolecules proceed via modification at the cyclopropene C3 position.
Cyclopropenes are first prepared via rhodium catalysed addition of ethyl
diazoacetate to alkynes, which are then modified at C3 to append biomolecules
such as lipids.
Finally, lipidation at C3 is not directly compatible with our
recently described ‘caged cyclopropene’ strategy, which provides
external control over the cyclopropene-tetrazine ligation (Fig.
2A).26 These caged cyclopropenes were inspired by the >7500-fold
difference in reaction rate between C3 mono-substituted and C3
di-substituted cyclopropenes.25,27 Essentially, a carbamate-caged
3-N spirocyclopropene mimics the unreactive C3 di-substituted
cyclopropene, whereas the uncaged, 3-N spirocyclopropene
mimics the more reactive C3 di-substituted cyclopropene, with the
addition of an electron withdrawing group at C3 critical to prevent
the ring opening isomerization to an allene or alkyne.28 The
constraints of the spirocyclopropene scaffold complicate efforts to
append biomolecules at C3, which contains the required electron
withdrawing group. As a result, biomolecules such as lipids must
be appended to C1/C2 or elsewhere on the scaffold to create target
Unfortunately, lipidation of cyclopropenes for biorthogonal
chemistry applications is typically restricted to addition of the lipid
to the C3 position of the cyclopropene. This is due to the limited
number of synthetic procedures that enable direct derivatization of
cyclopropenes with biomolecules at C1 or C2. For example, it is
possible to generate a cyclopropene that is already modified at C1
with an alkyl alcohol by the rhodium catalyzed addition of ethyl
diazoacetate to a protected alcoholic alkyne (R= protected alkyl
alcohol, Fig. 1). The protected alcohol could then be deprotected
and oxidized to obtain a carboxylic acid handle for further
elaboration. However, examples of the oxidation of such
cyclopropene C1-alcohols to the corresponding cyclopropene C1-
Scheme 1. Synthesis of five-membered scaffold 6 with a linker for 3-N spirocyclopropene formation.

3
compounds such as CpL1 or CpL2 (Fig. 2B), and both options
initial attempts using equimolar equivalents of DAST at low or
possess few synthetic precedents.
room temperature for varying amounts of time produced no
reaction. Doubling the molar equivalents of DAST and adding it
under cold conditions afforded 7 in 5% yield and tripling the
DAST equivalents improved the yield to 10%. However, extensive
efforts to further optimize the reaction through alterations to time,
solvents, and temperature, or through the use of a different
fluorinating agent Selectfluor, produced no further improvement
in yield.
Herein, we describe the synthesis of a novel class of lipidated
cyclopropene. We explore the addition of functionality onto the
spirocyclic ring as well as the cyclopropene C1/C2 position.
Additionally, we describe the application of a reagent that installs
an ester group at C1/C2 in one step from the corresponding
cyclopropene, and we employ this strategy to generate
cyclopropenes modified with two important classes of biologically
relevant lipids: ceramides and phospholipids.
We hypothesized that the bulky TBDPS group limits DAST’s
access to the ketone, so we switched to the less bulky MOM
protecting group (Scheme S2, ESI). For these transformations,
diazo 5 was stable to the requisite de- and re-protection conditions,
proceeding without issue to give deprotected alcohol S2 in 90%
yield. Interestingly, this is only the second report of fluoride-
mediated silyl ether deprotection in the presence of diazo
functionality and the first report employing TBAF deprotection of
TBDPS in these systems.32 Next, we MOM-protected the free
alcohol S2 to obtain S3 in 68% yield. Subsequent rhodium
catalyzed cyclization afforded S4, the MOM-protected derivative
of 7, in 93% yield as a mixture of diastereomers. However, despite
the diminutive MOM protecting group, our extensive efforts at
difluorinating ketone S4 produced S5 with yields in the 5% range
and never fully consumed the starting material. Ultimately,
although a maximum yield of 10% for the difluorinated 7 may
have been acceptable at late stages in the synthesis, it was not
feasible to carry out the next nine linear steps to generate the
desired lipidated cyclopropenes. Further, as described earlier, the
alkyne containing ceramides and phospholipids are either non-
existent or difficult to synthesize, suggesting that rhodium-
catalyzed cyclopropenation with an alkyne lipid would not be
straightforward; therefore, we explored the possibility of lipidation
at C1/C2, after the formation of the cyclopropene scaffold.
To begin, modification of the caged cyclopropene scaffold on
the pyrrolidine ring of the spirocyclic framework represents the
best possible option: no rate deceleration would be expected from
the addition of a bulky group adjacent to the tetrazine approach
trajectory, and we would not have to alter the nature of the
difluoromethylene substituent at the cyclopropene C3. To explore
this possibility, we sought to synthesize difluorinated
spirocyclopropene Cp1, which contains a carboxylic acid-bearing
linker on the carbon adjacent to the caged nitrogen group (Fig. 2C).
We began the synthesis of Cp1 with a NaBH4-mediated
reduction of bis-protected L-aspartic acid 1 to the corresponding
alcohol S1 (Scheme S1 in the ESI), which we protected using
TBDPSCl to obtain 2 in 92% yield over two steps (Scheme 1). We
then subjected 2 to Pd-mediated deprotection of the benzyl ester to
give carboxylic acid 3 in 85% yield, activated the resulting acid
using CDI, and proceeded directly to the Mg-mediated production
of β-keto ester 4 in 80% yield over two steps. The acidity of the
methylene sandwiched between the ketone and ester groups
allowed us to convert 4 to the corresponding diazo compound 5.
Subsequently, compound 5 was cyclized using Rh insertion29 with
a non-stereoselective catalyst30 to obtain the five membered, 3-
oxopyrrolidine-2-carboxylate based scaffold 6 in 96% yield as a
mixture of diastereomers.
Methods for attaching an amine or acid handle at the C1/C2
position of an intact cyclopropene were, with one exception,
unprecedented in the literature. The one exception is our recently
reported orthoformate strategy that installs an ester in one step
from the corresponding cyclopropene.26 Here, we explored a
variety of electrophiles in an effort to expand the scope for
installation of carboxylic acid functionality on 15 (Scheme S3,
The ketone intermediate 6 was an ideal candidate for
installation of the difluoro group, which is necessary for stability
of the cyclopropene in this bicyclic scaffold.28 To perform the
difluorination, we employed DAST, which has been successfully
used to carry out difluorinations of similar proline analogs.31 Our
Scheme 2. Synthesis of C1-ceramide, photocaged 3-N spirocyclopropene after installation of a C1-acid.

4
Tetrahedron
Scheme 3. Synthesis of C1-phospholipid, photocaged 3-N spirocyclopropene via a C1-acid containing cyclopropene.
ESI). For example, we attempted to install an alcohol using
oxirane or paraformaldehyde after treatment of the cyclopropene
with n-BuLi, but this produced only unreacted starting material.
We then explored the reaction with a tosyl-activated alcohol linked
to a dihydrooxazole-protected carboxylic acid. This reagent should
participate in base-mediated substitution of the tosylate at the
cyclopropene C1/C2, and the dihydrooxazole could be
subsequently hydrolysed to the carboxylic acid. However, our
attempts at nucleophilic substitution using n-BuLi produced a
mixture of unreacted starting material and oxazole decomposition.
Ultimately, of all electrophiles tested, the iodo-orthoformates were
the only electrophile that efficiently modified C1/C2 on the
cyclopropene, producing the orthoformate-modified cyclopropene
in high yield that quantitatively hydrolysed to the corresponding
ester upon silica gel chromatography, and, after saponification,
produced the racemic spirocyclopropene acid 16 (Scheme 2).
Importantly, employing the racemic compound 16 will produce a
mixture of diastereomers upon conjugation with biologically
active chiral lipids. However, the biological activity of lipids such
as the ceramides and phospholipids described below tolerates the
addition of structurally diverse tags, including large racemic trans-
cycloctenes33 and fluorophores.34
chloride/ruthenium-periodate conditions, so we proceeded with
ethyl trifluoroacetate protected analogs instead. We performed the
11–12 reaction sequence in one pot because our attempts to purify
the intermediates resulted in substantially lower overall yields due
to their decomposition on silica gel. Essentially, we converted
cyclic sulfate 11 to the sulfate ester-iodide using Bu4NI,
dehydrohalogentated the intermediate using DBU to produce the
sulfate alkene, and hydrolysed the sulfate under acidic conditions
to obtain 12 in 49% yield over three steps. Then, this N,O-bis
protected sphingosine 12 was TBDPS-deprotected using the
fluoride source Bu4NF to obtain a 23% yield of 13, which was
converted to the D-erythro-sphingosine 14 by base-mediated
hydrolysis in 82% yield.
The free amine sphingosine 14 was coupled to the 3-N
spirocyclopropene acid 16 using HATU to obtain the C1-ceramide
Boc-cyclopropene 17 in 76% yield. Finally, the lipidated-
cyclopropene was Boc-deprotected to obtain free amine C1-
ceramidated 3-N spirocyclopropene 18 in 22% yield. Importantly,
the low yields of 18 are due to difficulties inherent to the
purification of this charged lipid, not decomposition, because
similar cyclopropene scaffolds, including the Boc- and Nvoc-
protected variants of 18, have survived acidic HPLC and
deprotection conditions unscathed.26 Separately, the Nvoc
photocaged version was prepared directly without purifying the
Boc-deprotected intermediate 18 to obtain 19 in 89% yield over
two steps.
Finally, we explored lipidation of the carboxylic-acid-modified
cyclopropene C1 with two different classes of bioactive lipids:
ceramide and
a phospholipid. Ceramides are important
components of a eukaryotic cell lipidome. They make up
sphingomyelin, a major bilayer lipid, and control a variety of
cellular signaling processes.35,36 Consequently, functionalized
ceramides, such as a fluorophore-modified BODIPY-ceramide,
are employed for tracking the biological functions of ceramides in
the cell. Bioorthogonal chemistry-based applications include a
recently described trans-cyclooctene-containing ceramide analog
that Schepartz and co-workers used for super-resolution imaging
of the Golgi in living cells.33 The availability of a cyclopropene
analog of ceramide will further increase the available options for
bioorthogonal reagents that can be used to study ceramide
dynamics.
Like ceramides, phospholipids represent another important
class of biologically relevant lipids. The amphiphilic character of
phospholipids makes them a major component of the lipid bilayer
in the cell plasma membrane. The availability of a photocaged,
cyclopropene-containing phospholipid will permit its applications
as a bioorthogonal probe to study membrane biology. We installed
a commercially available phospholipid, 1,2-dioleoyl-sn-glycero-
3-phosphoethanolamine (18:1 (Δ9-cis) PE), at the C1 position of
cyclopropene 16 to obtain C1 phospholipidated 3-N
spirocyclopropene 20 in 21% yield, which, upon Boc deprotection,
afforded 21 in 40% yield. Similar to the photocaged ceramide
cyclopropene lipid, the Nvoc photocaged version 22 was prepared
without purifying the Boc-deprotected intermediate 21 to obtain
22 in 38% yield over two steps (Scheme 3). However, the amounts
obtained complicated our efforts at full spectroscopic
characterization other than HRMS due to the complexity of the
molecule, modest reaction yields, and high cost of the
phospholipid starting material.
To obtain a C1-ceramide containing spirocyclopropene we
started from D-ribo-phytosphingosine, a commercially available
reagent (Scheme 2, and Scheme S4, ESI). Ceramides are
sphingosines where the amine on the sphingosine contains
hydrophobic residues via an amide linkage. We converted D-ribo-
phytosphingosine to D-erythro-sphingosine using slight
modifications to the synthetic strategy reported by Kim and co-
workers.37 Briefly, the dual protection of the amine group on D-
ribo-phytosphingosine using ethyl trifluoroacetate to obtain 8, and
the primary alcohol with TBDPSCl to obtain 9 proceeded in
quantitative yield. Next, we converted 9 to cyclic sulfite 10 with
thionyl chloride. We found this cyclic sulfite to be unstable to
silica gel and overnight storage. Therefore, we subjected it
immediately to ruthenium-periodate oxidation to obtain the cyclic
sulfate 11 in 68% yield over two steps. Additionally, in our hands,
the trityl protected analogues were unstable to the required thionyl
In summary, we describe a method for the C1-lipidation of
cyclopropenes. We have generated two biologically relevant, C1-
lipidated cyclopropenes using an acid functionalized 3-N
spirocyclopropene scaffold. Both the C1-ceramide- and
phospholipid-linked spirocyclopropene represent the first
examples of cyclopropene modifications with biomolecules on the
alkenic C1/C2 position.

5
Acknowledgments
The authors thank B. O’Neill for critical reading of the manuscript.
This work was supported by a grant to S.T.L. from the National
Science Foundation (CHE1451366).
Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at
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6
Tetrahedron
 Cyclopropenes are popular bioorthogonal tags
for ligation with 1,2,4,5-tetrazines
Modification at cyclopropene alkene carbons is
synthetically challenging
Synthesis of biologically relevant cyclopropene-
modified lipids is described

