Photochemical Strain-Release-Driven Cyclobutylation of C(sp3)-Centered Radicals

Article abstract of DOI:10.1002/anie.201908951

A new photoredox-catalyzed decarboxylative radical addition approach to functionalized cyclobutanes is described. The reaction involves an unprecedented formal Giese-type addition of C(sp³)-centered radicals to highly strained bicyclo[1.1.0]but

Full text of DOI:10.1002/anie.201908951

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Accepted Article
Title: Photochemical Strain-Release Driven Cyclobutylation of C(sp3)-
centered Radicals
Authors: Guillaume Ernouf, Egor Chirkin, Lydia Rhyman, Ponnadurai
Ramasami, and Jean-Christophe Cintrat
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908951
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10.1002/anie.201908951
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Photochemical Strain-Release-Driven Cyclobutylation of C(sp3)-
centered Radicals
Guillaume Ernouf,*[a]+ Egor Chirkin,[a]+ Lydia Rhyman,[b] Ponnadurai Ramasami,[b] and Jean-Christophe
Cintrat*[a]
Abstract:
A
new photoredox-catalyzed decarboxylative radical
scope and the absence of photocatalyst, the BCB-boronate
complex has to be prepared in situ using t-BuLi and consecutive
1,2-metallate rearrangement needs to operate at –78 °C to afford
satisfying diastereoselectivity.
Acting in a complementary way, our approach relies on the
addition of highly nucleophilic radicals to the C–C central σ-bond
of BCBs for straightforward incorporation of the cyclobutane
moiety. While those radicals would be generated from the
abundant feedstock of α-amino acids by visible-light-mediated
decarboxylation,[15] the use of phenylsulfone as traceless BCB-
activating group would enable access to late-stage
“cyclobutylated” products after sequential reductive cleavage
(Scheme 1B).
addition approach to functionalized cyclobutanes is described. The
reaction involves an unprecedented formal Giese-type addition of
C(sp3)-centered radicals to highly strained bicyclo[1.1.0]butanes. The
mild photoredox conditions, which make use of a readily available and
bench stable phenyl sulfonyl bicyclo[1.1.0]butane, proved to be
amenable to a diverse range of α-amino and α-oxy carboxylic acids,
providing
a concise route to 1,3-disubstituted cyclobutanes.
Furthermore, kinetic studies and DFT calculations unveiled
mechanistic details on bicyclo[1.1.0]butane reactivity relative to the
corresponding olefin system.
In recent years, the development of synthetic methods toward
functionalized cyclobutanes has attracted substantial attention[1]
because they can act as conformationally restricted scaffolds [2]
and C(sp3)-rich complexity-generating building blocks.[3] Several
drugs such as the serotonin reuptake inhibitor sibutramine, [4] the
HCV-protease inhibitor boceprevir,[5] the analgesic nalbuphine[6]
and the drug candidate IGF-1R-inhibitor linsitinib,[7] contain the
four-membered ring (Scheme 1A).[8] Nonetheless, compared to
the high prevalence of common carbocycles such as
cyclohexanes and cyclopropanes in marketed drugs, the
occurrence of cyclobutanes is scarce.[9] In this regard, a direct and
prompt access to alkylated cyclobutanes would significantly
enlarge the chemical space explored in drug discovery programs.
To provide a novel synthetic toolkit toward functionalized
cyclobutanes, we envisaged to exploit the peculiar reactivity of the
bicyclo[1.1.0]butane (BCB) framework. BCBs display
a
remarkable ring strain energy[10] of 64 kcal.mol-1 and high
-character of the central C–C bond, which can serve as a
surrogate for the corresponding olefin.[11] The recent surge of
interest in strain-release strategies led to the preparation of
unusual strained bioisosters, such as bicyclo[1.1.0]pentanes,
azetidines and cyclobutanes, through nucleophilic additions[12] or
transition metal catalysis.[13] By contrast, radical additions to the
central bond of BCBs had been confined for a long time to a few
sporadic examples.[14] During the course of our investigation,
Aggarwal et al. reported the addition of electron-deficient radicals
to BCB-boronate complexes.[14b] Despite the wide substrate
Scheme 1. Cyclobutanes in medicinal chemistry (A) and decarboxylative
conjugate radical addition (B).
To investigate our proposed reaction, initial studies focused
on the decarboxylative reaction between N-Cbz-protected proline
1 and the bench-stable BCB 2a (Table 1).[16] After a screening of
bases (entries 2–4) and solvent systems (entries 5, 6), we were
delighted to discover that the cesium salt, formed by
[a]
[b]
[+]
Dr. G. Ernouf,+ Dr. E. Chirkin,+ Dr. J.-C. Cintrat
Service de Chimie Bio-organique et Marquage (SCBM), CEA,
Université Paris-Saclay, 91191 Gif-sur-Yvette, France.
E-mail: guillaume.ernouf@orange.fr
E-mail: jean-christophe.cintrat@cea.fr
Dr. L. Rhyman, Dr. P. Ramasami
Computational Chemistry Group, Department if Chemistry, Faculty
of Science, University of Mauritius, Réduit, 80837 Mauritius.
Department of Chemical Sciences, University of Johannesburg,
Doornfontein, Johannesburg 2028, South Africa.
These authors contributed equally to this work.
deprotonation of
extrusion/conjugate addition on BCB 2a upon irradiation with a
40 W blue LED lamp in the presence of
1
with Cs2CO3, led to the CO2-
Ir[dF(CF3)ppy]2(dtbbpy)PF6 in MeCN to afford the “cyclobutylated”
product 3a in 84% yield (entry 1). In line with previous reports on
nucleophilic addition of “turbo amides” on such systems, almost
no diastereoselectivity was observed.[12] Remarkably, only 0.5
mol % of the photocatalyst was sufficient to promote the reaction
with high efficiency on a 1 mmol scale (entry 7). During the
optimization, we noticed that the addition of water (10 equiv) was
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201908951
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crucial for the overall efficiency of this protocol, while the use of
anhydrous conditions dropped the yield to 68% (entry 8).
Presumably, water both assists in solubilizing the cesium
carboxylate and provides a proton source to quench the
intermediate anion after radical addition and reduction.[17] It is
worth noting that cyanobenzene-based organic photocatalyst
4CzIPN (entry 9) and biocatalytic cofactor riboflavin tetrabutyrate
(entry 10) could promote the conjugate addition, although with
limited efficacy. Finally, control experiments confirmed that both
the photocatalyst and visible light were essential for the desired
transformation to occur (entries 11, 12).
in excellent yields. Under the same conditions, N-pivaloyl-
protected proline furnished adduct 3d, albeit in a slightly lower
yield (58%). Given the importance of nitrogen-containing
saturated heterocycles in medicinal chemistry, we were delighted
to find that N-Boc-protected piperidine, azetidine, morpholine and
piperazine-based substrates readily participated in this
transformation providing products 9–12 in high yields (68–98%).
By contrast, the unproductive attempts to react cyclohexyl radical
with BCB 2a, highlighted the crucial role of the α-substituent for
the success of the reaction.[18] Because of the poor solubility of
the starting material, switching solvent from MeCN to DMSO was
necessary to generate N-Boc thiomorpholine adduct 13 in good
yield (53%). During our survey, the reaction was found to be quite
sensitive to the nature of the α-aminoalkyl radical. Thus, our initial
attempts to expand the scope of this transformation to substrates
bearing free NH group was met with limited success. In MeCN,
1,3-disubstituted cyclobutane 15 derived from glycine was only
isolated in 42% yield with a significant amount of unconverted
starting material, whereas N-methylated acyclic amino acids, e.g.
sarcosine (14), performed with good efficiency (Table S2).[16] The
choice of solvent was of essential importance for the inclusion of
NH amino acids as the yield of adduct 15 eventually rose to 67%
when DMA was used.
Table 1. Optimization studies.
Entry
1
Deviation from above
none
Yield 3a[a]
84 (16)[b]
40 (N.D.)
23 (36)
Table 2. Scope of bicyclo[1.1.0]butanes.
2
K2CO3
3
CsF
4
TMG
53 (24)
5
DMSO
58 (13)
6
DMF
47 (30)
7
0.5 mol %
w/o H2O
80 (N.D.)[c]
68 (28)
8
9
4CzIPN
19 (24)
10
11
12
riboflavin tetrabutyrate
w/o photocatalyst
w/o light
34 (48)
0 (91)
0 (N.D.)
Further exploration of amino acid inventory showed that these
slightly modified reaction conditions were compatible with a wide
range of N-Boc protected secondary amino acids, including
alanine, phenylalanine, cysteine and glutamine (16–19). Likewise,
N-Boc glutamic acid 5-benzyl ester and benzyl-protected histidine
were viable substrates, affording 20 (59%) and 21 (88%),
respectively. Remarkably, the unprotected indole moiety of N-Boc
tryptophan was rather well tolerated, giving adduct 22 in a
moderate 34% yield. The reaction also worked well in the
presence of pharmaceutically relevant fluorine, hydroxyl and
carbonyl substituents (23–25) and was compatible with the
tetrahydroisoquinoline moiety (26). Use of tertiary α-amino
cyclopropyl radical met with moderate success (27). The
surprising reluctance of N-Boc-N-methyl phenylglycine may arise
from the loss of the high-lying SOMO-character of the radical due
to the presence of phenyl ring (28).[16] α-Oxy radicals were also
suitable partners, yielding tetrahydrofuran 29 and tetrahydropyran
30 in 48% and 42% yield, respectively. In each instance, the
reaction proceeds with negligible diastereoselectivity.
[a] Isolated yield on 0.1 mmol scale. Recovered starting material in
parentheses. [b] Average of three runs. [c] 1 mmol scale. 4CzIPN = 1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyano-benzene, Cbz = carboxybenzyl, DMSO =
dimethylsulfoxide, DMF = N,N-dimethylformamide, dtbbpy = 4,4’-di-tert-
butyl-2,2’-dipyridyl, N.D. = not determined, ppy = 2-phenylpyridine, TMG =
1,1,3,3-tetramethylguanidine.
With optimal reaction conditions in hand, the scope of this
transformation with respect to the BCB partner was assessed
(Table 2). The reaction was found to be compatible with BCBs
bearing electron-withdrawing (4) and electron-donating (5) aryl
substituents with a slight drop in yield for the latter. Use of less
electron-withdrawing aryl sulfoxide instead of the corresponding
aryl sulfone afforded 6 in 55% yield. Finally, BCB carboxylate
derivatives reacted efficiently to give the corresponding addition
products in high yields (7, 8).
To expand the generality of the reaction, we next investigated
the scope of carboxylic acid component (Table 3). First, other α-
carbamyl radicals derived from protected proline were explored.
N-Boc and N-Bac protecting groups (3b, 3c) were shown to
perform similarly, delivering the desired “cyclobutylated” products
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Table 3. Scope of carboxylic acids.
All yields are isolated yields. Ratios of diastereomers determined by mass-directed RP-HPLC analysis of the crude reaction mixture lie between 1:1 and 3.5:1
(see SI). [a] In DMSO. [b] In DMA. [c] dr = 4:1, as determined by 19F NMR based on the desulfonylated product. Bac = tert-butylaminocarbonyl, Boc =
tert-butoxycarbonyl, Bn = benzyl, DMA = N,N-dimethylacetamide, Piv = pivaloyl.
To demonstrate the potential of our methodology for late-
stage functionalization, we turned our attention to more complex
radical precursors. A simple dipeptide Z-Gly-Pro-OH along with
more challenging tetrapeptide were proficient substrates (31, 32).
Furthermore, the mild reaction conditions were compatible with
densely functionalized antihypertensive drugs Valsartan (33) and
Ramipril (34). Upon ester cleavage, the latter compound can
afford an “elongated” carboxylic acid valuable for medicinal
chemistry studies.
We then showcased the synthetic usefulness of aryl sulfone
moiety through diverse transformations (Scheme 2). A traceless
cyclobutylation could easily be achieved through phenyl sulfone
cleavage under mild reductive conditions (Mg, MeOH) in excellent
yield (35). The exalted acidity of the proton adjacent to the phenyl
sulfonyl group enabled the deprotonation/alkylation sequence
giving rise to allyl cyclobutane 36 after reductive desulfonylation.
Interestingly, direct arylation of the sulfone was envisaged
through iron-catalyzed cross-coupling, albeit with limited
success.[19]
The mechanistic details on our photoredox decarboxylative
conjugate addition are outlined in Scheme 3A. Initial single-
electron transfer (SET) between the photoexcited Ir(III) catalyst
and the in situ formed cesium carboxylate I generates α-carboxyl
radical II that undergoes CO2-extrusion to form the carbon-
centered radical III. Upon Giese radical addition of the highly
nucleophilic species III to BCB 2a, strain-release driven rupture of
the central σ-bond generates the α-sulfonyl radical IV. Completion
of the photocatalytic cycle would then be achieved via reduction
of the radical intermediate IV with the strongly reducing Ir(II)
photocatalyst followed by protonation of the resultant α-sulfonyl
anion V to furnish the α-amino “cyclobutylated” sulfone 3a. The
proposed single-electron reduction of IV to the corresponding
Scheme 2. Product functionalization
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anion V was further supported by deuterium-labelling experiment.
When the reaction was carried out with the preformed cesium salt
in the presence of deuterium oxide, the desired product [2H]-3a
was formed with 72% d-incorporation α to the phenyl sulfonyl
group, thus confirming the formation of the transient α-sulfonyl
anion V (Scheme 3B). Interestingly, despite numerous reports on
IV, dissipated a very high stabilization energy of 38.9 kcal.mol-1
resulting from the strain release vs. 22.1 kcal.mol-1 for IV. These
calculations turned out to be in good accordance with the
experimental observations and comprehensively explained why
the radical addition to the BCB is less favored than to the
corresponding olefin.
BCB
polymerization
processes,[14,20] cyclobutyl
radical
intermediate IV did not undergo telomerization, showing that
reduction/protonation are faster processes.
Figure 1. Relative energies for radical addition to BCB 2a and vinyl sulfone 37.
In summary, we have demonstrated the utility of
bicyclo[1.1.0]butanes as radical acceptors for the direct and mild
C(sp3)–C(sp3) bond formation via visible light-mediated
photoredox catalysis. The protocol provides a concise access to
highly valuable alkylated cyclobutanes, thus allowing the
introduction of a high degree of structural complexity within one
synthetic step. From a synthetic standpoint, the mild reaction
conditions together with the tolerance toward a range of diverse
functional groups render the devised strategy potentially
amenable to late-stage derivatization of complex molecules. The
transition from the batch cyclobutylation to continuous flow
conditions is a subject of ongoing research in our laboratory.
Scheme 3. Mechanistic investigations and competition experiment.
Once the performance of bicyclo[1.1.0]butane 2a in this
decarboxylative Giese-type reaction was established, we
compared its reactivity to that of the corresponding phenyl vinyl
sulfone 37. In the competition experiment, the olefin 37 proved to
be more reactive than BCB 2a leading predominantly to adduct
38 in a 92:8 ratio (Scheme 3C). Kinetic studies carried out with
these electrophiles revealed that the addition of the radical to vinyl
sulfone went to completion within 0.5 h, while addition to the BCB
required several hours.[16] This finding was in agreement with
previously reported higher reaction rates of acrylates as
compared to various BCBs in a glutathione (GSH)-based
assay.[12b] Density functional theory (DFT) method (UM06-2x/6-
31G(d)) was then employed to corroborate the experimental
results and to provide insights into the reasons behind this drastic
difference in reactivity. End-on addition of pyrrolidine radical III to
BCB 2a proceeded smoothly with an 18.4 kcal.mol-1 free energy
of activation. Comparatively, phenyl vinyl sulfone acted as an
excellent radical acceptor with a free energy of activation
amounting to a mere 9.4 kcal.mol-1. On the other hand, the
cleavage of the central bond that led to BCB-radical intermediate
Acknowledgements
This work was supported by CEA. The authors thanks David-
Alexandre Buisson, Sabrina Lebrequier and Amélie Goudet
(DRF-JOLIOT-SCBM, CEA) for the excellent analytical support.
Keywords: bicyclo[1.1.0]butanes • cyclobutanes • late-stage
functionalization • photocatalysis • strained molecules
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[18] Under optimized condition in Table 1, cyclohexyl radical failed to provide
the adduct with BCB 2a. However, cyclohexyl radical readily reacted with
the phenyl vinyl sulfone 37 in 51% yield. More details and DFT
calculations given in Supporting Information.
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Entry for the Table of Contents
COMMUNICATION
High-lying SOMO radicals, generated
in situ under visible-light photoredox
conditions, undergo an efficient
G. Ernouf*, E. Chirkin, L. Rhyman, P.
Ramasami, and J.-C. Cintrat*
Page No. – Page No.
addition
to
highly
strained
bicyclo[1.1.0]butanes, providing
straightforward access to valuable
alkylated cyclobutanes.
a
Photochemical Strain-Release Driven
Cyclobutylation of C(sp3)-centered
Radicals
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