Guiding a divergent reaction by photochemical control: Bichromatic selective access to levulinates and butenolides

Article abstract of DOI:10.1039/c7sc05094a

Allylic and acrylic substrates may be efficiently transformed by a sequential bichromatic photochemical process into derivatives of levulinates or butenolides with high selectivity when phenanthrene is used as a regulator. Thus, UV-A photoinduced cross-metathesis (CM) couples the acrylic and allylic counterparts and subsequent UV-C irradiation initiates E-Z isomerization of the carbon-carbon double bond, followed by one of two competing processes; namely, cyclization by transesterification or a 1,5-H shift and tautomerization. Quantum chemical calculations demonstrate that intermediates are strongly blue-shifted for the cyclization while red-shifted for the 1,5-H shift reaction. Hence, delaying the double bond migration by employing UV-C absorbing phenanthrene, results in a selective novel divergent all-photochemical pathway for the synthesis of fundamental structural motifs of ubiquitous natural products.

Full text of DOI:10.1039/c7sc05094a

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Guiding a divergent reaction by photochemical control:
Bichromatic selective access to levulinates and butenolides†
Revannath L. Sutar,ab Saumik Sen,‡c Or Eivgi,‡a Gal Segalovich,a Igor Schapiro,c Ofer Reanyb and N.
Received 00th January 20xx,
Accepted 00th January 20xx
Gabriel Lemcoff*ad
DOI: 10.1039/x0xx00000x
Allylic and acrylic substrates may be efficiently transformed by a sequential bichromatic photochemical process into
derivatives of levulinates or butenolides with high selectivity when phenanthrene is used as a regulator. Thus, UV-A
photoinduced cross-metathesis (CM) couples the acrylic and allylic counterparts and subsequent UV-C irradiation initiates
E-Z isomerization of the carbon-carbon double bond, followed by one of two competing processes; namely, cyclization by
transesterification or a 1,5-H shift and tautomerization. Quantum chemical calculations demonstrate that intermediates
are strongly blue-shifted for the cyclization while red-shifted for the 1,5-H shift reaction. Hence, delaying the double bond
migration by employing UV-C absorbing phenanthrene, results in a selective novel divergent all-photochemical pathway
for the synthesis of fundamental structural motifs of ubiquitous natural products.
www.rsc.org/
During our studies on chromatically orthogonal metathesis
reactions using photo-switchable catalysts,11 the consecutive
irradiation at 350 nm and 254 nm UV light of a solution of α-
Introduction
Chemistry with light provides
a range of creative synthetic
vinylbenzyl alcohol and methyl acrylate resulted in the nonselective
synthesis of two products, butenolide and
levulinate.12
possibilities.1 Many chemical transformations promoted by light,
such as photosynthesis, the cis–trans photoisomerization of the
protonated Schiff base of 11-cis-retinal and the synthesis of vitamin
a
a
Levulinates13 and butenolides14 are exceptionally ubiquitous, and
some prominent natural products and derivatives containing these
motifs are highlighted in Fig. 1.15 Indeed, the development of
efficient synthetic routes for their preparation continues to be an
active area of interest to synthetic chemists and many
methodologies have been put forth recently.13,15a,c-e,16 The ability to
obtain different products utilizing the same starting materials and
intermediates, especially by photochemical processes under mild
conditions, may pose an important synthetic and industrial
advantage.17 Moreover; photochemistry possesses the inherent
property of being able to be remotely controlled.18
D
are vital for the existence of life on earth.2 Conversely,
photocycloadditions caused by UV radiation, may result in DNA
damage leading to cancer.3 To safeguard us from this, perhaps
mimicking organisms that evolved UV protecting molecules,4
chemists have developed sunscreens,5 which deflect or absorb
these harmful radiations. Inspired by the way evolution has
selected molecules to block certain UV wavelengths to follow
specific biochemical pathways,6 selective photochemical syntheses
of organic frameworks may be imposed depending on whether
molecular light filters are present or not. Indeed, photochemical
outcomes of divergent organic reactions may be controlled by
subtle changes in the substrate, reaction conditions or the use of
sensitizers.7 Recently, we employed UV light absorbing organic
molecules in a selective deprotection of photolabile protecting
groups and photo-induced cross-metathesis.8 Moreover, the
selective use of light of different frequencies to promote distinct
chemical reactions, i.e. chromatic orthogonality,9 has been applied
in synthetic procedures, including the synthesis of a natural peptide
product.10
Herein, we report selective divergent all-photochemical
syntheses of levulinates and butanolide derivatives using simple
starting materials. Following a UV-A photoinduced cross-metathesis
reaction, UV-C irradiation generates the desired products.
Mechanistic and computational studies elucidate the role of
phenanthrene as a UV-C modulator: the presence of phenanthrene
in the reaction suppresses the 1,5-H shift pathway leading to high
selectivity in the formation of butenolides, while excluding the
phenanthrene allows the opposite selectivity (Scheme 1). Several
examples are shown highlighting the scope and broad implications
of this method, including the selective synthesis of a natural
product molecule in a very efficient and convenient manner.
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Indeed, decreasing the reaction temperature by about 10 oC
reduced lactonization and shifted the reaction towards the
levulinate compound (see ESI† for details). Better still, higher than
90% selectivity for 5b was achieved when bulky 2b was used as the
CM partner in step 1 (Table 1, entry 2). Next, we tested whether the
addition of a bulky alcohol could help provide the necessary steric
barrier to inhibit the lactonization reaction by hydrogen bonding to
3. This could be quite practical if less sterically demanding acrylates
are desired as the CM partners, especially because methyl and butyl
acrylates are amongst the most important acrylic esters, with great
demand as commodity chemicals. In addition, the possibility to
apply different acrylates expands the scope of levulinate products
that may be directly obtained by the divergent sequence. To our
satisfaction, high selectivities for the 1,5-H shift were achieved
t
when one equivalent of BuOH was added to the reaction solution
during irradiation of E-3a with 254 nm light. Further optimization of
t
reaction conditions showed that a mixture of BuOH and DCM (1:4)
Fig. 1 Selected examples of natural products containing butenolides and
gave the best selectivity for 5a (Table 1, entry 1). Notably, reactions
with 2a and 2b were very convenient given that excess acrylate
could be easily removed by evaporation after the CM reactions,
allowing sequential reactions without purification of the
intermediate.
levulinates.
Results and Discussion
The first step of the desired sequence is a photoinduced CM
reaction between an allylic (1) and an acrylic (2) substrate.19 For
this, photolatent S-chelated ruthenium benzylidenes were used.20
Even though the CM reaction may also be efficiently promoted by
typical ruthenium metathesis catalysts, the use of photolatent
precatalysts allows for an all-photochemical method that can be
both spatially and temporally controlled.10 Thus, UV-A induced CM
between 1a and 2a or 2b was readily promoted by the robust
catalyst, cis-Ru I in good yields (Table 1, entries 1 and 2).
Evaporation of the excess acrylate, without the need for further
purification, set up the stage for the second photochemical step. In
more complex CM reactions, for example when acrylates 2c-2e or
allyl alcohols 1c and 1d were used (Tabe 1, entries 3-9), cis-Ru I
proved to be a less efficient CM catalyst. To our satisfaction, a
faster initiating photolatent catalyst (cis-Ru II)21 could perform
better in these difficult cases, highlighting the advantages of the
versatility of the S-chelated family of catalysts.
Table 1 Sequential photochemical reactions.a
CM Productb
Butenolidec
Keto esterd
Entry
Allyl alcohol
Acrylate
O
O
O
OH
O
Ph
Ph
O
OMe
1
OMe
OtBu
Ph
Ph
Ph
OMe
OH
Ph
O
1a
2a
3a, 89%
4a, 71%
5a, 73% (>25:1)
O
O
O
O
O
O
OH
Ph
O
O
OtBu
2
3
4
5
OtBu
OnBu
OBn
OH
Ph
O
1a
2b
3b, 94%
4a, 69%
5b, 60% (13:1)
O
O
OH
Ph
O
Ph
O
OnBu
OnBu
Ph
Ph
OH
Ph
O
1a
2c
3c, 77%
4a (7:2)
5c, 68% (40:1)
O
O
OH
Ph
O
Ph
O
OBn
OBn
OH
Ph
O
1a
2d
3d, 82%
4a (3:1)
O
5d, 67% (>25:1)
O
O
O
OH
Ph
O(4-tBu)Ph
Ph
O(4-tBu)Ph
Ph
O(4-tBu)Ph
OH
Ph
O
1a
2e
3e, 74%
4a (>25:1)
5e (Decomposition)
O
O
O
O
O
OH
O
nC9H19
OBn
O
6
OBn
nC9H19
nC9H19
OBn
2d
nC9H19
OH
O
1b
3f, 78%
4b, 60%
5f (2:1)
O
O
OH
O
nC9H19
O(4-tBu)Ph
O
7
8
nC9H19
O(4-tBu)Ph
nC9H19
O(4-tBu)Ph
nC9H19
OH
O
1b
2e
3g, 75%
4b (>25:1)
5g (1:>25)
Scheme 1 Bichromatic selective divergent reaction.
O
O
O
HO
O
HO
OtBu
HO
OtBu
OtBu
OH
1c
HO
Because ruthenium by-products are known to catalyze non-
metathetic processes,22 the possible role of the ruthenium species
in the second part of the sequence was examined. Two samples of
E-3a, one made by the aforementioned CM route and the other by
a metal-free route,23 were subjected to irradiation at 254 nm under
identical conditions. Similar results were obtained in both cases;
demonstrating that the conversion to 4a and 5a are sheer
photochemical processes not assisted by ruthenium. We then
surmised that the transesterification24 could be stifled by running
the reaction at lower temperature or by the use of a bulky acrylate.
OH
O
5h, 51% (15:1)e
2b
3h, 45%
4c, 61%
O
OH
OH
O
OH O
O
O
HO
HO
HO
9
OtBu
OtBu
OtBu
HO
OH
OH
O
OH
5i, 46% (25:1)e
1d
2b
3i, 10%
4d, 59%
aReactions were conducted at 0.01M concentration in DCM at 25-30 oC. 10 equiv. of
acrylate was used in the CM reaction. The reported yields are isolated yields. Product
ratios in parentheses are based on 1H NMR analyses. See ESI† for further details. b For
entries 1 and 2, cis-Ru I (3 mol%) was used. For entries 3–7, 3 mol% while for entries 8
c
and 9, 6 mol% cis-Ru II was used. For entries 1-5, 2.1 equiv. and for entries 6–9, 0.3
equiv. of phenanthrene was used. The product ratios in the parentheses are 4:5. d For
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entries 2, 8 and 9, DCM and for entries 1 and 3–7, tBuOH/DCM (1:4) was used as the
solvent. The product ratios in the parentheses are 5:4. 0.1 mM aq. solution of
phenanthrene is not sensitizing the cyclization reaction, but is
indeed inhibiting the 1,5-H shift.
e
adenosine was used as an external UV-C filter to minimize side reactions (vide infra).
To promote the opposite selectivity, we envisioned applying the
molecular ‘UV-C filter’ protocol8 to prevent the photochemically
more demanding 1,5-H shift (vide infra). Indeed, after screening
several UV-C filters and reaction conditions, the irradiation of a
DCM solution of E-3a with phenanthrene afforded 71% isolated
yield of the butenolide (Table 1, entry 1). The amount of
phenanthrene required for selective lactonization was found to be
dependent on the molar absorptivity of the substrate. Thus, for
allylic alcohols bearing aromatic substituents, about 2 equiv. of
phenanthrene were required to achieve optimal selectivity; while
substiochiometric (0.3 equiv.) amounts of phenanthrene were
sufficient for the allyl alcohols with aliphatic substituents (Table 1).
The type of acrylate used also had a significant effect on the
selectivity of the lactonization process; thus, lactonization with n-
butyl acrylates was somewhat more sluggish and led to lower
selectivity (Table 1, entry 3), while the increased leaving group
ability of 4-t-phenyl acrylate (Table 1, entries 5 and 7) resulted in
butanolide formation even without the addition of phenanthrene
(albeit in lower yields due to detrimental decomposition). The
functional group tolerance and selectivity of the reaction sequence
was also probed with more challenging starting materials that
could, in principle, form different ring-size lactones. With this in
mind, 3h was irradiated at 254 nm in the presence of phenanthrene
(Table 1, entry 8). Hydroxymethyl butyrolactone (4c)24,25 was
selectively obtained with full retention of chirality, as expected. In
the same manner, optically pure 4d was obtained from 3i (Table 1,
entry 9). High selectivities, and decent overall isolated yields, were
also obtained for the levulinates 5h and 5i, the only difference in
the procedure being that the UV absorbing phenanthrene was not
added to the reaction mixture.
To better understand this remarkable photochemical divergent
process, we decided to investigate possible reaction mechanisms. It
is reasonable to assume that formation of the lactone (4a) occurred
through a typical diabatic photochemical E-Z isomerization of the
olefin,26 followed by transesterification. Likewise, ketone 5a may be
formed through a 1,5-H shift, generating a dienol intermediate (i5),
which may tautomerize to afford the final product (Scheme 1).27
Supporting this hypothesis, Z-3a was appreciably observed by
1H NMR monitoring during UV-C irradiation of E-3a. Wavelengths of
350 nm, 380 nm or even thermal stimuli, e.g. heating to 140 oC, did
not lead to isomerization; however, upon irradiation with 300 nm
light some Z compound was observed (see ESI† for details). The
generation of the dienol intermediate (i5) was validated by
deuterium labelling studies (Scheme 2, A). The photochemical
reaction in the presence of D2O/CD2Cl2 showed the incorporation of
deuterium at both the α- and β- positions in product 5a-D. Also, UV-
C irradiation of deuterium labelled intermediate 3b-D afforded a
product without deuterium (Scheme 2, A). As a further control
experiment, a reaction of the corresponding TMS-protected E-3a
was performed in CD2Cl2, forming the expected TMS-enolate
intermediate (see ESI† for details). These experiments strongly
support a 1,5-hydrogen shift mechanism to produce the dienol
intermediate (i5) and refute the occurrence of a plausible
photochemically induced 1,3-hydrogen shift. The effect of
phenanthrene on cyclization was probed by UV-C irradiation of 1e,
a substrate that can only cyclize (Scheme 2 B) both with and
without phenanthrene. In both cases cyclization to the lactone was
observed; however, the reaction was slower when phenanthrene
was present. This experiment clearly suggests that the
Scheme 2 Mechanistic studies.
Quantum chemical calculations were used to further study the
reaction mechanisms involving these processes. The brightest
excited state was found to be S2 for E-3j (Scheme 1, R = R' = Me)
with 189 nm and S3 for Z-3j with 192 nm. The excitation energies of
the E and Z isomers are very close ( ꢀE = 0.09 eV), and therefore
both can be excited by irradiation of UV light of the same
wavelength. The S9 state of phenanthrene lies at 193 nm (Table S5),
overlapping with the main absorption of both isomers of 3j. It is
therefore expected that addition of phenanthrene should decrease
the rate of the E-Z interconversion. As well noted in the literature,28
the computed vertical excitation energies are shifted from the
experimentally observed absorption maxima due to lack of solvent
effects, vibrational effects and accuracy of the quantum chemical
methods. Hence, we need to consider the excitation wavelength of
254 nm to be blue shifted in the theoretical context. To assess the
effect of the solvent on the vertical excitation energies, quantum
chemical calculations were carried out using an implicit solvent
model (see Table S5). In solution phase the spectra show a red shift
in the range of 2 to 16 nm. Hence, inclusion of the solvent model
shifts the vertical excitation energies towards the experimental
values. In order to rationalize the effect of phenanthrene on the
photochemical reactions, intermediates of the two divergent
reaction pathways were analyzed theoretically. The intermediate
for the levulinate formation pathway is a dienol (Scheme 1, i5j), and
the intermediate for the cyclization pathway is i4e. Excited state
energies reveal the brightest state (S2) of dienol intermediate i5j at
237 nm which is nearly coinciding with the wavelength of a high-
lying excited state S4 of the phenanthrene (240 nm). Although both
states are around 14-17 nm (0.29–0.35 eV) away from the
experimental excitation wavelength (energy), considering (i) the
blue shift of the computed vertical excitation energies with respect
to the experimental absorption maxima, (ii) the broadness of the
excitation source (ca 10 nm) and (iii) the deformation of the
geometry due to thermal energy, the excitation in this energy range
is feasible. This is supported by the experimental finding that also
excitation at 300 nm leads to levulinate formation. In case of the
cyclization reaction, i4e (S4) is found to absorb at 155 nm which
overlaps with the absorption of phenanthrene at 153 nm (S31).
However, the energy difference to the excitation source is
significantly higher considering the blue-shifted calculated energies
(at least 1.5 eV compared to 3j). In addition, the cyclic geometry is
more rigid than that of the dienol. The higher rigidity would lead to
smaller distortion from the minimum structure and a more narrow
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absorption band. Hence, the probability of light activation of dehalogenation29 during the isomerization to ketone (to afford 5a),
cyclization reaction is negligible. Therefore, we conclude that the while the aryl chloride was stable under these conditions (3n).
major role of the phenanthrene is to filter the wavelength that However, in the presence of phenanthrene, the radical
triggers 1,5-H shift and to suppress the pathway of levulinate dehalogenation is avoided, yielding the corresponding bromoaryl
formation while the cyclization is expected to proceed largely lactones (4f and 4g); and underlining the versatility of the UV-C
unaffected.
filter method in yet another photochemical reaction. CM of 2a with
methyl 4-hydroxyhex-5-enoate (1e) gave rise to a diester (3q) which
in principle could form two different cyclic esters in the presence of
phenanthrene: the saturated or unsaturated lactone. Interestingly,
compound 4k was the major product when phenanthrene was
added, verifying that the trans-cis isomerization process is faster
than simple cyclization. On the other hand, when 3q was irradiated
in the absence of phenanthrene (with added tBuOH) the symmetric
ketodiester 5o was exclusively produced. Unfortunately, tertiary
allyl alcohol CM products (3r and 3s) did not isomerize to the
ketoester (no alkyl shift) by UV-C irradiation, but did follow the
lactone pathway when protected by phenanthrene (4l, 4m).
a
Table 2 Reaction scope with allylic alcohols
.
Further prospects for this selective photochemical
transformation were investigated by probing the reaction sequence
on amines and amides. Due to the known susceptibility of
metathesis catalysts for amine containing substrates,30 N-Boc
protected allyl amine (1n) was used as the CM partner with methyl
acrylate (2a), which upon N-Boc-deprotection and irradiation with
254 nm light in the presence of phenanthrene, afforded the desired
lactam 4n.31 On the other hand, γ-ketoamides (5p and 5q) were
obtained in decent yields by the irradiation of CM products of α-
t
vinyl benzyl alcohol (1a) and acrylamides in the presence of BuOH,
as expected for the irradiation without UV protection (Scheme 3).
Moreover, the UV-C irradiation of 3t without phenanthrene
resulted in a complex mixture; highlighting the special role that
phenanthrene has in these reactions.
Scheme 3 Photochemical synthesis of N-containing compounds.
Finally, the applicability of this divergent tandem photochemical
process was rigorously tested in the total synthesis of a member of
the anti-allergenic cladospolide family, iso-cladospolide B,15a and
the enantiomer precursor (5r) of another natural product isolated
from the endophytic fungal strain Cladosporium tenuissimum of
Maytenus hookeri32 (Scheme 4). Thus, R-(+)-propylene oxide (7) was
opened with a Grignard reagent prepared from 8-iodoocta-1,3-
diene33 in the presence of CuI. The diene intermediate obtained
was selectively dihydroxylated using AD-mix-α to afford the novel
allyl alcohol 1o with high enantioselectivity (see ESI† for details).
Irradiation of 1o at 350 nm wavelength with 2b in the presence of
cis-Ru II, furnished 3w in good yields, notwithstanding the presence
of three hydroxyl groups in the molecule.19a,b Due to the relative
instability of the intermediates, further irradiation with 254 nm light
in the absence of UV-C filter gave a more complex mixture than
a Reported yields are isolated yields after purification and for the reaction times, see
ESI†. b For 3j, 3k, 3q and 3s, 0.3 equiv., for 3l–3p, 2.1 equiv., and for 3r, 2.3 equiv. of
phenanthrene was used as internal UV-C filter during lactonization. c cis-Ru II (3 mol%)
was used for metathesis reaction. d Around 21% of the saturated lactone was obtained.
The scope of the sequential chromatic divergent process was
scrutinized with several other substituted allyl alcohols and the
results are displayed in Table 2. Both aromatic and aliphatic
substrates underwent the expected photochemical transformations
resulting in moderate to good isolated yields of the corresponding
products. Notably, aryl bromides (3l and 3m) underwent radical
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usual. The use of a dilute adenosine aqueous solution following the The Israel Science Foundation is gratefully acknowledged for a
external UV-C filter protocol effectively inhibited the side reactions
and CM product 3w underwent a smooth and selective conversion
to ketone 5r, a valuable intermediate towards a biologically
relevant twelve-membered macrocycle and complex levulinate
F.I.R.S.T. grant 1067/15 (OR and NGL) and an individual ISF grant
537/14 (NGL) that funded this research. The Open University is
acknowledged for partial financial support. I.S. gratefully
acknowledges funding by European Research Council (ERC) under
the European Union's Horizon 2020 research and innovation
program (grant agreement No 678169 "PhotoMutant").
containing compounds.15e The alternative pathway,
a
photochemical tour de force, was achieved by irradiation with 254
nm light in the presence of phenanthrene as internal UV-C filter,
following the isomerization-cyclization path to give iso-cladospolide
B (4o),15a a natural product isolated from marine fungi; in four
protecting group free steps, the final two of which are
photochemical transformations and with a total overall yield of
26%.34
Notes and references
(1) K. Glusac, Nat. Chem., 2016, 8, 734–735.
(2) E. Ross, Nature, DOI:10.1038/nature.2017.21617.
(3) (a) W. J. Schreier, T. E. Schrader, F. O. Koller, P. Gilch, C. E. Crespo-
Hernández, V. N. Swaminathan, T. Carell, W. Zinth and B. Kohler, Science,
2007, 315, 625–629; (b) D. Mitchell, Proc. Natl. Acad. Sci., 2006, 103, 13567–
13568.
(4) (a) A. R. Osborn, K. H. Almabruk, G. Holzwarth, S. Asamizu, J. LaDu, K. M.
Kean, P . Karplus, R. L. Tanguay, A. T. Bakalinsky and T. Mahmud, eLife, 2015,
4, e05919; (b) Q. Gao and F. Garcia-Pichel, Nat. Rev. Microbiol., 2011, 9,
791–802.
(5) (a) V. G. Stavros, Nat. Chem., 2014, 6, 955–956; (b) U. Osterwalder and B.
Herzog, in Clinical guide to sunscreens and photoprotection; ed. H. W. Lim
and Z. D. Draelos; Informa Healthcare, New York, 2009; pp 11–38.
(6) A. A. Beckstead, Y. Zhang, M. S. Vries and B. Kohler, Phys. Chem. Chem.
Phys., 2016, 18, 24228–24238.
(7) For recent selected examples see: (a) E. Gorobets, N. E. Wong, R. S.
Paton and D. J. Derksen, Org. Lett., 2017, 19, 484–487; (b) W. Shu and C.
Nevado, Angew. Chem. Int. Ed. 2017, 56, 1881–1884; (c) C. Roscini, K. L.
Cubbage, M. Berry, A. J. Orr-Ewing and K. I. Booker-Milburn, Angew. Chem.
Int. Ed., 2009, 48, 8716 –8720.
(8) (a) O. Eivgi, R. L. Sutar, O. Reany and N. G. Lemcoff, Adv. Synth. Cat.,
2017, 359, 2352-2357; (b) O. Eivgi, E. Levin and N. G. Lemcoff, Org. Lett.,
2015, 17, 740−743.
Scheme 4 Application of a divergent photochemical sequence in total
synthesis.
a A 0.1 mM aqueous solution of adenosine was used as external UV-C filter. b 0.3 equiv.
of phenanthrene was used as internal UV-C filter.
(9) (a) M. J. Hansen, W. A. Velema, M. M. Lerch, W. Szymanski and B. L.
Feringa, Chem. Soc. Rev., 2015, 44, 3358–3377; (b) C. G. Bochet, Angew.
Chem. Int. ed., 2001, 40, 2071–2073.
(10) J-L. Débieux and C. G. Bochet, Chem. Sci., 2012, 3, 405–406.
(11) E. Levin, S. Mavila, O. Eivgi, E. Tzur and N. G. Lemcoff, Angew. Chem. Int.
Ed., 2015, 54, 12384–12388.
(12) R. L. Sutar, E. Levin, D. Butilkov, I. Goldberg, O. Reany and N. G. Lemcoff,
Angew. Chem. Int. Ed., 2016, 55, 764–767.
Conclusions
In summary, we have shown that by addition of phenanthrene as a
UV regulator, commonly available starting materials may be
selectively transformed into complex organic molecules by two
consecutive light induced reactions. Quantum chemical calculations
and experimental studies revealed important mechanistic aspects
of this photochemical process, highlighting the fundamental role of
phenanthrene in guiding the divergent reaction towards a selective
product by hindering a 1,5-H shift. The scope of the presented
sequential reactions and its limitations were exposed by the use of
several allylic and acrylic substrates as CM partners to produce a
wide variety of final products; including a natural product in a very
efficient manner. This method presents an original divergent
synthetic pathway and may inspire other types of controlled
photochemistry by adaptation of this protocol.
(13) A. Démolis, N. Essayem and F. Rataboul, ACS Sustainable Chem. Eng.,
2014, 2, 1338−1352.
(14) Q. Zhang, M. Cheng, X. Hu, B-G. Li and J-X. Ji, J. Am. Chem. Soc. 2010,
132, 7256–7257.
(15) (a) J. T. Edwards, R. R. Merchant, K. S. McClymont, K. W. Knouse, T. Qin,
L. R. Malins, B. Vokits, S. A. Shaw, D-H Bao, F-L. Wei, T. Zhou, M. D. Eastgate
and P. S. Baran, Nature, 2017, 545, 213–218; (b) S. Liu, H. Dai, G. Makhloufi,
C. Heering, C. Janiak, R. Hartmann, A. Mándi, T. Kurtán, W. E. G Müller, M. U.
Kassack, W. Lin, Z. Liu and P. Proksch, J. Nat. Prod., 2016, 79, 2332–2340; (c)
H. Renata, Q. Zhou, G. Dünstl, J. Felding, R. R. Merchant, C-H Yeh and P. S.
Baran, J. Am. Chem. Soc., 2015, 137, 1330−1340; (d) M. Paladino, J. Zaifman
and M. A. Ciufolini, Org. Lett., 2015, 17, 3422−3425; (e) A. Fürstner and T.
Nagayo, J. Am. Chem. Soc., 2007, 129, 1906−1907; (f) D. J. Edwards, B. L.
Marquez, L. M. Nogle, K. McPhai, D. E. Goeger, M. A. Roberts and W. H.
Gerwick, Chem. Biol., 2004, 11, 817−833; (g) F. Vergara, F. Plum and T. E
Duffy, Science, 1974, 183, 81–83.
(16) For reviews on the synthesis of butenolides and γ-lactams see: (a) B.
Mao, M. Fañanás-Mastral and B. L. Feringa, Chem. Rev., 2017, 117, 10502–
10566; (b) J. Caruano, G. G. Mucciolib and R. Robiette, Org. Biomol. Chem.,
2016, 14, 10134–10156; (c) D. W. Knight, Contemp. Org. Synth., 1994, 1,
287–315; (d) Y. S. Rao, Chem. Rev., 1976, 76, 625–694. For classical synthesis
of butenolides see: (e) Y. Kawamata, T. Hashimoto and K. A. Maruoka, J. Am.
Chem. Soc., 2016, 138, 5206–5209; (f) Y. Hoshimoto, T. Ohata, Y. Sasaoka,
M. Ohashi and S. Ogoshi, J. Am. Chem. Soc., 2014, 136, 15877−15880; (g) B.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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ARTICLE
Journal Name
Mao, K. Geurts, M. Fañanás-Mastral, A. W. van Zijl, S. P. Fletcher, A. J.
Minnaard and B. L. Feringa, Org. Lett., 2011, 13, 948–951; (h) G. B.
Bajracharya, P. S. Koranne, R. N. Nadaf, R. K. M. Gabr, K. Takenaka, S.
Takizawa and H. Sasai, Chem. Commun., 2010, 46, 9064–9066.
(17) D. Ghislieri, K. Gilmore and P. H. Seeberger, Angew. Chem. Int. Ed.,
2015, 54, 678 –682.
(18) (a) A. J. Teator and C. W. Bielawski, J. Polym. Sci. A Polym. Chem., 2017,
55, 2949–2960; (b) R. Göstl, A. Senf and S. Hecht, Chem. Soc. Rev., 2014, 43,
1982–1996.
(19) (a) K. Ramakrishna and K. P. Kaliappan, Org. Biomol. Chem., 2015, 13,
234–240; (b) C. M. Smith and G. A. O’Doherty, Org. Lett., 2003, 5, 1959–
1962; (c) A. K. Chatterjee, T-L. Choi, D. P. Sanders and R. H. Grubbs, J. Am.
Chem. Soc., 2003, 125, 11360–11370.
(20) A. Ben-Asuly, A. Aharoni, C. E. Diesendruck, Y. Vidavsky, I. Goldberg, B.
F. Straub and N. G. Lemcoff, Organometallics, 2009, 28, 4652–4655.
(21) Y. Ginzburg, A. Anaby, Y. Vidavsky, C. E. Diesendruck, A. Ben-Asuly, I.
Goldberg and N. G. Lemcoff, Organometallics, 2011, 30, 3430–3437.
(22) (a) G. K. Zieliński and K. Grela, Chem. Eur. J., 2016, 22, 9440–9454; (b) Y.
H. Nam and M. L. Snapper in Handbook of metathesis second edition volume
2: applications in organic synthesis ed. R. H. Grubbs, D. J. Ơleary; Wiley-VCH,
Weinheim 2015, p. 311; pp 311–380; (c) T. J. Donohoe, J. F. Bower and L. K.
M. Chan, Org. Biomol. Chem., 2012, 10, 1322−1328; (d) B. Alcaide, P.
Almendros and A. Luna, Chem. Rev., 2009, 109, 3817–3858; (e) D. Finnegan,
B. A. Seigal and M. L. Snapper, Org. Lett., 2006, 8, 2603–2606.
(23) C. T. Meta and K. Koide, Org. Lett., 2004, 6, 1785–1787.
(24) (a) J. Cardellach, C. Estopaj, M. Moreno-Manãs, R. M. Ortuño, F.
Sanchez-Ferrando, S. Valle and L. Vilamaio, Tetrahedron, 1982, 38, 2377–
2394; (b) C. Estopà, J. Font, M. Moreno-Mañas, F. Sánchez-Ferrando, S. Valle
and L. Vilamajó, Tetrahedron: Lett., 1981, 22, 1467–1470.
(25) A. L. Flourat, A. A. M. Peru, A. R. S. Teixeira, F. Brunissen and F. Allais,
Green Chem., 2015, 17, 404–412.
(26) (a) F. Parrino, A. D. Paola, V. Loddo, I. Pibiri, M. Bellardita and L.
Palmisano, Appl. Catal. B-Enviro., 2016, 182, 347–355; (b) J. B. Metternich
and R. Gilmour, Synlett., 2016, 27, 2541−2552; (c) N. W. A. Geraghty and E.
M. Hernon, Tetrahedron Lett., 2009, 50, 570–573; (d) K. A. B. Austin, M. G.
Banwell, D. T. J. Loong, A. D. Rae and A. C. Willis, Org. Biomol. Chem., 2005,
3, 1081–1088.
(27) (a) R. Mortezaei, D. Awandi, F. Henin, J. Muzart, J-P. Pete, J. Am. Chem.
Soc., 1988, 110, 4824−4826; (b) J. A. Barltrop, J. Wills, Tetrahedron Lett.,
1968, 9, 4987−4990; (c) P.J. Kropp, H. J. Krauss, J. Org. Chem., 1967, 8,
3222−3223.
(28) (a) M. Schreiber, M. R. Silva-Junior, S. P. A. Sauer and W. Thiel, J. Chem.
Phys., 2008, 128, 134110−134125 (b) E. R. Davidson and A. A. Jarzęcki,
Chem. Phys. Lett., 1998, 285, 155–159.
(29) J. T. Pinhey and R. D. G. Rigby, Tetrahedron Lett., 1969, 16, 1267–1270.
(30) B. J. Ireland, B. T. Dobigny and D. E. Fogg, ACS Catal., 2015, 5,
4690−4698.
(31) M. Sakamoto, K. Shiratsuki, N. Uemura, H. Ishikawa, Y. Yoshida, Y.
Kasashima and T. Mino, Chem. Eur. J., 2017, 23, 1717−1721.
(32) H-Q. Dai, Q-J. Kang, G-H. Li and Y. M. Shen, Helv. Chimi. Acta., 2006, 89,
527−531.
(33) A. G. Ross, X. Li and S. J. Danishefsky, J. Am. Chem. Soc., 2012, 134,
16080−16084.
(34) 4o was recently synthesized by a new methodology (ref. 15a) in 6 steps
starting from diethyl tartarate and in less than 10% yield, highlighting the
efficiency of our proposed photochemical method.
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