Stereoselective total syntheses of (-)-flueggine A and (+)-virosaine B

Article abstract of DOI:10.1002/anie.201208261

Convergent approach: The total syntheses of (-)-flueggine A and (+)-virosaine B (see scheme) have been accomplished in a concise and convergent manner. Key steps in these approaches were relay ring-closing metathesis reactions for rapid construction of the key intermediates, and 1,3-dipolar cycloaddition reactions for the formation of the natural products. Copyright

Full text of DOI:10.1002/anie.201208261

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Angewandte
Communications
DOI: 10.1002/anie.201208261
Natural Products
Stereoselective Total Syntheses of (ꢀ)-Flueggine A and
(+)-Virosaine B**
Hao Wei, Chuang Qiao, Gang Liu, Zhen Yang,* and Chuang-chuang Li*
The identification of new chemical entities is of paramount
importance to the biomedical sciences for the development of
novel therapeutic agents, and natural products have recently
been the subject of renewed and considerable attention in this
particular context.[1] Securinega alkaloids are an important
family of natural products derived from several Euphorbia-
ceae and Phyllanthus species of the Euphorbiaceae plant
family,[2] and have been used for years in traditional Chinese
and the Amazonia folk medicines.[3] More recently, these
alkaloids have been reported to exhibit important biological
activities, including diuretic, hepatic protection, antimicro-
bial, antibacterial, and GABAA receptor and tagonism.[4]
One merging class of the Securinega alkaloids include (ꢀ)-
Figure 1. Naturally occurring Securinega alkaloids.
flueggine A (1)[5] and (+)-virosaine B (2)[6] (Figure 1), which
were isolated from the twigs and leaves of Flueggea virosa by
Ye et al. in 2011 and 2012, respectively. Their structures and
absolute configurations were elucidated by means of NMR
spectroscopy, single-crystal X-ray diffraction, and circular
dichroism (CD) analyses. Other naturally occurring Secur-
inega alkaloids include (ꢀ)-norsecurinine (3),[7] (+)-allonor-
securinine (4),[8] securinine (5),[7] and flueggine B (6).[5]
Structurally, both flueggine A (1) and (+)-virosaine B (2)
possess a unique structural framework based on their
isoxazolidine and 7-oxa-1-azabicyclo[3.2.1]octane rings,
which is unprecedented in the Securinega alkaloids. In
addition to their unique structural features, 1 exhibited
anticancer activities in three cell lines with IC50 values of
60 ꢁ 4 mm (MCF-7), 86 ꢁ 9 mm (MDA-MB-231), and 68 ꢁ 7 mm
(MCF-7/ADR).[5]
In an extension of our continuing efforts toward the total
syntheses of biologically active natural products,[9] we decided
to synthesize these structurally novel natural products to
allow the effective evaluation of their biological properties.
Herein, we report the first total syntheses of (ꢀ)-flueggine A
(1) and (+)-virosaine B (2) with relay ring-closing meta-
thesis[10] (RRCM) and 1,3-dipolar cycloaddition reactions[11]
as the key steps of the approaches.
Retrosynthetically, we envisioned that (ꢀ)-flueggine A
(1) could be generated from (ꢀ)-norsecurinine (3) and
nitrone 7 through a concerted[12] 1,3-dipolar cycloaddition
reaction according to the proposed biogenetic pathway
(Figure 2).[5] (ꢀ)-Norsecurinine (3)[13] itself could be gener-
ated from the substituted dihydrobenzofuranone 9 by a bro-
mination–substitution sequence. In turn, compound 9 could
be generated from enyne 8 through an RRCM reaction. Thus,
our strategy for the total synthesis of (ꢀ)-flueggine A (1)
could be traced back to the construction of enyne 8, which we
envisaged could be derived from d-proline (6).
[*] Dr. H. Wei, C. Qiao, G. Liu, Prof. Dr. Z. Yang, Prof. Dr. C.-C. Li
Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School
Shenzhen, 518055 (China)
Following the biomimetic transformation proposed by Ye
and workers,[6] we envisaged that (+)-virosaine B (2) could be
formed by the intramolecular 1,3-dipolar cycloaddition from
nitrone 10, which could in turn be prepared from (+)-allo-
norsecurinine (4),[8,14] through a process involving a [2,3]-
Meisenheimer rearrangement[15] followed by a concerted
[1,3]-sigmatropic rearrangement[16] (see also Schemes 4 and
5). It was envisaged that the construction of (+)-allonorse-
curinine (4) could be achieved from d-proline (6) according
to a similar process to that descried for the construction of
(ꢀ)-norsecurinine (3) via the key intermediates 11 and 12
(Figure 2).
E-mail: zyang@pku.edu.cn
chuangli@pku.edu.cn
Prof. Dr. Z. Yang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS), and Peking-Tsinghua Center for Life
Sciences, Peking University
Beijing, 100871 (China)
[**] This work was supported by the 973 Program (Grant nos.
2011CB512002, 2010CB833201, and 2012CB722602), the Natural
Science Foundation of China (Grant nos. 21172009 and 20902007),
and Shenzhen Basic Research Program (JC200903160352A,
JC201005260097A, and CXB201005260053A). We also thank Profs.
Wei-Cai Ye and Ying Wang of Jinan University of China for sharing
the information of virosaine B.
The key step in our proposed synthesis was the tandem
RCM reaction. This reaction represents a powerful synthetic
tool and was initially developed by Grubbs et al.[17] in 1994 for
the preparation of fused bicyclic ring systems. The reaction
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208261.
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reactions[10a] to generate more active ester–carbene com-
plexes to afford dihydrobenzofuranones 9 and 11, respec-
tively.
The implementation of our synthetic plan started with the
asymmetric syntheses of enynes 8 and 12 (Scheme 2) accord-
ing to a method originally developed by Honda and co-
Figure 2. Retrosynthetic analysis. Boc=tert-butyloxycarbonyl.
has subsequently been used by many other groups for the
construction of a number of complex scaffolds.[18] Encouraged
by our recent model study toward the total synthesis of
nanolobatolide,[19] we decided to apply this powerful reaction
to the construction of (ꢀ)-norsecurinine (3) and (+)-allonor-
securinine (4).
Scheme 2. Syntheses of enynes 8 and 12. TBAF=tetra-n-butylammo-
nium fluoride, TFA=trifluoroacetic acid, TMS=tert-butyldimethylsilyl.
In 2004, Honda et al. attempted to construct the core
structure of (ꢀ)-securinine through a tandem RCM reac-
tion.[20] Unfortunately, however, the reaction did not provide
the desired g-lactone B from A, but gave d-lactone C in 69%
yield, because the catalyst[21] reacted preferentially with the
butenyl group rather than the acrylate moiety[22] to afford the
corresponding ruthenium–carbene complex, which undergoes
the tandem enyne metathesis (Scheme 1).
We speculated that the ruthenium-based catalyst would
react preferentially with the terminal olefin moieties of
substrates 8 and 12 to generate more active ester–carbene
complexes,[23] which would initiate the tandem enyne meta-
thesis for the formation of the corresponding annulated
products 9 and 11 (Scheme 3). The rationale behind this
strategy rests on the fact that the less sterically encumbered
terminal olefins in enynes 8 and 12 would react with the
ruthenium catalyst first, and then undergo relay metathesis
workers.[20] First, the commercially available Weinreb amide
13 was reacted with Grignard reagent 14 to give ketone 15 in
57% yield. This material was then treated with lithium
trimethylsilylacetylide (16) in the presence of CeCl3 to give
a tertiary alcohol 17 as the sole product in accordance with the
Felkin–Anh model. Subsequent removal of the TMS group in
17 with TBAF followed by acylation of the resulting tertiary
alcohol with acryloyl chloride derivative 18 in the presence of
EtMgBr as a base in THF at ꢀ788C gave trienyne 8 in 69%
yield over two steps.
For the synthesis of enyne 12, ketone 15 was treated with
TFA to remove its Boc group, and without isolation the
resulting secondary amine containing ketone was directly
reacted with lithium trimethylsilylacetylide (16), affording the
chelation-controlled[24] product 19 in 72% yield. Protection of
the amine with a Boc group and removal of the TMS group in
19, followed by acylation of the resulting tertiary alcohol with
acryloyl chloride 18, gave trienyne 12 in 57% yield over two
steps.
With enynes 8 and 12 in hand, we proceeded to explore
our proposed RRCM reaction for the formation of dihydro-
benzofuranones 9 and 11 (Scheme 3). The RRCM reactions
of enynes 8 and 12 were tested with several commercially
available metathesis catalysts, including Grubbsꢀ second
generation, Hoveyda–Grubbsꢀ, and Zhan-1b catalysts, with
Scheme 1. Synthesis of d-lactone C. Mes=2,4,6-trimethylphenyl.
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in acetone, the desired (+)-allonorsecurinine (4) was not
obtained. In contrast, (+)-allonorsecurinine (4) was formed in
49% yield when 11 was initially deprotected with TFA,
followed by annulation with K2CO3 in THF.
Interestingly, when the latter reaction was carried out in
the presence of nBu4NI, the yield for the formation of
(+)-allonorsecurinine (4) was improved to 87%, presumably
as a consequence of a bromo–iodo exchange reaction. The
physical properties of synthetic 4 were in good agreement
with those reported for the natural material.[8]
With (ꢀ)-norsecurinine (3) and (+)-allonorsecurinine (4)
in hand, we proceeded toward our proposed total syntheses of
(ꢀ)-flueggine A (1) and (+)-virosaine B (2).
Following the protocol developed by Magnus et al.,[27]
(ꢀ)-norsecurinine (3) was treated with mCPBA in MeOH
to chemoselectively afford N-oxide 20 (Scheme 4). The N-
oxide was then heated to reflux in xylene to initiate the
Scheme 3. Syntheses of (ꢀ)-norsecurinine (3) and (+)-Allonorsecuri-
nine (4). AIBN=azobisisobutyronitrile, NBS=N-bromosuccinimide.
the Zhan-1b catalyst providing the best results (see the
Supporting Information for further details). Thus, under the
optimized conditions, dihydrobenzofuranones 9 and 11 were
obtained in 64% and 67% yield, respectively. We infer that
the reaction proceeded via the active ester–carbene com-
plexes 8a and 12a as key intermediates. To the best of our
knowledge, the successful intramolecular reaction of “an
active ester–carbene complex” with an alkyne[25] to form an
a,b-unsaturated lactone has not been reported to date.
To complete the synthesis of (ꢀ)-norsecurinine (3), 9 was
initially converted to an allylic bromide by treatment with
NBS in the presence of AIBN.[20] During our preliminary
investigation, a literature procedure[20] was employed to
annulate the newly generated allylic bromide, involving the
removal of the Boc group with TFA, followed by a K2CO3-
mediated cyclization, giving (ꢀ)-norsecurinine (3) in 64%
yield. We later discovered that the bromide could be directly
annulated under the optimized conditions in the presence of
AgSbF6 in acetone to give (ꢀ)-norsecurinine (3) in 85% yield.
In this reaction, AgSbF6 might play the roles of both the
Lewis acid to deprotect the Boc group in the presence of trace
amounts of water,[26] and the Ag+ ion that captures the newly
formed bromide ion, thus making the latter a better leaving
group. The physical properties of the synthetic (ꢀ)-norse-
curinine (3) were compared to those reported for the natural
product and found to be in good agreement,[7] including the
1H and 13C NMR data and the optical rotation.
Scheme 4. Total Synthesis of (ꢀ)-flueggine A (1). mCPBA=meta-
chloroperoxybenzoic acid.
sequential [2,3]-Meisenheimer and [1,3]-sigmatropic rear-
rangements to afford O-alkylhydroxylamine 21 in 90%
yield via intermediate 20a. Further treatment of 21 with
mCPBA[27,28] gave nitrone 7 via 21a. Compound 7 was then
reacted with (ꢀ)-norsecurinine (3) in refluxing toluene for
12 h to afford (ꢀ)-flueggine A (1) through a 1,3-dipolar
1
addition in 77% yield. The H and 13C NMR spectra of the
synthesized (ꢀ)-flueggine A (1) were identical to those
reported for the natural product. The optical rotation was
30
also in good agreement (synthetic 1: ½aꢂD ¼ꢀ32.8 (c = 0.20,
20
CH3OH); natural 1: ½aꢂD ¼ꢀ31.9 (c = 0.25, CH3OH)).
For the total synthesis of (+)-virosaine B (2), (+)-allo-
norsecurinine (4) was chemoselectively oxidized to its corre-
sponding N-oxide 22 in 98% yield (Scheme 5). The N-oxide
was then heated to reflux in toluene to afford O-alkylhydrox-
ylamine 23 in 84% yield. During our initial investigation, the
intramolecular 1,3-dipolar cycloaddition reaction of nitrone
10, which was readily formed by further oxidation of 23 with
In a similar fashion, 11 was converted to the correspond-
ing bromide in 79% yield with NBS and AIBN. Unfortu-
nately, however, when the bromide was treated with AgSbF6
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F. Busquꢂ, M. Figueredo, Targets Heterocycl. Syst. 2005, 9, 281,
and references therein.
[5] B. X. Zhao, Y. Wang, D. M. Zhang, R. W. Jiang, G. C. Wang,
J. M. Shi, X. J. Huang, W. M. Chen, C. T. Che, W. C. Ye, Org.
Lett. 2011, 13, 3888.
[6] B. X. Zhao, Y. Wang, D. M. Zhang, X. J. Huang, L. L. Bai, Y.
Yan, J. M. Chen, T. B. Lu, Y. T. Wang, Q. W. Zhang, W. C. Ye,
Org. Lett. 2012, 14, 3096.
[7] a) R. Rouffiac, J. Parello, Plant. Med. Phytother. 1969, 3, 220;
b) D. Gonzꢃlez-Gꢃlvez, E. Garcꢄa-Garcꢄa, R. Alibꢂs, P. Bayꢁn, P.
de March, M. Figueredo, J. Font, J. Org. Chem. 2009, 74, 6199.
[8] M. R. Medeiros, J. L. Wood, Tetrahedron 2010, 66, 4701.
[9] a) L.-Z. Liu, J.-C. Han, G.-Z. Yue, C.-C. Li, Z. Yang, J. Am.
Chem. Soc. 2010, 132, 13608; b) J. Gong, G. Lin, W. Sun, C.-C. Li,
Z. Yang, J. Am. Chem. Soc. 2010, 132, 16745; c) H. Shi, L. Fang,
C. Tan, L. Shi, W. Zhang, C.-C. Li, T. Luo, Z. Yang, J. Am. Chem.
Soc. 2011, 133, 14944.
[10] a) T. R. Hoye, C. S. Jeffrey, M. A. Tennakoon, J. Wang, H. Zhao,
J. Am. Chem. Soc. 2004, 126, 10210; b) D. Wallace, Angew.
Chem. 2005, 117, 1946; Angew. Chem. Int. Ed. 2005, 44, 1912;
selected examples for the application of RRCM reactions in the
total synthesis, see: c) X. Wang, E. J. Bowman, B. J. Bowman,
J. A. Porco, Angew. Chem. 2004, 116, 3685; Angew. Chem. Int.
Ed. 2004, 43, 3601; d) P. A. Roethle, I. T. Chen, D. Trauner, J.
Am. Chem. Soc. 2007, 129, 8960; e) S. Y. Yun, M. Kim, D. Lee,
D. J. Wink, J. Am. Chem. Soc. 2009, 131, 24; f) T. R. Hoye, M. E.
Danielson, A. E. May, H. Zhao, J. Org. Chem. 2010, 75, 7052;
g) K. D. Schwartz, J. D. White, Org. Lett. 2011, 13, 248.
[11] a) J. J. Tufariello in 1,3-Dipolar Cycloaddition Chemistry, Vol. 2
(Ed.: A. Padwa), Wiley, New York 1984, p. 83; b) K. B. G.
Trossell, Nitrile Oxides, Nitrones and Nitronates in Organic
Synthsis, VCH, New York 1988; c) K. Gothelf, K. A. Jørgensen,
Acta Chem. Scand. 1996, 50, 652; d) K. Gothelf, K. A. Jørgensen,
Chem. Rev. 1998, 98, 863; e) F. Cardona, A. Goti, Angew. Chem.
2005, 117, 8042; Angew. Chem. Int. Ed. 2005, 44, 7832; f) L. M.
Stanley, M. P. Sibi, Chem. Rev. 2008, 108, 2887.
Scheme 5. Synthesis of (+)-virosaine B (2). DCE=1,2-dichloroethane.
mCPBA in DCE, furnished (+)-virosaine B (2) in 46% yield.
Interestingly, however, when the reaction was carried out in
the presence of AcOH, the yield of the desired product
(+)-virosaine B (2) was further improved to 76%. The
spectroscopic data of the synthesized (+)-virosaine B were
consistent with those reported for the natural product.[6] The
optical rotation of the synthetic sample was also in good
agreement with that of the natural product (synthetic 2:
30
20
½aꢂD ¼ =+ 65.7 (c = 0.70, CH3OH), natural 2: ½aꢂD ¼ + 62.7
(c = 0.50, CH3OH)).
In summary, concise and asymmetric syntheses of (ꢀ)-
flueggine A (1) and (+)-virosaine B (2) have been achieved
for the first time through biomimetic approaches[5] starting
from the commercially available Weinreb amide 13, and the
absolute configurations of these natural products have been
established. The total syntheses of 1 and 2 proceed in 11 and
10 steps with 5.92% and 6.68% overall yield, respectively,
with tandem RRCMs and 1,3-dipolar cycloadditions as the
key steps. This novel synthetic strategy for the formation of
dihydrobenzofuranones could be used as a general method
for organic synthesis.
[12] R. J. Huisgen, Org. Chem. 1976, 41, 403.
[13] For selected examples of total syntheses of norsecurinine (3),
see: a) C. H. Heathcock, T. W. von Geldern, Heterocycles 1987,
25, 75; b) P. A. Jacobi, C. A. Blum, R. W. DeSimone, U. E. S.
Udodong, J. Am. Chem. Soc. 1991, 113, 5384; c) P. Magnus, J.
Rodrꢄguez-Lopez, K. Mulholland, I. Matthews, J. Am. Chem.
Soc. 1992, 114, 382; d) G. Han, M. G. LaPorte, J. J. Folmer, K. M.
Werner, S. M. Weinreb, Angew. Chem. 2000, 112, 243; Angew.
Chem. Int. Ed. 2000, 39, 237.
[14] For the total synthesis of (ꢀ)-allonorsecurinine, see: R. Alibꢂs,
M. Ballbꢂ, F. Busquꢂ, P. de March, L. Elias, M. Figueredo, J.
Font, Org. Lett. 2004, 6, 1813.
[15] a) J. Meisenheimer, Ber. Dtsch. Chem. Ges. 1919, 52, 1667;
b) R. F. Kleinschmidt, A. C. Cope, J. Am. Chem. Soc. 1944, 66,
1929; c) H. Bao, X. Qi, U. K. Tambar, J. Am. Chem. Soc. 2011,
133, 1206.
Received: October 14, 2012
Published online: November 21, 2012
Keywords: (+)-virosaine B · (ꢀ)-flueggine A ·
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asymmetric synthesis · natural products · total synthesis
[1] a) J. Clardy, C. Walsh, Nature 2004, 432, 829; b) F. E. Koehn,
G. T. Carter, Nat. Rev. Drug Discovery 2005, 4, 206; c) I.
Paterson, E. A. Anderson, Science 2005, 310, 451; d) W. Fenical,
P. R. Jensen, Nat. Chem. Biol. 2006, 2, 666.
[2] For a review, see: V. Snieckus in The Alkaloids, Vol. 14 (Ed.:
R. H. F. Manske), Academic Press, New York, 1973, p. 425.
[3] a) L. A. Van der Woerd, Genneskd. Tijdschr. Ned.-Indie 1941,
81, 1963; b) R. M. Serra, An. Univ. St. Domingo 1944, 8, 295;
c) S. M. Weinreb, Nat. Prod. Rep. 2009, 26, 758; d) W. Zhang, J.-
Y. Li, P. Lan, P.-H. Sun, Y. Wang, W.-C. Ye, W.-M. Chen, J. Chin.
Pharm. Sci. 2011, 3, 203.
[4] a) A. K. Nadkarni, Indiana Materia Medica, Vol. 1, Popular
Prakashan Prt., Bombay, 1976, p. 948; b) R. N. Chopra, S. L.
Nayar, I. C. Chopra, Indian Med. Plants 1956, 191; c) D. Rognan,
T. Boulanger, R. Hoffmann, D. P. Vercauteren, J.-M. Andre, F.
Durant, C. G. Wermuth, J. Med. Chem. 1992, 35, 1969; d) G.
Han, M. G. LaPorte, J. J. Folmer, K. M. Werner, S. M. Weinreb,
J. Org. Chem. 2000, 65, 6293, and references therein; e) P. Bayꢁn,
[16] a) T. Nakano, S. Terao, H. Lee, Y. Saeki, L. J. Dueham, J. Org.
Chem. 1966, 31, 2274; b) K. C. Majumdar, G. H. Jana, J. Org.
Chem. 1997, 62, 1506; c) J.-Y. Li, B.-X. Zhao, W. Zhang, C. Li,
X.-J. Huang, Y. Wang, P.-H. Sun, W. C. Ye, W.-M. Chen,
Tetrahedron 2012, 68, 3972.
[17] S.-H. Kim, N. Bowden, R. H. Grubbs, J. Am. Chem. Soc. 1994,
116, 10801.
[18] a) S.-H. Kim, W. J. Zuercher, B. B. Bowden, R. H. Grubbs, J.
Org. Chem. 1996, 61, 1073; b) S. B. Garber, J. S. Kingsbury, B. L.
Gray, A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 8168; c) F.-D.
Boyer, I. Hanna, L. Ricard, Org. Lett. 2001, 3, 3095; d) F.-D.
Boyer, I. Hanna, Org. Lett. 2007, 9, 2293; e) S. Mukherjee, D.
Lee, Org. Lett. 2009, 11, 2916; f) H. Park, Y.-L. Hong, Y. B. Kim,
Y.-L. Choi, Org. Lett. 2010, 12, 3442; g) S. Knꢅppel, V. O.
Rogachev, P. Metz, Eur. J. Org. Chem. 2010, 6145; h) M.
Angew. Chem. Int. Ed. 2013, 52, 620 –624
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
623

.
Angewandte
Communications
Schubert, P. Metz, Angew. Chem. 2011, 123, 3011; Angew. Chem.
Int. Ed. 2011, 50, 2954.
[19] L. Chang, H. Jiang, J. Fu, B. Liu, C.-C. Li, Z. Yang, J. Org. Chem.
2012, 77, 3609.
[20] T. Honda, H. Namiki, K. Kaneda, H. Mizutani, Org. Lett. 2004, 6,
87.
[21] K. Grela, S. Harutyunyan, A. Michrewska, Angew. Chem. 2002,
114, 4210; Angew. Chem. Int. Ed. 2002, 41, 4038.
[22] T.-L. Choi, R. H. Grubbs, Chem. Commun. 2001, 2648.
[23] M. Ulman, T. R. Belderrain, R. H. Grubbs, Tetrahedron Lett.
2000, 41, 4689.
[24] M. Tramontini, Synthesis 1982, 604.
[25] G. Mehta, S. Lakshminath, Tetrahedron Lett. 2006, 47, 327.
[26] a) J. A. Stafford, M. F. Brackeen, D. S. Karanewsky, N. L.
Valvano, Tetrahedron Lett. 1993, 34, 7873; b) Z. Y. Wei, E. E.
Knaus, Tetrahedron Lett. 1994, 35, 847.
[27] P. Magnus, J. Rodrꢄguez-Lꢁpez, K. Mulholland, I. Matthews,
Tetrahedron 1993, 49, 8059.
[28] a) J. J. Tufariello, Acc. Chem. Res. 1979, 12, 396; b) In Magnusꢀ
total synthesis of nirurine, a similar route was attempted,
however, a mixture of unidentified products was obtained (see
Ref. [27] for details).
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