Zeolite-Based Organic Synthesis (ZeoBOS) of Acortatarin A: First Total Synthesis Based on Native and Metal-Doped Zeolite-Catalyzed Steps

Article abstract of DOI:10.1002/chem.201605048

Similarly to polymer-supported assisted synthesis (PSAS), organic synthesis could be envisaged being performed by using zeolites, native or metal-doped, as heterogeneous catalysts. To illustrate this unprecedented Zeolite-Based Organic Synthesis (ZeoBOS),

Full text of DOI:10.1002/chem.201605048

A Journal of
Accepted Article
Title: Zeolite-Based Organic Synthesis (ZeoPOS) of Acortatarin A:
First Total Synthesis Based on Native and Metal-Doped Zeolite-
Catalyzed Steps
Authors: Eric Wimmer, Sophie Borghese, Aurelien Blanc, Valerie
Beneteau, and Patrick H. R. Pale
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Zeolite-Based Organic Synthesis (ZeoBOS) of Acortatarin A:
First Total Synthesis Based on Native and Metal-Doped Zeolite-
]
Catalyzed Steps[∗∗
Eric Wimmer, Sophie Borghèse, Aurélien Blanc, Valérie Bénéteau* and Patrick Pale*
Abstract: Similarly to polymer-supported assisted synthesis (PSAS),
organic synthesis could be envisaged being performed by using
zeolites, native or metal-doped, as heterogeneous catalysts. To
illustrate this unprecedented Zeolite-Based Organic Synthesis
(ZeoBOS), the total synthesis of acortatarin A was achieved through
a novel strategy and using five out of eleven synthetic steps
catalyzed by H- or metal-doped zeolites as catalysts. Notably, the
formation of an yne-pyrrole intermediate with a copper-doped zeolite
and the spiroketalization of an alkyne diol with a silver-doped zeolite
have been developed as key steps of the synthesis.
and to the best of our knowledge, no total synthesis of a natural
product has so far been performed based on such solid catalysts.
In this context, we have attempted to validate this ZeoBOS way
through the synthesis of a complex molecule, and we embarked
on the total synthesis of acortarin A, involving as much as
possible zeolite-catalyzed steps (Schemes 1-2). We reported
here our results.
Since its early origin, organic synthesis, including total synthesis,
has always been performed in solution, without any possibility to
recover and recycle any reagent, especially catalyst. To alleviate
such problems, substrates or reagents have been grafted to
polymeric supports, leading to the so-called solid-phase organic
synthesis (SPOS) or polymer-supported assisted synthesis
(PSAS), especially used in parallel and combinatorial
chemistry.[1] Lately, many efforts are undertaken to simplify
organic synthesis, including total synthesis of complex organic
molecules,[2] for which automation is considered as a key
issue.[3]
Currently developing new synthetic methods based on
heterogeneous and recyclable catalysts derived from zeolites,
either native,[4] or transition metal-doped,[5] we have envisaged
an alternative way to solution- and solid-phase organic
syntheses. In this new approach, each step could be performed
through a zeolite or a related material to catalytically convert a
molecule to another more complex one (Figure 1). Ultimately,
this strategy, coined zeolite-based organic synthesis (ZeoBOS),
could also be run with automated systems,[6] as for the now
conventional PSAS and in line with the current developments of
automated organic synthesis.[3]
Figure 1. Zeolite-Based Organic Synthesis (ZeoBOS) of Complex Organic
Compounds.
Recently discovered in the rhizome of Acorus tatarinowii,[8] this
spiroketal alkaloid exhibits useful antioxidant properties,
especially against the production of reactive oxygen species
(ROS) in renal cells, one of the lethal consequences of diabete.
Simultaneously or recently, related compounds such as
pollenopyrroside A, capparisine B or xylapyrroside A and B,
have been isolated from plants or fungus (Figure 2).[9] All these
natural products exhibit unique spiromorpholino and
pyrrolomorpholine motifs. Such uniqueness and the attractive
antioxidant properties of acortatarin A have already stimulated
[9d-10]
interest from organic and medicinal chemists
The synthetic
efforts so far developed to achieve the acortatarin A synthesis
mostly relied on the classical spiroketal formation based on the
cyclization of an appropriate ketodiol in acidic homogeneous
conditions.
Zeolites are cheap, very stable and recyclable solids catalysts,
made of pores of different (and tunable) shapes and sizes,
which allow for molecular selectivity either by selecting the
reagent or the product or the transition state. These
discrimination effects have been used for decades in
petrochemistry to provide common building blocks and
monomers for the chemical industry. However, such effects
have rarely been applied to organic transformations and zeolite
development in organic synthesis remains scarce.[7] Furthermore,
[*]
E. Wimmer, S. Borghèse, Dr. A. Blanc, Dr. V. Bénéteau, Prof. Dr. P.
Pale
Laboratoire de Synthèse, Réactivité Organiques et Catalyse, UMR
7177 associé au CNRS
Institut de Chimie, Université de Strasbourg
4 rue Blaise Pascal, 67070 Strasbourg, France
E-mail: beneteau@unistra.fr, ppale@unistra.fr
Figure 2. The Newly Discovered Family of Natural Products Exhibiting the
Supporting information of this article can be found under http://...
Pyrrolomorpholine and Spiroketal Motifs.
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Since we recently demonstrated that silver-doped zeolites could
catalyze the double cyclization of alkynediols to spiroketals,[4i]
we envisaged producing the spiroketal unit of acortatarin A 1
through such a zeolite-promoted cyclization (Scheme 1, Ag-zeo
step). This would require starting from an appropriate
bishydroxylated N-alkynyl pyrrole 2. Actually, N-alkynyl pyrroles
are very rare in the literature, probably due to their sensitivity
and/or the instability of the starting pyrrole derivatives, as well as
the lack of convenient methods to prepare them [11] We recently
showed that copper-doped zeolites could catalyze the coupling
of bromoalkynes and various amino derivatives, including some
N-heterocycles.[5j] We thus envisaged to extend this approach to
Among various examined groups, tert-butyldimethylsilyl and
triethylsilyl (TBS and TES respectively) proved useful as
protecting groups (vide infra). Both were introduced under
classical conditions. Further elimination of bromide from 9a-b,
with LiHMDS in THF at -78°C,[16] provided the alkynyl bromides
3a-b required for an efficient ynamide coupling.[17]
The second key partners for the copper-catalyzed coupling,
namely the pyrroles 4a-b, were obtained from the commercial
ethyl pyrrole-2-carboxylate in gram scale over three steps
(Scheme 3). Vilsmeir-Haack formylation of the latter afforded 10
in 69% yield, along with 22% of the 4-formyl regioisomer.[18]
Reduction of the formyl group at low temperature, followed by
protection of the resulting hydroxyl with the same silyl groups as
in 3a-b afforded the 2,5-disubstituted pyrroles 4a-b in nearly
quantitative yields.
N-alkynyl
pyrroles
in
an
unprecedented
and
first
heterogeneously catalyzed synthesis of such compounds.
Applying this copper-zeolite catalyzed method to our target
(Scheme 1, Cu-zeo step), would require the two partners 3 and
4. The latters could be obtained respectively from 2-deoxy-D-
ribose, through a known Wittig-type reaction, and from the
commercially available ethyl pyrrole-2-carboxylate. For those
building blocks, we also tried to set up zeolite-catalyzed steps to
fully implement the ZeoBOS strategy mentioned above.
The so-designed strategy opens up a new way to approach the
acortatarin family of natural products, as well as pioneering the
use of zeolites in total synthesis.
Scheme 1. Planned ZeoBOS Strategy Based on Copper(I) and Silver(I)-doped
Zeolites towards Acortatarin A. PG = protecting group.
Scheme 2. Access to the Key Bromoalkynes 3a-b involving two H-Zeolite-
Catalyzed Steps. Reagents and Conditions: a) H-ZSM-5, MeOH, 50°C, 1h30;
b) NaH, BnBr, DMF, 0°C to rt; 2 h, 77% for 2 steps; c) H-USY, H2O/THF (9/1),
120°C, 2h30, 68%; d) Ph3P+-CHBr2, Br-, t-BuOK, THF, rt, 5 h, 91%; e) TBSCl
or TESCl, Imidazole, DMF, rt, 24 h, 97% for 9a (TBS) and 80% for 9b (TES); f)
LiHMDS, THF, -78°C to rt, 6 h, 88% for 3a (TBS) and 76% for 3b (TES). ZSM-
A gram-scale synthesis of the bromoalkynes 3a-b could be
achieved in 6 steps starting from 2-deoxy-D-ribose (Scheme 2).
Rewardingly, two acid-catalyzed steps involving zeolites in their
protic form (H-zeo) could be introduced in the synthetic pathway.
Indeed, 2-deoxy-D-ribose was readily and quantitatively
converted, without need of purification, to the corresponding
methyl furanoside 5 with methanol and a catalytic amount of H-
ZSM5.[12] After benzylation of the hydroxyl groups under
classical conditions, the so-obtained furanoside 6 could be
hydrolyzed in a mixture of water and THF in the presence of a
catalytic amount of H-USY, which exhibits larger pores and
mesoporosity.[13] The resulting 3,5-di-O-benzyl-2-deoxy-D-
5
=
Zeolite Socony Mobil–5, DMF
Ultrastable Y-Type Zeolite, THF
Butyldimethylsilyl chloride, TESCl = Triethylsilyl chloride.
=
N,N-Dimethylformamide, USY
=
=
tetrahydrofuran, TBSCl tert-
=
ribofuranose
7 was submitted to a Wittig reaction with
dibromomethyltriphenylphosphonium bromide[14] and potassium
tert-butoxide as a base. The so-formed dibromoalkenyl alcohol 8
needed to be protected for the sake of the remaining steps.[15]
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Scheme 3. Preparation of Functionalized Pyrroles 4a-b. Reagents and
Conditions: a) POCl3, DMF, DCE, 80°C, 2 h, 69%; b) NaBH4, THF, -78°C,
2h30, 98%; c) TBSCl or TESCl, Imidazole, DMF, rt, 98% for 4a (TBS) in 20 h
and 90% for 4b (TES) in 1h15. DMF = N,N-Dimethylformamide, DCE =
alkynyl diol 2 in the presence of 10 mol % Ag-USY gave as
expected the corresponding spiroketal as a mixture of epimers
13/epi-13, in 46% yield. Interestingly, the pyrrolomorpholino
derivative 14, resulting from a single umpolung-type 6-endo-dig
cyclization, was also isolated in 32% yield. A control experiment
with silver acetate (10 mol%) instead of Ag-USY revealed the
key role of the zeolite, because 14 was mainly produced under
such conditions (46% yield) without detectable spiroketal 13. As
the morpholino derivative 14 may be seen as an intermediate in
the spiroketal formation, we submitted it to cyclization conditions.
The acid-promoted cyclization of 14 to 13/epi-13 could be
achieved with H-USY (1 eq.) in hot ethanol, but the reaction was
rather slow. Therefore, the concomitant presence of Lewis and
Brønsted acid sites (respectively Ag+ and H+) in Ag-USY[25]
seems essential for the spiroketal formation leading to 13/epi-13
from 2.
We thus took benefit of this Ag-USY duality in a more direct
route. Indeed, we thought that the TES deprotection of 12b
could be achieved with the protic sites of Ag-USY and combined
with the Ag-promoted spiroketalization, leading to 13 in a one-
pot cascade. Ag-USY alone was able to give the expected 13
(30% yield) together with 14 (22% yield), although in a long
reaction (48 h).[26] Rewardingly, a catalytic mixture of both Ag-
and H-USY readily provided the spiroketal and its epimer 13/epi-
13, again with the monocyclized product 14. Interestingly,
comparing the results obtained from 12a and 12b, similar yields
of both cyclized products (45-46% for 13/epi-13 and 30-32% for
14) as well as the same diastereomeric ratio (around 60/40)
were obtained,[27] indicating that the TES groups removal might
be quantitative under the conditions used.
Dichloroethane; THF
= tetrahydrofuran, TBSCl = tert-Butyldimethylsilyl
chloride, TESCl = Triethylsilyl chloride.
With these fragments in hands, their copper-catalyzed coupling
was investigated. CuI-USY[19] proved to be more efficient as
catalyst than other copper sources, including homogeneous
ones (Table 1, entries 1-2). Notably, two other heterogeneous
catalytic systems with copper grafted either on a polymeric
support (Table 1, entry 3, CuI onto dimethylaminomethyl
polystyrene, CuI@A21),[20] or on a mesoporous silica (Table 1,
entry 4, CuII-SBA-15)[21] were less effective. 1,10-Phenanthroline
and potassium phosphate were respectively the best ligand and
the best base among those screened, and a 2 to 1 ratio between
the two partners 3 and 4 provided the best results. Therefore
and rewardingly, it turned out that our previously set up
procedure, with CuI-USY as catalyst (10 mol%),[5j] gave the best
results, providing the ynamide derivative 12a from 3a and 4a
(Table 1, entry 5). The corresponding 3b and 4b gave similar
results (Table 1, entry 6). The required long reaction times were
due to the low reactivity of the pyrroles 4a-b in this coupling
reaction.[22]
Table 1. Copper-Catalyzed Coupling of 3a-b and 4a-b towards Ynamides 12a-b.
Comparison of Copper Catalysts.
Entry
Partners
3a + 4a
“
Copper Catalyst
CuCl
CuSO4
Yield (%)[a]
1
2
12a
“
18
21
3
4
5
6
“
CuI@A21[b]
CuII-SBA-15[c]
CuI-USY[d]
CuI-USY
“
34
44
50
40
“
“
“
“
3b + 4b
12b
[a] Isolated yield. [b] CuI onto dimethylaminomethyl polystyrene. [c] copper(II)
loaded silica based mesoporous material. [d] copper(I)-doped USY.
®
1,10-phen = 1,10-phenanthroline, A21 = Amberlyst A21 free base, SBA =
Santa Barbara Amorphous type material, USY = Ultrastable Y-Type Zeolite.
With this coupling product in hands, we were just one step
ahead from the key Ag-USY-catalyzed spiroketalisation. An a
priori simple deprotection of derivatives 12 would provide the
bishydroxylated N-alkynyl pyrrole
2
required for this
spiroketalisation. TBS deprotection of 12a could best be
achieved with an equimolar mixture of tetrabutylammonium
fluoride and acetic acid in THF (Scheme 4). Being more labile,[23]
the TES group of 12b could be deprotected in an additional acid
zeolite-catalyzed step.[24] H-USY proved to be the best choice for
this step, leading to 2 in 65% isolated yield.
The second metal-doped zeolite-catalyzed key step of the
synthetic pathway towards acortatarin A was then implemented
(Scheme 4). Under the conditions previously set up,[5i] the
Scheme 4. Synthesis of 13/epi-13 by Silver-Doped Zeolite-Catalyzed
Spiroketalisation. Reagents and Conditions: a) TBAF, AcOH, THF, 0°C to rt,
39 h, 88%, from 12a; b) H-USY (40 mol%), EtOH, 80°C, 3 h, 65%; c) Ag-USY
(10 mol%), EtOH, 80°C, 24 h, 46%; d) Ag-USY (20 mol%) / H-USY (20 mol%),
EtOH, 80°C, 45%, 24 h from 12b. e) H-USY (1 eq.), EtOH, 80°C, 47 h, 50%;
THF = Tetrahydrofuran; USY = Ultrastable Y-Type Zeolite.
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[1]
[2]
For some leading references, see: a) M. J. Kurth Comb. Chem. 1997,
39–64; b) C. Watson Angew. Chem. Int. Ed. 1999, 38, 1903–1908; c) A.
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Eds.; Wiley 2012, p 359-394.
With the core structure of acortatarin A in hand, two final
transformations remained to reach the natural product: reduction
of the ethyl ester to aldehyde and cleavage of the benzyl groups
(Scheme 5). Direct reduction of the ester to the aldehyde with
DIBAL-H at low temperature was unsuccessful; therefore, a
mixture of spiroketal 13 and its epimer epi-13 was first reduced
to the corresponding very unstable hydroxymethyl derivatives,
which were directly oxidized with MnO2. The final removal of the
benzyl groups was performed under the conditions previously
used by Sudhakar et al..[10b] A separable mixture of Acortatarin A
1 and its epimer epi-1 (Xylapyrroside B) was thus obtained in a
combined yield of 69%. [27]
[3]
See i.a. the comment : M. Peplow Nature 2014, 512, 20-22;
For selected references, see: a) K. Machida, Y. Hirose, S. Fuse, T.
Sugawara, T. Takahashi Chem. Pharm. Bull. 2010, 58, 87-93; b) E. M.
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[4]
[5]
a) A. Sani Souna Sido, S. Chassaing, M. Kumarraja, P. Pale, J.
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Sommer Chem. Eur. J. 2008, 14, 6713–6721; b) M. K. Patil, M. Keller,
M. B. Reddy, P. Pale, J. Sommer Eur. J. Org. Chem. 2008, 4440–4445;
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Org. Chem. 2009, 423–429; d) M. Keller, A. Sani Souna Sido, P. Pale,
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1907–1914; h) A. Olmos, B. Louis, P. Pale Chem. Eur. J. 2012, 18,
4894–4901; i) S. Borghèse, P. Drouhin, V. Bénéteau, B. Louis, P. Pale
Green Chem. 2013, 15, 1496–1500. j) H. Harkat, S. Borghèse, M. D.
Nigris, S. Kiselev, V. Bénéteau, P. Pale Adv. Synth. Catal. 2014, 356,
3842–3848; k) V. Magné, T. Garnier, M. Danel, P. Pale, S. Chassaing
Org. Lett. 2015, 17, 4494–4497.
Scheme 5. The Final Stage of the Synthesis of Acortatarin
A 1 and
Xylapyrroside B epi-1. Reagents and Conditions: a) LiAlH4, THF, 0 °C to r.t., 2
h; b) MnO2, DCM, rt, 3.5 h, 48% for 2 steps; c) TiCl4, DCM, 0°C, 3 h, 69%.
DCM = Dichloromethane.
In conclusion, acortatarin A was obtained in 11 steps (for the
longest linear sequence) by using 5 zeolite-catalyzed reactions.
Among them, the two key steps were achieved by an Ag-zeolite
catalyzed spiroketalization and an unprecedented CuI-zeolite
catalyzed cross-coupling of bromoalkynes with pyrroles. The
three other zeolite-catalyzed reactions exploited the acidic
character of such heterogeneous catalysts. This total synthesis
implements for the first time the ZeoBOS strategy, and validates
the possibility of zeolite-based organic synthesis as an
alternative to solution- and solid-phase organic syntheses.
Furthermore, the proposed strategy offers a novel route towards
the acortatarin family of natural products and analogs.
[6]
[7]
Automation on parallel synthesizers is under development in our group.
M. J. Climent, A. Corma, S. Iborra, in Zeolites and Catalysis. Synthesis,
Reactions and Applications; J. Cejka, A. Corma, S. Zones, Eds; Wiley-
VCH Verlag 2010.
[8]
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Acknowledgements
We gratefully acknowledge the ANR (Grant 13-BS07-0017-01),
the CNRS and the French Ministry of Research for financial
support. EW thanks the ANR for a PhD fellowship. SB thanks
the Loker Hydrocarbon Research Institute, USC, and the Morris
Smith Foundation for a PhD fellowship. We thank Nadège Lubin-
Germain and Florian Gallier for a supply of CuII-SBA-15. We
warmly thank Julien Ségard and Raphaël Lamare for their useful
technical assistance.
[11] For the few examples based on the original ynamine synthesis (J. Ficini,
C. Barbara, Bull. Soc. Chim. Fr. 1965, 871), see: a) M. S. Paley, D. O.
Frazier, H. Abeledeyem, S. P. McManus, S. E. Zutau J. Am. Chem. Soc.
1992, 114, 3247-3251; b) L. Brandsma, A. G. Mal'kina, B. A. Trofimov
Synth. Commun. 1994, 24, 2721-2724.
Keywords: Doped-Zeolite • Silver• Copper • Spiroketalization •
Ynamide Formation
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For the sole example of N-alkynylpyrroles obtained by a copper-
catalyzed coupling reaction, see: Y. Zhang, R. P. Hsung, M. R. Tracey,
K. C. M. Kurtz, E. L. Vera, Org. Lett. 2004, 6, 1151–1154.
For reviews on ynamides, see: a) G. Evano, K. Jouvin, A. Coste,
Synthesis 2013, 17–26; b) G. Evano, A. Coste, K. Jouvin, Angew.
Chem. Int. Ed. 2010, 49, 2840–2859; c) K. A. DeKorver, H. Li, A. G.
Lohse, R. Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev. 2010,
110, 5064–5106.
[12] H-ZSM5 was obtained by calcination (550°C, 12h) of commercial NH4-
ZSM5 from Zeolyst (CBV 5524G). Si/Al=25; number of acidic sites =
0.90 mmol.g-1. Channel-type topology (pore diameters: 5.1 x 5.5 Å and
5.3 x 5.6 Å)
[13] H-USY was obtained by calcination (550°C, 12h) of commercial NH4-
USY from Zeolyst (CBV 500). Si/Al=2.9; number of acidic sites = 3.80
mmol.g-1. Cage-type topology (pore diameter: 7.4 Å; cavity diameter: 12
Å).
[14] F. Dolhem, C. Lièvre, G. Demailly Tetrahedron 2003, 59, 155–164.
[15] Without protection, alcohol 8 readily cyclized in the following step to the
corresponding Z-bromomethyleneoxolane; see: D. Grandjean, P. Pale,
J. Chuche Tetrahedron Lett. 1992, 33, 4905–4908.
[16] D. Grandjean, P. Pale, J. Chuche Tetrahedron Lett. 1994, 35, 3529–
3530.
[17] The dibromoalkenes 9a-b did not react in our Cu-zeolite coupling
conditions, in agreement with results showing that pyrroles are non
participating in Cu-catalyzed coupling reactions with dibromoalkenes,
under homogeneous conditions; see: K. Jouvin, A. Coste, F. Legrand,
G. Karthikeyan, K. Tadiparthi, G. Evano, Organometallics 2012, 31,
7933–7947.
[18] D. M. Wallace, S. H. Leung, M. O. Senge, K. M. Smith J. Org. Chem.
1993, 58, 7245–7257.
[19] ICP-AES analysis accounted for 2.5 mmol Cu.g-1. For the preparation of
the catalyst, see Supporting Information.
[20] C. Girard, E. Önen, M. Aufort, S. Beauvière, E. Samson and J.
Herscovici, Org. Lett., 2006, 8, 1689–1692.
[21] I. Jlalia, F. Gallier, N. Brodie-Linder, J. Uziel, J. Augé, N. Lubin-
Germain, J. Mol. Catal. A: Chemical, 2014, 393, 56–61.
[22] Incomplete conversion and partial degradation of 4a-b were observed.
[23] T. D. Nelson, R. D. Crouch, Synthesis, 1996, 1031–1069.
[24] A. Itoh, T. Kodama, Y. Masaki, Synlett 1999, 3, 357–359.
[25] Obtained upon calcination of Ag-NH4-USY, itself prepared by Ag
impregnation of NH4-USY, Ag-USY contained 1.02 mmol/g of Ag (See
S.I.). Ag ions have thus replaced nearly one fourth of the acid sites in
this zeolite (4.39 mmol/g for H-USY).
[26] The Brønsted acid sites may not be either strong enough or accessible
for the deprotection step.
[27] Concerning the epimer formation, it is worth mentioning that the
previously
described
syntheses
provided
similar
ratios.
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10.1002/chem.201605048
Chemistry - A European Journal
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Eric Wimmer, Sophie Borghèse,
Aurélien Blanc, Valérie Bénéteau* and
Patrick Pale*
Page No. – Page No.
Zeolite-Based Organic Synthesis
(ZeoBOS) of Acortatarin A:
Total Synthesis Based on Native and
Metal-Doped Zeolite-Catalyzed Steps
First
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