Concise, stereocontrolled and modular syntheses of the anti-influenza rubrolides R and S

Article abstract of DOI:10.1016/j.tetlet.2019.151307

The fungal metabolites rubrolide R and S were synthesized in concise, entirely stereoselective fashion through the combined use of bromine-stereodirected vinylogous aldol condensation (SVAC) and Suzuki cross-coupling. A bioinspired, high-yield conversion

Full text of DOI:10.1016/j.tetlet.2019.151307

Journal Pre-proofs
Concise, stereocontrolled and modular syntheses of the anti-influenza rubrolides
R and S
Thaís A. Moreira, Raphaël Lafleur-Lambert, Luiz C.A. Barbosa, John
Boukouvalas
PII:
S0040-4039(19)31091-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151307
TETL 151307
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 September 2019
12 October 2019
21 October 2019
Please cite this article as: Moreira, T.A., Lafleur-Lambert, R., Barbosa, L.C.A., Boukouvalas, J., Concise,
stereocontrolled and modular syntheses of the anti-influenza rubrolides R and S, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.151307
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Concise, stereocontrolled and modular syntheses of the anti-influenza
rubrolides R and S
a,b
a
Thaís A. Moreira , Raphaël Lafleur-Lambert ,
b
a,b,
Luiz C. A. Barbosa , John Boukouvalas *
aDepartment of Chemistry and Centre for Green Chemistry and Catalysis, Pavillon Alexandre-
Vachon, Université Laval, 1045 Avenue de la Médecine, Quebec City, Quebec G1V 0A6, Canada
b
Department of Chemistry, Instituto de Ciências Exatas, Universidade Federal de Minas
Gerais (UFMG), Av. Pres. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte, 31270-901,
MG, Brazil.
*
Corresponding author. Tel.: (418) 656-5473; fax: (418) 656-7916;
e-mail: john.boukouvalas@chm.ulaval.ca
Keywords: Biomimetic cyclization, Butenolides, Chromanes, Vinylogous aldol condensation.
Abstract – The fungal metabolites rubrolide R and S were synthesized in concise, entirely stereoselective
fashion through the combined use of bromine-stereodirected vinylogous aldol condensation (SVAC) and
Suzuki cross-coupling. A bioinspired, high-yield conversion of rubrolide R to rubrolide S is also reported.
Introduction
Influenza, or flu, is a highly contagious viral infection causing recurrent epidemics that bring about
an enormous burden to the economy along with significant morbidity and mortality, particularly in
young children and the elderly [1]. According to the World Health Organization (WHO), annual
epidemics result in 3-5 million cases of severe illness, millions of hospitalizations and up to 650,000
deaths worldwide [2]. Because vaccination provides only modest protection against seasonal
influenza (typically 10-60%) and no protection against novel strains [3], small molecule
therapeutics are vital to control the spread of the disease [4]. However, like antibiotics, antiviral
drugs are loosing their efficacy due to the emergence of resistant viral strains [5]. Consequently,
there is a pressing need for new anti-influenza agents, especially those with modes of action that
circumvent existing resistance mechanisms [6,7].
The diverse biological properties and distinctive arylbenzylidenebutenolide framework
associated with the rubrolide family of natural products have attracted considerable attention since
the 1990s [8-10], when the first such compounds were isolated from the marine ascidian Ritterella
rubra [8a]. While the vast majority of the members of this family come from ascidia [8], a pair of
prenylated analogues, named rubrolide R and S (1-2, Figure 1), have recently been isolated from
marine and terrestrial-derived Aspergillus fungi [11a,b].

HO
HO
O
O
O
O
1
2
rubrolide R
rubrolide S
HO
O
Figure 1. Structure of rubrolides R and S.
Besides possessing an unprecedented carbon skeleton, 1 and 2 display significant antiviral
activities, being superior to the nucleoside drug ribavirin against seasonal and pandemic influenza A
viruses (cf. H3N2 and pH1N1) [11a,12b]. One of these molecules, rubrolide S (2), was also shown
to be a potent uncompetitive inhibitor of glucosidase (K = 1.42 M) [11c]. Inhibitors of this
i
enzyme are believed to exert their anti-influenza effects by targeting the host glycosylation
machinery. This indirect mechanism of action not only allows broad-spectrum antiviral activity, but
also provides protection against the development of drug resistance [7].
To date, two syntheses of rubrolide R and S have been reported, one by Jun and the other by
Schützenmeister. That of Jun begins from 4-methoxyacetophenone and requires a deprotection-
reprotection-deprotection cycle to reach rubrolides in 6 steps [12a]. Schützenmeister’s route is
shorter and protecting group-free (3-steps from tetronic acid) but leads to mixtures of Z/E-isomers,
requiring sequential purification by silica gel and reversed-phase C18 chromatography to obtain Z-
rubrolides [12b]. Furthermore, direct comparison of the anti-influenza activities of the Z/E-mixtures
with those of isomerically pure 1 and 2 revealed that the Z-stereochemistry is crucial for high
potency against both H3N2 and pH1N1 viruses [12b].
Herein, we report a strategically distinct approach to rubrolides and their analogues (cf. A, Scheme
1

a) that is concise and entirely stereoselective. A key objective in our approach was to introduce the
aryl substituent late in the synthesis, so as to facilitate future SAR studies on the importance of
this substituent. Retrosynthetically, we envisioned generating A through Suzuki arylation of
Z)benzylidenebromobutenolides B which would in turn arise from bromobutenolide 3 by
(
utilizing our laboratory’s previously described bromine-stereodirected vinylogous aldol
condensation (SVAC) methodology [13,14]. Crucially, bromine was to serve a dual role in the
synthesis, first as a stereocontrol element enabling the benzylidene appendage to be installed with
the desired Z-configuration, and second, as a leaving group in the ensuing coupling event. We now
describe the successful execution of this plan (cf. Scheme 1a) and further demonstrate the hitherto
unrealized, bioinspired [15] cationic cyclization of rubrolide R to rubrolide S (1  2, Scheme 1b).

a)
b)
Suzuki
Ar
Br
Br
O
O
O
O
O
O
ArCHO
3
Ar
A
Ar
B
SVAC
Ar
Ar
Ar = p-HOPh
O
O
O
H
biomimetic
cyclization
O
1
2
HO
O
+
Scheme 1. Our synthesis plan.
Results and discussion
The development of a rapid route to rubrolide S (2) began from commercially available or
inexpensively prepared bromobutenolide 3 [16] and 2,2-dimethylchromane-6-carbaldehyde 4
[
17] (Scheme 2). Assemblage of the pivotal (Z)benzylidenebutenolide 5 was best accomplished
by application of our one-pot vinylogous aldol condensation procedure [13]. Thus, sequential
treatment of 3 with TBSOTf, Hünig’s base and aldehyde 4, followed by in situ elimination of the
aldol adduct(s) with DBU, afforded 5 as a single stereoisomer in 70% yield after flash column
chromatography. In contrast, subjection of 3 and 4 to classical Knoevenagel conditions, e.g.
piperidine or sodium carbonate in MeOH at 25-50 ºC, which had previously worked well with some
carbon-substituted butenolides and benzaldehydes [12a,18], led to complex mixtures containing
only traces of 5 (<10%). Clearly, the serviceability of conventional procedures depends to a
considerable degree upon the structure of the reactants [19].
Br
Br
O
O
3
O
O
+
i
5
7
0%
O
CHO
O
4
path a
path b
iv 74%
ii 91%
MeO
HO
B(OH)2
OR
iii
00%
1
O
O
O
O
6
2
7
7
a R = Me
b R = H
O
O
Scheme 2. Reagents and conditions: (i) 3, TBSOTf, i-Pr
DCM, 0 ºC, 30 min, then 4, -78 ºC, 1 h, then DBU, -78 ºC to rt,
h, 70%; (ii) method A: 7a, PdCl (PPh , CsF, Et NBnCl,
2
PhMe/H O, rt, 36 h, 91%, method B: 7a, PdCl (MeCN) , Ag O,
2
NEt,
3
2
3
)
2
3
2
2
2

AsPh
3 3
, THF, reflux, 36 h, 85%; (iii) BBr , DCM, 0 ºC to rt, 2 h,
1
00%; (iv) As in (ii)-method A but using 7b, 110 ºC, 36 h, 74%.
With reliable access to 5, attention turned to its Suzuki coupling with 4-methoxyphenylboronic acid
a (Scheme 2, path a). Being mindful of the susceptibility of  kylidenebutenolides to alkaline
7
hydrolysis [20], our exploration of the Suzuki reaction focused on protocols employing mild,
essentially nonbasic conditions. Among those tried, the best consisted in the use of
PdCl
PdCl
2
(PPh
(MeCN)
3
)
2
/CsF/phase-transfer technology at room temperature (cf. method A) [21], or
/Ag O/AsPh in THF under reflux (method B) [10a,22], affording the cross-coupled
2
2
2
3
product 6 in yields of 91 and 85%, respectively. Demethylation of 6 with boron tribromide,
followed by standard aq. NaHCO work-up, delivered isomerically pure rubrolide S 2 quantitatively
without recourse to chromatography.
3
We also explored the possibility of cutting-off a step in the synthesis of 2 by replacing 7a with 4-
hydroxyphenylboronic acid 7b (Scheme 2, path b). Initial attempts to couple 7b with 5 using the
optimal conditions identified in path a (cf. method A, room temperature) failed to deliver 2. This
negative result was not wholly unexpected considering the low reactivity of 7b compared to that of
7
a [9i,23]. Whereas the desired coupling was ultimately achieved under harsher conditions, product
yields were not as high as those obtained with 7a. Indeed, the yield of 2 was maximized at 74%
method A, 110 ºC, 36 h), making the 2-step route somewhat less efficient overall than its 3-step
(
variant (52% vs 64%).
With a practical synthesis of rubrolide S achieved, attention turned to establishing a unified route to
both rubrolides R and S (Scheme 3). Subjection of the easily prepared aldehyde 8 [24] to our SVAC
protocol afforded Z-configured benzylidenebutenolide 9 in 64% yield after flash chromatography.
Suzuki arylation of 9 with commercially available 4-(tert-butyldimethylsilyloxy) phenylboronic
acid 7c [25] was best performed using PdCl
2
(MeCN)
2
/Ag
2
O/AsPh (cf. method B) to furnish cross-
3
coupled product 10 (76%), whose desilylation uneventfully delivered rubrolide R 1 in 90% isolated
yield. Happily, rubrolide R, as well as intermediates 9 and 10, were obtained as single
stereoisomers, suggesting that no Z to E isomerization occurred during the synthesis or flash
chromatography on silica gel [9i,26].

CHO
Br
Br
i
+
O
64%
O
O
O
3
9
TBSO
8
TBSO
TBSO
HO
B(OH)2
7c
ii 76%
RO
iv
3%
9
O
O
O
O
2
O
RO
0 R = TBS
iii
1
90%
1
R = H
Scheme 3. Reagents and conditions: (i) 3, TBSOTf, i-Pr
2
NEt,
DCM, 0 ºC, 30 min, then 8, -78 ºC, 1 h, then DBU, -78 ºC to rt,
3
3
h, 64%; (ii) 7c, PdCl
6 h, 76%; (iii) TBAF, THF, 0 ºC, 15 min, 90%;
2 2 2 3
(MeCN) , Ag O, AsPh , THF, reflux,
(iv) TfOH (0.8 equiv), THF, rt, 12 h, 93%.
At this point, all that remained was to trigger cationic cyclization of the ortho-prenylphenol in 1 to
generate rubrolide S 2 (cf. Scheme 1b). After screening several acids at different temperatures,
.
including the commonly employed HCl [15], TsOH [24a], and BF
3
OEt [27], and the superacid
2
TfOH, we were pleased to find that the latter was uniquely effective in promoting cyclization at
ambient temperature, cleanly providing rubrolide S 2 in an excellent 93% isolated yield (Scheme 3).
Conclusion
In conclusion, we have developed practical, entirely stereoselective syntheses of the antiviral
natural products rubrolide R and S from commercially available bromobutenolide and easily
prepared benzaldehydes. The foregoing work demonstrates (i) the serviceability of a new strategy
for constructing Z
arylbenzylidenebutenolides combining bromine-
stereodirected vinylogous aldol condensation with Suzuki cross-coupling (cf. Scheme 1a), and (ii)
the previously unrealized biomimetic transformation or rubrolide R to rubrolide S. Furthermore,
because the aryl substituent is introduced at a late stage, the present approach should facilitate
SAR studies on the importance of this substituent.

Acknowledgments
We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial support.
We also thank FRQNT-Québec for a doctoral scholarship to R.L.L. and CNPq-Brazil for a visiting
scholarship to T.A.M., a special visiting researcher fellowship to J.B. and a research fellowship to L.C.A.B.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
References
[
[
1] F. Zhou, M.-C. Trieu, R. Davies, R.J. Cox, Curr. Opin. Immunol. 53 (2018) 88–95.
2] World Health Organization. Influenza (Seasonal). Geneva: Media Center. Available at:
<
http://www.who.int/mediacentre/factsheets/fs211/en> [accessed August 18, 2019].
[
[
[
[
[
3] C.I. Paules, H.D. Marston, R.W. Eisinger, D. Baltimore, A.S. Fauci, Immunity 47 (2017) 599−603.
4] H. Ju, J. Zhang, B. Huang, D. Kang, B. Huang, X. Liu, P. Zhan, J. Med. Chem. 60 (2017) 3533–3551.
5] L. Naesens, A. Stevaert, E. Vanderlinden, Curr. Opin. Pharmacol. 30 (2016) 106−115.
6] R.U. Kadam, I.A. Wilson, Proc. Natl. Acad. Sci. U.S.A. 114 (2017) 206−214.
7] (a) E.J. Stavale, H. Vu, A. Sampath, U. Ramstedt, K.L. Warfield, PLoS ONE 10 (2015) 3: e0121662;
(
b) B.E. Tyrrell, A.C. Sayce, K.L. Warfield, J.L. Miller, N. Zitzmann, Crit. Rev. Microbiol. 43 (2017)
21–545.
8] (a) S. Miao, R.J. Andersen, J. Org. Chem. 56 (1991) 6275–6280;
5
[
(
(
b) M.J. Ortega, E. Zubía, J.M. Ocaña, S. Naranjo, J. Salvá, Tetrahedron 56 (2000) 3963–3967;
c) A.N. Pearce, E.W. Chia, M.V. Berridge, E.W. Maas, M.J. Page, V.L. Webb, J.L. Harper, B.R. Copp,
J. Nat. Prod. 70 (2007) 111–113;
d) J. Sikorska, S. Parker-Nance, M.T. Davies-Coleman, O.B. Vining, A.E. Sikora, K.L. McPhail, J. Nat.
Prod. 75 (2012) 1824–1827;
e) W. Wang, H. Kim, S.-J. Nam, B. J. Rho, H. Kang, J. Nat. Prod. 75 (2012) 2049–2054.
9] Synthesis of ascidian rubrolides:
(
(
[
(
(
(
(
(
(
(
(
a) M. Kotora, E. Negishi, Synthesis (1997) 121–128;
b) J. Boukouvalas, N. Lachance, M. Ouellet, M. Trudeau, Tetrahedron Lett. 39 (1998) 7665–7668;
c) F. Bellina, C. Anselmi, R. Rossi, Tetrahedron Lett. 43 (2002) 2023–2027;
d) A. Kar, N.P. Argade, Synthesis (2005) 2284–2286;
e) S.P. Chavan, A.B. Pathak, A. Pandey, U.R. Kalkote, Synth. Commun. 37 (2007) 4253–4263;
f) S. Cacchi, G. Fabrizi, A. Goggiamani, A. Sferrazza, Synlett (2009) 1277–1280;
g) J. Boukouvalas, L.C. McCann, Tetrahedron Lett. 51 (2010) 4636–4639;
h) N.P. Tale, A.V. Shelke, G.B. Tiwari, P.B. Thorat, N.N. Karade, Helv. Chim. Acta 95 (2012) 852–
857;
(
(
i) M. Karak, J.A.M. Acosta, L.C.A. Barbosa, J. Boukouvalas, Eur. J. Org. Chem. (2016) 3780–3787;
j) M. Karak, L.C.A. Barbosa, C.R.A. Meltha, T.M. Silva, J. Boukouvalas, Tetrahedron Lett. 58 (2017)
2830–2834.
[
10] Synthesis of rubrolide analogues:
(
(
(
(
a) F. Bellina, C. Anselmi, S. Viel, L. Mannina, R. Rossi, Tetrahedron 57 (2001) 9997–10007;
b) F. Bellina, C. Anselmi, F. Martina, R. Rossi, Eur. J. Org. Chem. (2003) 2290–2302;
c) Q. Zhu, L. Wang, R. Fathi, Z. Yang, J. Org. Chem. 68 (2003) 670–673;
d) R. Zhang, G. Iskander, P. da Silva, D. Chan, V. Vignevich, V. Nguyen, M.M. Bhadbhade, D.S.
Black, N. Kumar, Tetrahedron 67 (2011) 3010–3016;

(
e) L.C.A. Barbosa, C.R.A. Maltha, M.R. Lage, R.C. Barcelos, A. Donà, J.W.M. Carneiro, G. Forlani, J.
Agric. Food Chem. 60 (2012) 10555–10563;
f) U.A. Pereira, L.C.A. Barbosa, C.R.A. Maltha, A.J. Demuner, M.A. Masood, A.L. Pimenta, Eur. J.
Med. Chem. 82 (2014) 127–138;
g) U.A. Pereira, T.A. Moreira, L.C.A. Barbosa, C.R.A. Maltha, I.S. Bomfim, S.S. Maranhão, M.O.
Moraes, C. Pessoa, F.W.A. Barros-Nepomuceno, Med. Chem. Commun. 7 (2016) 345–352;
h) A.C.M. Miranda, L.C.A. Barbosa, M.A. Masood, J.O.S. Varejꢀo, M. Sordi, C.A.M. Benfatti, A.L.
(
(
(
Pimenta, ACS Omega 3 (2018) 18475−18480.
[
[
11]
(a) T. Zhu, Z. Chen, P. Liu, Y. Wang, Z. Xin, W. Zhu, J. Antibiot. 67 (2014) 315–318;
(
b) K. Zhou, L. Zhou, X. Wang, T. Zhang, Y. Wang, W. Dong, B. Ji, H. Yang, G. Du, Q. Hu, M.
Zhou, Chem. Nat. Compd. 52 (2016) 591–594;
(
c) K. Sun, G. Zhu, J. Hao, Y. Wang, W. Zhu, Tetrahedron 74 (2018) 83–87.
12]
(a) K. Damodar, J-K. Kim, J-G. Jun, Tetrahedron Letters 58 (2017) 50–53;
(
b) M. Schacht, G.J. Boehlich, J. Vries, S. Bertram, G. Gabriel, P. Zimmermann, P. Heisig, N.
Schützenmeister, Eur. J. Org. Chem. (2017) 1745–1748.
J. Boukouvalas, P.P. Beltrán, N. Lachance, S. Côté, F. Maltais, M. Pouliot, Synlett (2007) 219–222.
Recent synthetic applications:
[
[
13]
14]
(
a) J.A.M. Acosta, R. Muddala, L.C.A. Barbosa, J. Boukouvalas, J. Org. Chem. 81 (2016)
6883–6886;
(
b) T. Khotavivattana, T. Khamkhenshorngphanuch, K. Rassamee, P. Siripong, T. Vilaivan,
Tetrahedron Lett. 59 (2018) 2711–2715.
[
[
[
15]
16]
17]
R.R. Parvatkar, C. D’Souza, A. Tripathi, C.G. Naik, Phytochemistry 70 (2009) 128–132.
G. Jas, Synthesis (1991) 965–966.
R.P. Tripathi, S.S. Bisht, V.P. Pandey, S.K. Pandey, S. Singh, S.K. Sinha, V. Chaturvedi, Med.
Chem. Res. 20 (2011) 1515–1522.
[
18]
(a) J. Boukouvalas, C. Thibault, J. Org. Chem. 80 (2015) 681–684;
(
(
b) R. Muddala, J.A.M. Acosta, L.C.A. Barbosa, J. Boukouvalas, J. Nat. Prod. 80 (2017) 2166–2169;
c) H.-W. Xu, J.-F. Wang, G.-Z. Liu, G.-F. Hong, H.-M. Liu, Org. Biomol. Chem. 5 (2007)
1247–1250.
[
19]
(a) L.C.A. Barbosa, J.O.S. Varejꢀo, D. Petrollino, P.F. Pinheiro, A.J. Demuner, C.R.A. Maltha, G.
Forlani, Arkivoc 2012 (v) 15–32;
(
b) G.-Y. Liu, B.-Q. Guo, W.-N. Chen, C. Cheng, Q.-L. Zhang, M.-B. Dai, J.-R. Sun, P.-H. Sun, W.-
M. Chen, Chem. Biol. Drug Des. 79 (2012) 628–638;
c) F. Uhrner, F. Lederle, J.C. Namyslo, M. Gjikaj, A. Schmidt, E.G. Hübner, Tetrahedron 73 (2017)
472–4480.
(
4
[
[
[
[
20]
21]
22]
23]
S. Seo, M.C. Willis, Org. Lett. 19 (2017) 4556−4559.
J. Zhang, P.G. Blazecka, D. Belmont, J.G. Davidson, Org. Lett. 4 (2002) 4559–4561.
J. Boukouvalas, M. Pouliot, Synlett (2005) 343–345.
(a) B. Schmidt, M. Riemer, J. Org. Chem. 79 (2014) 4104–4118;
(
b) T.H. Kwon, K.Y. Cho, K.-Y. Baek, H.G. Yoon, B.M. Kim, RSC Adv. 7 (2017) 11684–11690.
Prepared by phenolic C-prenylation and O-silylation of 4-hydroxybenzaldehyde:
a) G.V. Rao, B.N. Swamy, V. Chandregowda, G.C. Reddy, Eur. J. Med. Chem. 44 (2009)
239–2245.
b) J.-Q. Weng, A. Ali, A. Estep, J. Becnel, S.L.F. Meyer, D.E. Wedge, M. Jacob, A. M.
[
24]
(
2
(
Rimando, Chem. Biodiversity 13 (2016) 1165–1177.
[
[
[
25]
26]
27]
J. Boukouvalas, L.C. McCann, Tetrahedron Lett. 52 (2011) 1202–1204.
D. Hermann, D. Arican, R. Brückner, Synthesis 49 (2017) 326–352.
(a) T. Narender, K.P. Reddy, Tetrahedron Lett. 48 (2007) 7628–7632.
(
(
b) T.N. Barrett, B.H. Patel, A.G.M. Barrett, Tetrahedron 70 (2014) 6894–6901.
c) K. Sreenivas, F.A. Khan, Tetrahedron Lett. 59 (2018) 1244–1248.

Highlights:
•
Bromine-stereodirected vinylogous aldol condensation led uniquely to Z-configured
benzylidenebutenolides.

•
•
The aryl substituent is introduced late in the synthesis.
Triflic acid enables highly efficient biomimetic conversion of rubrolide R
to rubrolide S.

Concise, stereocontrolled and modular syntheses of the anti-influenza rubrolides R and S
Thaís A. Moreira, Raphaël Lafleur-Lambert, Luiz C. A. Barbosa, John Boukouvalas*
HO
biomimetic cyclization (93%)
HO
Br
3
steps
4%
2-3 steps
52-64%
O
O
O
O
O
O
4
rubrolide R
ArCHO
rubrolide S
(
i) stereodirected vinylogous
aldol condensation
HO
O
(ii) Suzuki cross-coupling