Preparation of anacardic acids` analogous, possible inhibitors of the T

Total Synthesis of Rubrolides B, I and K
Milandip Karaka,b, Luiz C. A. Barbosaa,b *, Jaime A. M. Acostaa and John Boukouvalasc
a
Departamento de Química, Universidade Federal de Viçosa (UFV) – Brazil. bDepartamento de Química,
Universidade Federal de Minas Gerais(UFMG) – Brazil. cDépartement de Chimie, Université Laval – Canada
*e-mail: [email protected] / [email protected]
Keywords: Suzuki cross-coupling, Vinylogous aldol condensation, Selective bromination.
conditions to be uncovered for the all-important
selectivity of the bromination step, notably for
reaching rubrolide I and K.
INTRODUCTION
The rubrolides are a family of ca. 20 butenolides
isolated mainly from ascidia (tunicates),1a-e but also
from a marine fungus.1f Most rubrolides contain
brominated phenol groups, and nearly half of them
further possess a chloro substitutent attached
directly to the butenolide nucleus (1-2, Figure 1).
Besides densely functionalized structures, the
rubrolides and their synthetic analogues display
highly sought biological properties including
antibactertial,
antidiabetic,
antiviral,
antiinflammatory and herbicidal activities.1
HO
Y
X
1
Br
HO
Cl
O
O
O
O
HO
Br
Br
X = H or Br
Y = H or Br
Br
HO
HO
HO
Cl
O
O
1) Br2 (2.1 equiv), rt
2) BBr3
1) BBr3
2) Br2 (2.5 equiv)
KBr, 0-5 °C
MeO
Br
O
Br
Cl
O
O
Cl
O
O
Br
Br
Br
HO
rubrolide B (74%)
X
HO
Cl
O
5
2
Br
X
1) BBr3
2) Br2 (4.5 equiv)
KBr, rt
Y
HO
X
MeO
Br
rubrolide I (62%)
HO
rubrolide K (69%)
Scheme 2. Conversion of 5 to rubrolides B, I and K
Figure 1. Generic structures of rubrolides
CONCLUSION
Although numerous syntheses of simple rubrolides 1
have been reported,2 approaches to their chloro
counterparts 2 have been few and far between.3
Reported herein is the first synthesis of three such
targets, namely, rubrolide B, I, and K, using latestage bromination of a common intermediate.
The first synthesis of rubrolides B, I, and K has been
accomplished by a unified pathway from readily
available intermediate 5. In doing so, we have
demonstrated a versatile strategy for late-stage
bromination that should be applicable to the
preparation of other rubrolides and new analogues.
RESULTS AND DISCUSSION
ACKNOWLEDGEMENTS
Access to relay intermediate 5 was easily gained
from commercially available dichlorobutenolide
3 by site-selective Suzuki cross-coupling, followed
by vinylogous aldol condensation (Scheme 1).1a,3
We are grateful to CNPq and CAPES for research
fellowships and FAPEMIG for financial support.
MeO
Cl
Suzuki
cross-coupling
Cl
O
3
B(OH)2
O
MeO
Cl
O
4
vinylogous
aldol
condensation
O
MeO
a) Miao, S.; Andersen, R. J. J. Org. Chem. 1991, 56, 6275. b) Ortega, M.
, E.; Ocaña, J. M.; Salvá, J. Tetrahedron 2000, 56, 3963. c)
Manzanaro, S.; Salvá, J.; de la Fuente, J. Á. J. Nat. Prod. 2006, 69, 1485.
d) Pearce, A. N.; Chia, E. W.; Berridge, M. V.; Mass, E. W.; Page, M. J.;
Webb, V. L.; Harper, J. L.; Copp, B. R. J. Nat. Prod. 2007, 70, 111. e)
Sikorska, J.; Parker-Nance, S.; Davies-Coleman, M. T.; Vining, O. B.;
Sikora, A. E.; McPhail, K. L. J. Nat. Prod. 2012, 72, 1824. f) Zhu, T.; Chen,
Z.; Liu, P.; Wang, Y.; Xin, Z.; Zhu, W. J. Antibiot. 2014, 67, 315. g)
Barbosa, L. C. A.; Maltha, C. R. A.; Lage, M. R.; Barcelos, R. C.; Donà, A.;
Carneiro, J. W. M.; Forlani, G. J. Agric. Food Chem. 2012, 60, 10555. h)
Varejão, J. O. S.; Barbosa, L. C. A.; Ramos, G. Á.; Varejão, E. V. V.; KingDíaz, B.; Lotina-Hennsen, B. J. Photochem. Photobiol. B 2015, 145, 11.
2
a) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau, M. Tetrahedron
Lett. 1998, 39, 7665. b) Tale, N. P.; Shelke, A. V.; Tiwari, G. B.; Thorat, P.
B.; Karade, N. N. Helv. Chim. Acta 2012, 95, 852 and cited references.
3
a) Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett. 2002, 43, 2023. b)
Boukouvalas, J.; McCann, L. C. Tetrahedron Lett. 2010, 51, 4636.
Cl
O
MeO
O
O
5
51%
62%
REFERENCES
1
MeO
Scheme 1. Preparation of relay intermediate 5
As shown in Scheme 2, completion of the synthesis
of rubrolides B, I, and K from 5 was achieved by
judicious choice of the demethylation/bromination
sequence. Careful experimentation enabled optimal
th
th
16 Brazilian Meeting on Organic Synthesis – 16 BMOS – November 15-18, 2015 - Búzios, Brazil