Total syntheses of secalonic acids A and D

Article abstract of DOI:10.1002/anie.201311260

Total syntheses of the dimeric tetrahydroxanthone natural products secalonic acids A and D are described. Key steps involve kinetic resolution of the tetrahydroxanthone core structure using homobenzotetramisole catalysis and late-stage copper(I)-mediated homodimerization of complex aryl stannane monomers. It takes two: Concise syntheses of the natural products secalonic acids A and D using copper(I)-mediated dimerization of complex aryl stannane monomers to construct the requisite 2,2′-biphenol linkage are reported. Highly efficient kinetic resolution of the monomeric tetrahydroxanthone core structures was achieved using homobenzotetramisole catalysis. DMA=N,N-dimethyl acetamide, MOM=methoxymethyl.

Full text of DOI:10.1002/anie.201311260

Angewandte
Chemie
DOI: 10.1002/anie.201311260
Natural Product Synthesis
Hot Paper
Total Syntheses of Secalonic Acids A and D**
Tian Qin and John A. Porco Jr.*
Abstract: Total syntheses of the dimeric tetrahydroxanthone
natural products secalonic acids A and D are described. Key
steps involve kinetic resolution of the tetrahydroxanthone core
structure using homobenzotetramisole catalysis and late-stage
copper(I)-mediated homodimerization of complex aryl stan-
nane monomers.
(3) and rugulotrosin A[6] (4), both of which possess axial
chirality. Recently, our group[7] as well as those of Brꢀse,[8]
Nicolaou,[9] and Tietze[10] have accomplished syntheses of
monomeric tetrahydroxanthone natural products. Herein, we
describe the first total syntheses of the dimeric natural
products secalonic acids A and D by utilizing copper(I)-
mediated dimerization of complex aryl stannane monomers
to construct the requisite 2,2’-biphenol linkage.
D
imeric tetrahydroxanthones belong to a class of mycotox-
ins[1] which connect tetrahydroxanthone monomers by a 2,2’-
On the basis of the proposed biosynthetic relationship[11]
between tetrahydroxanthones and chromone lactones, and
our previous synthetic studies,[7] we anticipated that secalonic
acid D (2) could be obtained from the dimeric chromone
lactone 5[12] by double Dieckmann cyclization (Figure 2). We
biphenol linkage (Figure 1). Among these compounds, the
Figure 1. Representative dimeric tetrahydroxanthone natural products.
Figure 2. Initial retrosynthetic analysis for secalonic acid D.
secalonic acids[2] were first isolated in 1960 and were found to
exhibit interesting bioactivities. Secalonic acid B (1) has
antitumor activity and its diastereomer secalonic acid D (2)
shows potent cytotoxicity to HL60/K562 cells by down-
regulation of c-Myc.[3a] The compound 2 has also been
reported to inhibit DNA topoisomerase I.[3b] The enantiomer
of 2, secalonic acid A (not shown, ent-2) has antitumor
properties and also reduces colchicine toxicity in rat cortical
neurons.[4] Related natural products include gonytolide A[5]
initially envisioned that oxidative coupling of the chromone
lactone 6 could be used to access the dimeric precursor 5. By
following our developed methodology,[7] compound 6 may be
obtained by vinylogous addition of 2-(trimethylsiloxy)furan
to a siloxybenzopyrylium species derived from the chromone
ester 7.
We first evaluated the possibility for oxidative coupling of
a chromone lactone monomer as a result of the likely
instability of the tetrahydroxanthone core structure. Accord-
ingly, we prepared the model chromone lactone 8[7]
(Scheme 1) on a gram scale and investigated a number of
oxidative coupling conditions[13] (e.g. VOCl3, [Mn(acac)3],
FeCl3). However, we found that oxidative conditions afforded
2,2’-linked-chromone lactone dimers in very low yield, and in
the case of VOCl3, chlorinated products were formed. We
then changed our focus to prefunctionalization of the mono-
mers to achieve dimerization of the chromone lactone, an
approach which we anticipated could provide selectivity for
biaryl coupling. Both thallium-acetate-directed[14] or
Me3NBnICl2-directed iodination[15,16] of 8 afforded a major
ortho-iodinated product and subsequent base-mediated O-
methylation provided the aryl iodide 9 (Scheme 1). Notably,
traditional copper-mediated Ullmann coupling of 9 (10 equiv
Cu, 1608C) led to deiodination and decomposition products.
Stannylation of 9 was mediated by palladium(0) catalysis in
[*] T. Qin, Prof. Dr. J. A. Porco Jr.
Department of Chemistry and Center for Chemical Methodology
and Library Development (CMLD-BU), Boston University
590 Commonwealth Avenue, Boston, MA 02215 (USA)
E-mail: porco@bu.edu
[**] Financial support from the NIH (GM-099920 and GM-067041) and
Vertex Pharmaceuticals, Inc. (graduate fellowship to T.Q.) is
gratefully acknowledged. We thank Dr. Jeffery Bacon (Boston
University) for X-ray crystal structure analyses, Prof. Shu-Hua Qi
(South China Sea Institute of Oceanology, CAS) for kindly providing
a natural sample of secalonic acid D, and Prof. Xiaoguang Lei
(National Institute of Biological Sciences, Beijing) and Prof.
Zhigang She (SunYat-sen University) for helpful information con-
cerning secalonic acid derivatives.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311260.
Angew. Chem. Int. Ed. 2014, 53, 3107 –3110
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3107

.
Angewandte
Communications
Scheme 2. Attempted double Dieckmann cyclization.
Scheme 1. Synthesis of a racemic, model 2,2’-linked chromanone
dimer. dba=dibenzylideneacetone, DMA=N,N-dimethyl acetamide.
which case nBu4NI[17] was found to be an essential additive to
obtain full conversion to stannane 10. With both 9 and 10 in
hand, a number of palladium sources, ligands, and solvents
were investigated for biaryl couplings. However, in these
experiments the desired dimer was obtained in trace amounts.
Intriguingly, we found that 10 was converted into an
inseparable mixture of the C2-dimer 11 and Cs-dimer 12
when the commercial reagent CuCl[18,19] was used as an
additive for palladium(0)-mediated cross-coupling. Surpris-
ingly, this pathway was totally suppressed using freshly
prepared CuCl and degassed solvent. We found that using
ambient air as the oxidant[20,21] was critical to enable
reproducible dimerization chemistry, and that the polar
aprotic solvent DMA enhanced the rate of transmetallation
of tributyltin to copper(I). Treatment of the resulting dimers
11/12 with BBr3 cleanly afforded the deprotected dimers 13/
14.
With the chromone lactone dimers in hand, we anticipated
that double Dieckmann cyclization[7] could provide access to
the dimeric tetrahydroxanthone. However, in contrast to
monomeric substrates,[7] treatment of the dimers 11/12 or 13/
14 under basic conditions (e.g. NaH/THF, NaH/Mg(OTf)2,
Et3N/TMSOTf), did not lead to significant production of
dimeric tetrahydroxanthone products or mono-rearranged
products, but only led to decomposition of the starting
material (Scheme 2). Accordingly, we investigated dimeriza-
tion of the tetrahydroxanthone core structure. Protection of
the enol moiety was necessary because of its high reactivity.
The tetrahydroxanthone 15[7] was successfully methylated
with (trimethylsilyl)diazomethane to afford the desired enol
ether 17 in 57% yield along with the isomer 16 (20%;
Scheme 3). Strict control of reaction temperature and time
was required to prevent double O-methylation. By employing
the previous ortho-iodination conditions, iodide 18 was
obtained in 80% yield. Utilizing the homobenzotetramisole
(HBTM) catalyst 19 developed by Birman and co-workers,[22]
kinetic resolution[23] proceeded smoothly to afford (À)-18 in
48% yield (96% ee) and (+)-20 in 49% yield (96% ee; s =
146). Furthermore, we were able to obtain (À)-18 in 99% ee
Scheme 3. Kinetic resolution on a model system. DIEA=diisopropyle-
thylamine
using a longer reaction time (13 h). The absolute stereochem-
istry of the kinetic resolution products was verified by single-
crystal analysis of the deiodinated congener (À)-17.[16,24] We
propose that the observed high selectivity for the kinetic
resolution results from p stacking between the tetrahydrox-
anthone substrate and the HBTM catalyst,[22] thus leading to
an assembly which minimizes steric repulsion (Scheme 4a).
Steric repulsion between the phenyl group and the tetrahy-
droxanthone in (Scheme 4b) renders the latter assembly less
favorable.
With the monomer (À)-18 in hand, and after evaluating
several protecting groups, we next prepared MOM-protected
(+)-21 (81% yield) which was then subjected to stannylation
to afford the key intermediate (+)-22 (Scheme 5). As before,
Scheme 4. Proposed assemblies for kinetic resolution.
3108
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 3107 –3110

Angewandte
Chemie
Scheme 5. Synthesis of a model 2,2’-linked tetrahydroxanthone dimer.
DMAP=4-(N,N-dimethylamino)pyridine, MOM=methoxymethyl.
Scheme 7. Synthesis of secalonic acid D.
the additive nBu4NI was found to be crucial for palladium(0)-
catalyzed stannylation. Furthermore, longer reaction times or
increased amounts of additives led to enol ether deprotection.
Gratifyingly, copper-mediated coupling of (+)-22 proceeded
smoothly to afford the 2,2’-linked dimer (À)-23 in 60% yield.
Finally, treatment of 23 with 3m HCl led to the fully
deprotected tetrahydroxanthone dimer (À)-24 in 89% yield.
Encouraged by our model studies, we initiated syntheses
of secalonic acids A and D using the racemic blennolide B
(25; Scheme 6).[7] Following previously optimized reaction
Figure 3. X-ray crystal structure of (+)-31.
((+)-31) whose absolute and relative stereochemistry were
unambiguously verified by X-ray crystal structure analysis
(Figure 3).[24] Global deprotection under acidic conditions
provided secalonic acid D (2) in 81% yield. NMR spectra,
UPLC retention times, and aD values for 2 were found to be
identical to those reported for the natural material.[16]
In a similar manner, the other compound accessed from
kinetic resolution, (À)-28, was advanced to secalonic acid A
(ent-2; Scheme 8). After MOM protection and stannane
synthesis, (+)-32 was obtained in 41% yield after two steps.
Treatment of (+)-32 with CuCl and air led to the production
of the dimer (À)-33 in 60% yield. Final deprotection using 3m
HCl/acetonitrile afforded secalonic acid A (ent-2), the enan-
tiomer of secalonic acid D, in 85% yield.
In summary, the bioactive tetrahydroxanthone dimers
secalonic acids A and D have been synthesized for the first
time. Birmanꢁs homobenzotetramisole (HBTM) catalysts
were found to be highly effective for kinetic resolution of
highly functionlized tetrahydroxanthone monomers. In addi-
tion, we found that copper(I) chloride under mild oxidative
conditions could be used to access 2,2’-biphenols from
complex aryl stannanes. These extremely mild dimerization
conditions show excellent functional-group tolerance and
should be useful for the synthesis of a range of dimeric 2,2’-
linked chromone lactone and tetrahydroxanthone natural
Scheme 6. Kinetic resolution of a blennolide derivative.
conditions, methyl enol ether protection and ortho-iodination
afforded the blennolide derivative 28. Because of the
presence of an additional methyl group on the C ring,
acylative kinetic resolution was much slower in comparison
to the model substrate (25 h, 08C). However, a longer
reaction time and higher temperature provided both (À)-28
and (+)-29 in excellent yield and enantioselectivity. Fortu-
nately, after recrystallization, both (+)-29 and (À)-28 could be
obtained in greater than 99% ee.
With (+)-29 in hand, we conducted MOM protection
followed by stannane formation to obtain the enantioen-
riched tetrahydroxanthone (À)-30 (Scheme 7). Copper-medi-
ated oxidative coupling provided a single dimeric product
Angew. Chem. Int. Ed. 2014, 53, 3107 –3110
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3109

.
Angewandte
Communications
Gꢃrared, S. Brꢀse, Chem. Eur. J. 2008, 14, 8086 – 8089; g) N.
Volz, M. C. Brçhmer, M. Nieger, S. Brꢀse, Synlett 2009, 550 –
553; h) M. C. Brçhmer, E. B. Bourcet, M. Nieger, S. Brꢀse,
Chem. Eur. J. 2011, 17, 13706 – 13711; i) A. M. Linsenmeier, S.
Brꢀse, Eur. J. Org. Chem. 2012, 6455 – 6459; j) A. C. Meister, M.
Nieger, S. Brꢀse, Chem. Eur. J. 2013, 19, 10836 – 10839.
[9] K. C. Nicolaou, A. Li, Angew. Chem. 2008, 120, 6681 – 6684;
Angew. Chem. Int. Ed. 2008, 47, 6579 – 6582.
[10] a) L. F. Tietze, D. A. Spiegl, F. Stecker, J. Major, C. Raith, C.
Große, Chem. Eur. J. 2008, 14, 8956 – 8963; b) L. F. Tietze, S.
Jackenkroll, C. Raith, D. A. Spiegl, J. R. Reiner, M. Claudia, O.
Campos, Chem. Eur. J. 2013, 19, 4876 – 4882; c) L. F. Tietze, L.
Ma, J. R. Reiner, S. Jackenkroll, S. Heidemann, Chem. Eur. J.
2013, 19, 8610 – 8614.
[11] For the biosynthesis of secalonic acid A, see: a) I. Kurobane,
L. C. Vining, A. G. McInnes, J. A. Walter, J. L. C. Wright,
Tetrahedron Lett. 1978, 19, 1379 – 1382; b) I. Kurobane, L. C.
Vining, J. Antibiot. 1979, 32, 1256 – 1266; for the possible
relationship between tetrahydroxanthones and chromone lac-
Scheme 8. Synthesis of secalonic acid A.
¯
tones, see: c) N. Tabata, H. Tomada, K. Matsuzaki, S. Omura, J.
Am. Chem. Soc. 1993, 115, 8558 – 8564; d) N. Tabata, H. Tomoda,
Y. Iwai, S. Omura, J. Antibiot. 1996, 49, 267 – 271.
products. Further studies on the detailed mechanism of
copper-mediated coupling of aryl stannanes as well as
asymmetric syntheses of additional tetrahydroxanthone nat-
ural product targets are currently under investigation and will
be reported in due course.
¯
[12] For synthesis of an isomer of the chromone lactone dimer
paecilin A, see: L. F. Tietze, L. Ma, S. Jackenkroll, J. R. Reiner, J.
Hierold, B. Gnanaprakasam, S. Heidemann, Heterocycles 2014,
88, 1101 – 1119.
[13] For a review on aryl – aryl bond formation, see: J. Hassan, M.
Sꢃvignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002,
102, 1359 – 1470.
[14] R. C. Cambie, P. S. Rutledge, T. Smith-Palmer, P. D. Woodgate,
J. Chem. Soc. Perkin Trans. 1 1976, 1161 – 1164.
[15] S. Kajigaeshi, T. Kakinami, H. Yamasaki, S. Fujisaki, M. Kondo,
T. Okamoto, Chem. Lett. 1987, 2109 – 2112.
Received: December 28, 2013
Published online: February 12, 2014
Keywords: dimerization · kinetic resolution · natural products ·
.
stannanes · total synthesis
[16] See the Supporting Information for complete experimental
details.
[17] a) M. Piber, A. E. Jensen, M. Rottlander, P. Knochel, Org. Lett.
1999, 1, 1323 – 1326; b) J.-F. Nguefack, V. Bolitt, D. Sinou,
Tetrahedron Lett. 1996, 37, 5527 – 5530; c) N. A. Powell, S. D.
Rychnovsky, Tetrahedron Lett. 1996, 37, 7901 – 7904.
[18] X. Han, B. M. Stoltz, E. J. Corey, J. Am. Chem. Soc. 1999, 121,
7600 – 7605.
[19] For copper-chloride-mediated coupling of aryl stannanes, see:
a) E. Piers, J. G. K. Yee, P. L. Gladstone, Org. Lett. 2000, 2, 481 –
484; b) K. Nabatame, M. Hirama, M. Inoue, Heterocycles 2008,
76, 1011 – 1016; for copper-chloride-mediated couplings of vinyl
stannanes, see: c) E. Piers, M. A. Romero, J. Am. Chem. Soc.
1996, 118, 1215 – 1216; for copper-nitrate-mediated arylstannane
coupling, see: d) S. Ghosal, G. P. Luke, K. S. Kyler, J. Org. Chem.
1987, 52, 4296 – 4298; For catalytic copper(II)-chloride-mediated
stannane coupling, see: e) S.-K. Kang, T.-G. Baik, X. H. Jiao, Y.-
T. Lee, Tetrahedron Lett. 1999, 40, 2383 – 2384.
[1] a) S. Brꢀse, A. Encinas, J. Keck, C. F. Nising, Chem. Rev. 2009,
109, 3903 – 3990; b) K.-S. Masters, S. Brꢀse, Chem. Rev. 2012,
112, 3717 – 3776.
[2] a) For the isolation of secalonic acid A, see: B. Franck, E. M.
Gottschalk, U. Ohnsorge, G. Baumann, Angew. Chem. 1964, 76,
438 – 439; Angew. Chem. Int. Ed. Engl. 1964, 3, 441 – 442; b) B.
Franck, G. Baumann, U. Ohnsorge, Tetrahedron Lett. 1965, 6,
2031 – 2037; c) B. Franck, E. M. Gottschalk, U. Ohnsorge, F.
Hꢂper, Chem. Ber. 1966, 99, 3842 – 3862; First the isolation of
secalonic acid D, see: d) P. S. Steyn, Tetrahedron 1970, 26, 51 –
57.
[3] a) J. Zhang, L. Tao, Y. Liang, Y. Yan, C. Dai, X. Xia, Z. She, Y.
Lin, L. Fu, Cell Cycle 2009, 8, 2444 – 2450; b) R. Hong, Pharm.
Biol. 2011, 49, 796 – 799.
[4] A. Zhai, Y. Zhang, X. Zhu, J. Liang, X. Wang, Y. Lin, R. Chen,
Neurochem. Int. 2011, 58, 85 – 91.
[5] a) H. Kikuchi, M. Isobe, M. Sekiya, Y. Abe, T. Hoshikawa, K.
Ueda, S. Kurata, Y. Katou, Y. Oshima, Org. Lett. 2011, 13, 4624 –
4627; b) H. Kikuchi, M. Isobe, S. Kurata, Y. Katou, Y. Oshima,
Tetrahedron 2012, 68, 6218 – 6223.
[6] M. Stewart, R. J. Capon, J. M. White, E. Lacey, S. Tennant, J. H.
Gill, M. P. Shaddock, J. Nat. Prod. 2004, 67, 728 – 729.
[7] T. Qin, R. P. Johnson, J. A. Porco, Jr., J. Am. Chem. Soc. 2011,
133, 1714 – 1717.
[8] a) B. Lesch, S. Brꢀse, Angew. Chem. 2004, 116, 118 – 120; Angew.
Chem. Int. Ed. 2004, 43, 115 – 118; b) C. F. Nising, U. K.
Ohnemꢂller, S. Brꢀse, Angew. Chem. 2005, 117, 313 – 315;
Angew. Chem. Int. Ed. 2006, 45, 307 – 309; c) U. K. Ohnemꢂl-
ler (nꢃe Schmid), C. F. Nising, M. Nieger, S. Brꢀse, Eur. J. Org.
Chem. 2006, 1535 – 1546; d) C. F. Nising, A. Friedrich, S. Brꢀse,
Synlett 2007, 2987 – 2990; e) U. K. Ohnemꢂller, C. F. Nising, A.
Encinas, S. Brꢀse, Synthesis 2007, 2175 – 2185; f) E. M. C.
[20] For a review on oxidation of organocuprates, see: D. S. Surry,
D. R. Spring, Chem. Soc. Rev. 2006, 35, 218 – 225.
[21] See the Supporting Information for details on the evaluation of
copper sources, solvents, and oxidants.
[22] a) V. B. Birman, X. Li, Org. Lett. 2006, 8, 1351 – 1354; b) V. B.
Birman, X. Li, Org. Lett. 2008, 10, 1115 – 1118; c) X. Li, H. Jiang,
E. W. Uffman, L. Guo, Y. Zhang, X. Yang, V. B. Birman, J. Org.
Chem. 2012, 77, 1722 – 1737.
[23] For a recent review of organocatalytic, enantioselective acyl
transfer, see: C. E. Mꢂller, P. R. Schreiner, Angew. Chem. 2011,
123, 6136 – 6167; Angew. Chem. Int. Ed. 2011, 50, 6012 – 6042.
[24] CCDC 961591 [(À)-17}, 961692 [(+)-31] contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3110
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 3107 –3110