Vinylogous addition of siloxyfurans to benzopyryliums: A concise approach to the tetrahydroxanthone natural products

Article abstract of DOI:10.1021/ja110698n

A concise approach to the tetrahydroxanthone natural products employing vinylogous addition of siloxyfurans to benzopyryliums and a late-stage Dieckmann cyclization has been developed. With this methodology, chiral, racemic forms of the natural products blennolides B and blennolide C have been synthesized in a maximum of four steps from a 5-hydroxychromone substrate. The regio- and diastereoselectivity of the vinylogous additions was probed using computational studies, which suggested the involvement of Diels-Alder-like transition states.

Full text of DOI:10.1021/ja110698n

COMMUNICATION
pubs.acs.org/JACS
Vinylogous Addition of Siloxyfurans to Benzopyryliums:
A Concise Approach to the Tetrahydroxanthone Natural Products
Tian Qin,† Richard P. Johnson,‡ and John A. Porco, Jr.*,†
†Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Boston,
Massachusetts 02215, United States
‡Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, United States
S Supporting Information
b
ABSTRACT: A concise approach to the tetrahydroxanthone
natural products employing vinylogous addition of siloxyfurans
to benzopyryliums and a late-stage Dieckmann cyclization
has been developed. With this methodology, chiral, racemic
forms of the natural products blennolides B and blennolide C
have been synthesized in a maximum of four steps from a
5-hydroxychromone substrate. The regio- and diastereoselec-
tivity of the vinylogous additions was probed using compu-
tational studies, which suggested the involvement of Diels-
Alder-like transition states.
etrahydroxanthones are a class of mycotoxins1 bearing both
monomeric and dimeric frameworks. The recently isolated
T
tetrahydroxanthones blennolide A (1) and B (2) (Figure 1)2 are
monomer units of the antitumor agents secalonic acids B (3)
and D (4), respectively,3 the latter which exhibits antibacterial,
cytostatic, and anti-HIV properties.4 Blennolide C (5), the methyl
isomer of 1, and the antifungal agent parnafungin A (6)5 also possess
the characteristic dihydro-2H-xanthenone framework found in many
tetrahydroxanthones. Related isomeric natural products, including
paecilin B (7) (stereochemistry unassigned) containing the isomeric
chromone lactone moiety, have also been reported.6 Recently, Br€ase
and Nicolaou reported elegant approaches to blennolide C (5) and
the related natural product diversonol employing biomimetic con-
struction of the tetrahydroxanthone core.7 Herein, we describe a
concise approach to racemic blennolides and related tetrahydrox-
anthones employing a “retrobiomimetic” process8 involving vinylo-
gous addition of siloxyfurans to benzopyryliums.
Figure 1. Tetrahydroxanthones and related natural products.
Biosynthetically, the blennolides appear to be derived from a
sequence involving oxidation of benzophenone ester 8, oxa-Michael
addition, and reduction to dihydro-2H-xanthenone 9 (Figure 2a).9
The chromone lactone structure 10 found in paecilin B (7)6
appears to be derived from hydrolysis/lactonization of the tetra-
hydroxanthone framework.6b,6c We envisioned that precursor 11
may be obtained by vinylogous addition of siloxyfurans10 to
activated benzopyrylium salts 12.11 Conjugate reduction of butenolide
11 should afford chromone lactone 10. The last step in the
sequence entails a “retrobiomimetic”transformation8 in which tetra-
hydroxanthones 9 may be produced by Dieckmann cyclization7k
of chromone lactones 10 (Figure 2b).
Figure 2. (a) Biosynthetic pathway vs (b) “retrobiomimetic” synthesis.
substantial adduct formation. In light of the high reactivity of 4-siloxy-
1-benzopyrylium salts toward carbon nucleophiles,11a,b we focused
our efforts on silyl triflate activation of chromone 13. In particular, we
reasoned that dialkylsilyl ditriflate reagents, which are generally used
to protect diols as silylenes,14 may directly afford activated siloxyben-
zopyrylium species. In the event, treatment of 13 with diisopropylsilyl
ditriflate in the presence of 2,6-lutidine led to the formation of
benzopyrylium 14.13 Treatment of 14 with 2-trimethylsiloxyfuran
We initiated our study by treating the readily available 5-hydroxy-
chromone 1312,13 with a number of Lewis acids in an effort to
promote vinylogous addition of 2-trimethylsilyloxyfuran (Scheme 1).
Unfortunately, in our initial experiments we did not observe
Received: November 29, 2010
Published: January 25, 2011
r
2011 American Chemical Society
1714
dx.doi.org/10.1021/ja110698n J. Am. Chem. Soc. 2011, 133, 1714–1717
|

Journal of the American Chemical Society
COMMUNICATION
Scheme 1. Model Studies
Table 1. Evaluation of Time and Temperature
entry R1
R2 temp (°C) time (h) yield (%)a
ratiob
1
2
3
4
5
6
7
8
H
H
-30
0
3
95
90
91
64
96
97
89
85
3:1 (15:17)
1:2 (15:17)
3:1 (15:17)
1:2 (15:17)
20:1 (19:20)
1:2 (19:20)
2:1 (21:22)
1:2 (21:22)
H
H
3
H
H
0
0.5
3
H
H
40
-78
0
Me
Me
H
H
1
at -78 °C cleanly led to formation of chromone butenolide 15 (dr =
H
3
15:1) after desilylation with Et3N 3HF. Crystallization of 15 facili-
3
tated X-ray crystal structure analysis of the major diastereomer.13
Finally, conjugate reduction of butenolide 15 with nickel boride15
provided chromone lactone 16.
Me
Me
-78
0
1
H
3
a Determined by crude 1H NMR analysis using 1,3,5-trimethoxy-
benzene as an internal standard. b Determined by crude 1H NMR analysis.
We next evaluated the effect of time and temperature for vinylo-
gous additions (Table 1). Interestingly, increasing the reaction tem-
perature led to reduced diastereoselectivities in additions to 14,leading
to a preference for diastereomer 17 at higher temperature (entries 1
and 2). Conducting the reaction at 0 °C for 0.5 h (entry 3) led to an
inseparable 3:1 mixture of 15 and 17 which supports epimerization at
higher temperatures and longer reaction times (see below).16 Similar
results were obtained for vinylogous additions to chromone 18 leading
to adducts 19 and 20 (entries 5 and 6). Addition of 4-methyl-2-
trimethylsiloxyfuran to 14 (entry 7) led to reduced diastereoselectivity
(2:1) in comparison with 2-trimethylsiloxyfuran (dr = 15:1; cf.
Scheme 1). On the basis of our experimental data, we propose the
generalized mechanism shown in Scheme 2. Initial vinylogous addi-
tion of 2-trimethylsiloxyfuran to 14 at -78 °C leads to the kinetic
adduct 23, which may lose TMSOTf to afford silylene 24, a precursor
to chromone 15. At higher temperature, thermodynamic equilibration
of 23 to 25 may occur by butenolide enolization16b through silylated
Figure 3. Composite surfaces of the B3LYP/6-31G(d) LUMO of 14
and HOMO of 2-trimethylsiloxyfuran mapped onto an electron density
isosurface using Spartan '08. Reactive sites are shown in blue.
Scheme 2. Proposed Mechanism for Vinylogous Addition
1
intermediate 26. The equilibration process was confirmed by H
NMR studies.13 Computational studies indicated that adduct 27 is
∼1 kcal/mol more stable than diastereomer 24.13
To understand the observed regio- and diastereoselectivity of
vinylogous additions, we employed density functional theory methods
to model the reaction of benzopyrylium 14 with 2-trimethyl-
siloxyfuran.13 Frontier molecular orbital analyses showed that C2 of
14 and C5 of the siloxyfuran should be the most reactive sites
(Figure 3). Thirteen candidate transition state (TS) structures were
generated by conformational variation about the nascent C2-C5
bond and optimized at the B3LYP/6-31G(d) level of theory.13 Similar
TSs have been proposed for vinylogous Mukaiyama aldol reactions.17
The lowest-energy Re-Si (or Si-Re) structure (TS-A in Figure 4)
that leads to the observed major product bears a striking resemblance
to an asynchronous endo [4 þ 2] TS; other TS candidates of like
stereochemistry were > 4.3 kcal/mol higher in energy. The most
favorable Re-Re (or Si-Si) TS structure (TS-B) is 2.68 kcal/mol
above TS-A, consistent with the stereochemistry observed for the
minor, kinetic product. With 4-methyl-2-trimethylsiloxyfuran (cf.
Table 1, entry 7), TS structures similar to TS-A would be disfavored
by steric factors, explaining the loss of diastereoselectivity.
found that treatment of 16 with NaOMe in THF19 led to observable
precipitation to a presumed dianion intermediate and formation of
dihydro-2H-xanthenones 29 and 30 after workup. After evaluation of
several bases, NaH was found to be superior to NaOMe, affording
29 in 67% yield (dr = 20:1 by 1H NMR analysis). To evaluate the
cyclization of the diastereomer of 16, we subjected a 2:1 mixture of
butenolides 17 and 15 to conjugate reduction (NiB2), whichafforded
an inseparable mixture of 31 and 16 in a 2:1 ratio; subsequent
Dieckmann cyclization (NaH/THF) afforded 30 and 29 in a 1:2 ratio
(Scheme 4). These studies support a mechanism for equilibration to
favor the syn configuration of the hydroxyl group in 29 as shown in
Scheme 5.5,6b,c,20 Enolate 32 derived from 31 may condense with the
lactone to form tetrahedral intermediate 33. After ring opening, the
Having achieved the synthesis of chromone lactone structures,
we next turned our attention to Dieckmann-type cyclizations
(Scheme 3).7k,18 Treatment of 16 with NaOMe in MeOH led
exclusively to the ring-opened hydroxy ester 28. Gratifyingly, we
1715
dx.doi.org/10.1021/ja110698n |J. Am. Chem. Soc. 2011, 133, 1714–1717

Journal of the American Chemical Society
COMMUNICATION
Scheme 5. Proposed Mechanism for Cyclization/Isomerization
Figure 4. Lowest-energy transition state structures for Re-Si (TS-A) and
Re-Re (TS-B) addition in the reaction of 14 and 2-trimethylsiloxyfuran.
Scheme 6. Synthesis of (()-epi-Blennolide C
Scheme 3. Dieckmann Cyclization
Scheme 7. Synthesis of (()-Blennolide C
Scheme 4. Equilibration of Dieckmann Products
Scheme 8. Synthesis of (()-Blennolide B
resulting dianion 34 (a precursor to 30) may equilibrate by retro-
Michael addition to 35, which may be followed by oxa-Michael
addition7a,b to provide diastereomer 36 and thence 29 after workup.
After completion of the model studies, we synthesized both
(()-epi-blennolide C (Scheme 6) and (()-blennolide C
(Scheme 7) from butenolides 19 and 20. Conjugate reduction
of a 20:1 mixture of 19 and 20 using NiB2 led to chromone lactones
37 (dr = 20:1). Dieckmann cyclization of 37 using NaH/THF
led to production of epi-blennolide C 39 (72% isolated yield).
Similar transformations were used to obtain blennolide C (5)
from a 2:1 mixture of 20 and 19 via lactone 38. The spectroscopic
properties of synthetic 5 and epi-blennolide C 39 were in com-
plete agreement with previously published data.2,7b,c
The natural product blennolide B (2)2 has syn, anti stereochem-
istry of the ester, hydroxyl, and methyl groups on the dihydro-2H-
xanthenone core. Based on our model studies and the hypothesis that
butenolide reduction should occur anti to the 5-substituent,15 we
initiated our synthesis from a 2:1 mixture of butenolides 21 and 22
(Table 1, entry 7). Nickel boride chemoselectively reduced the
butenolide to afford a mixture of four chromone lactone diastereo-
mers. Interestingly, when Rh/Al2O3 was used for the conjugate
reduction,21 we obtained 40 as a single diastereomer and the separa-
ble, overreduced hydroxyl chromone lactones 41 and 42 (Scheme 8).
Figure 5. X-ray crystal structures of compounds 40 and 44.
1716
dx.doi.org/10.1021/ja110698n |J. Am. Chem. Soc. 2011, 133, 1714–1717

Journal of the American Chemical Society
COMMUNICATION
Alcohols 41 and 42 could be reoxidized to lactones 40 and 44,
respectively, using the Bobbitt reagent 43 (50 wt % on SiO2).22 The
stereochemistries of chromone lactones 40 and 44 were confirmed
by X-ray crystal structure analyses (Figure 5). The NMR data for
chromone lactones 40 and 44 were not in agreement with data
reported for paecilin B6 (Figure 1), indicating that 7 is a diastereomer
of both 40 and 44. Treatment of 40 with NaH in THF afforded (()-
blennolide B (2), whose spectroscopic properties were identical to
reported data.2,13 Interestingly, cyclization of chromone lactone 44
(NaH) led to the isolation of (()-blennolide B (73%) with only
negligible amounts of diastereomer 45 being observed in the crude
1H NMR spectrum. This result further supports the isomerization
process shown in Scheme 5 which likely occurs due to unfavorable
repulsion between the ester and methyl groups in diastereomer 45.13
In conclusion, we have developed a concise and “retrobio-
mimetic” approach to tetrahydroxanthones employing vinylogous
addition of siloxyfurans to benzopyryliums as a key step. The
regio- and diastereoselectivity of the vinylogous additions was
probed using computational studies, which suggested the invol-
vement of Diels-Alder-like transition states. With this methodology,
the natural products (()-blennolides B and C were synthesized in
a maximum of four steps from readily available 5-hydroxychro-
mones. Further studies, including the development of an asym-
metric variant of the vinylogous addition, are currently under
investigation and will be reported in due course.
(5) (a) Parish, C. A.; et al. J. Am. Chem. Soc. 2008, 130, 7060. For
synthetic studies, see: (b) Zhou, Q.; Snider, B. B. Org. Lett. 2009, 11,
2936. (c) Zhou, Q.; Snider, B. B. J. Org. Chem. 2010, 75, 8224.
(6) (a) Guo, Z.; She, Z.; Shao, C.; Wen, L.; Liu, F.; Zheng, Z.; Lin, Y.
Magn. Reson. Chem. 2007, 45, 777. Xanthonequinodins: (b) Tabata, N.;
Tomada, H.; Matsuzaki, K.; Omura, S. J. Am. Chem. Soc. 1993, 115, 8558.
(c) Tabata, N.; Tomoda, H.; Iwai, Y.; Omura, S. J. Antibiot. 1996, 49,
267. Chaetomanone: (d) Pontius, A.; Krick, A.; Kehraus, S.; Foegen,
S. E.; M€uller, M.; Klimo, K.; Gerh€auser, C.; K€onig, G. M. Chem. Eur. J.
;
2008, 14, 9860.
(7) (a) Nising, C. F.; Ohnem€uller, U. K.; Br€ase, S. Angew. Chem., Int. Ed.
2006, 45, 307. (b) Nicolaou, K. C.; Li, A. Angew. Chem., Int. Ed. 2008, 47,
6579. (c) Gꢀerard, E. M. C.; Br€ase, S. Chem. Eur. J. 2008, 14, 8086. For
;
additional synthetic studies, see: (d) Franck, B.; St€ockigt, J.; Zeidler, U.;
Franckowiak, G. Chem. Ber. 1973, 106, 1198. (e) Gabbutt, C. D.; Hepworth,
J. D.; Urquhart, M. W. J.; Vazquez de Miguel, L. M. J. Chem. Soc., Perkin
Trans. 1 1997, 1819. (f) Letcher, R. M.; Yue, T.-Y.; Chiu, K.-F.; Kelkar, A. S.;
Cheung, K.-K. J. Chem. Soc., Perkin Trans. 1 1998, 3267. (g) Lesch, B.; Br€ase,
S. Angew. Chem., Int. Ed. 2004, 43, 115. (h) Ohnem€uller, U. K.; Nising, C. F.;
Nieger, M.; Br€ase, S. Eur. J. Org. Chem. 2006, 1535. (i) Nising, C. F.;
Friedrich, A.; Br€ase, S. Synlett 2007, 2987. (j) Ohnem€uller, U. K.; Nising,
C. F.; Encinas, A.; Br€ase, S. Synthesis 2007, 2175. (k) Tietze, L. F.; Spiegl,
D. A.; Stecker, F.; Major, J.; Raith, C.; Grosse, C. Chem. Eur. J. 2008, 14,
;
8956. (l) Tatsuta, K.; Yoshihara, S.; Hattori, N.; Yoshida, S.; Hosokawa, S.
J. Antibiot. 2009, 62, 469. (m)Volz, N.; Br€ohmer, M. C.; Nieger, M.; Br€ase, S.
Synlett 2009, 550 and references therein.
(8) For “retrobiomimetic” synthesis, see: (a) Andriamialisoa, R. Z.;
Langlois, N.; Langlois, Y. J. Org. Chem. 1985, 50, 961. (b) Martynow,
J. G.; Kirst, H. A. J. Org. Chem. 1994, 59, 1548.
(9) (a) Kurobane, I.; Vining, L. C.; McInnes, A. G.; Walter, J. A.;
Wright, J. L. C. Tetrahedron Lett. 1978, 19, 1379. (b) Kurobane, I.;
Vining, L. C.; McInnes, A. G. J. Antibiot. 1979, 32, 1256.
(10) For recent reviews of vinylogous additions of siloxyfurans, see:
(a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev.
2000, 100, 1929. (b) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.
Synlett 2009, 1525.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental and computa-
b
tional details, complete ref 5a, and CIF files for 15, 40, and 44.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(11) For addition of carbon nucleophiles to 4-siloxy-1-benzopyr-
ylium salts, see: (a) Ohkata, K.; Ishimaru, K.; Lee, Y.-G.; Akiba, K. Chem.
Lett. 1990, 1725. (b) Lee, Y.-G.; Ishimaru, K.; Iwasaki, H.; Ohkata, K.;
Akib, K. J. Org. Chem. 1991, 56, 2058. For vinylogous addition of
siloxyfurans to isoquinolinium salts, see: (c) Hermange, P.; Tran Huu
Dau, M. E.; Retaileau, P.; Dodd, R. H. Org. Lett. 2009, 11, 4044.
(12) Wu, L.; Lal, J.; Simon, K. A.; Burton, E. A.; Luk, Y.-Y. J. Am.
Chem. Soc. 2009, 131, 7430.
(13) See the Supporting Information for complete experimental and
computational details.
(14) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871.
(15) For a review on the chemistry of nickel boride, see: Khurana,
J. M.; Gogia, A. Org. Prep. Proc. Int. 1997, 29, 1.
’ AUTHOR INFORMATION
Corresponding Author
porco@bu.edu
’ ACKNOWLEDGMENT
We thank the National Institutes of Health (GM-073855 to
J.A.P.) and the National Science Foundation (CHE-0910826 to
R.P.J.) for research support and Drs. JeffreyBacon(BostonUniversity)
and Emil Lobkovsky (Cornell University) for X-ray crystal struc-
ture analyses. We also thank the NSF (CHE-0443618) for the
high-resolution mass spectrometer used in this work.
(16) Fortemperature-dependent siloxyfuranadditions, see: (a)Wieland,
L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 570. For isomerization of butenolides, see: (b) Lee, H.; Kim, K. W.; Park,
J.;Kim, H.;Kim, S.; Kim, D.;Hu, X.; Yang, W.; Hong, J.Angew. Chem., Int. Ed.
2008, 47, 4200.
’ REFERENCES
(1) Br€ase, S.; Encinas, A.; Keck, J.; Nising, C. F. Chem. Rev. 2009,
109, 3903.
(2) Zhang, W.; Krohn, K.; Ullah, Z.; Fl€orke, U.; Pescitelli, G.; Di Bari,
L.; Antus, S.; Kurtꢀan, T.; Rheinheimer, J.; Draeger, S.; Schulz, B.
ꢀ
ꢀ
(17) Lꢀopez, C. S.; Alvarez, R.; Vaz, B.; Niet Faza, O.; De Lera, A. R.
J. Org. Chem. 2005, 70, 3654.
Chem. Eur. J. 2008, 14, 4913.
;
(18) For a review of the Dieckmann reaction, see: Davis, B. R.;
Garratt, P. J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 2, p 806.
(19) Gerard, B.; Jones, G., II; Porco, J. A., Jr. J. Am. Chem. Soc. 2004,
126, 13620.
(3) (a) Franck, B.; Gottschalk, E. M.; Ohnsorge, U.; Baumann, G.
Angew. Chem., Int. Ed. Engl. 1964, 3, 441. (b) Franck, B.; Baumann, G.;
Ohnsorge, U. Tetrahedron Lett. 1965, 6, 2031. (c) Franck, B.; Gottschalk,
E. M.; Ohnsorge, U.; H€uper, F. Chem. Ber. 1966, 99, 3842. (d) Steyn,
P. S. Tetrahedron 1970, 26, 51.
(20) Burobane, I.; Vining, L. C.; McInnes, A. G. Ger. Offen. DE 80-
3002761, 1980.
(4) (a) Stoll, A.; Renz, J.; Brack, A. Helv. Chim. Acta 1952, 35, 2022.
(b) Kurobane, I.; Iwahashi, S.; Fukuda, A. Drugs Exp. Clin. Res. 1987, 13,
339. (c) McPhee, F.; Caldera, P. S.; Bemis, G. W.; McDonagh, A. F.;
Kuntz, I. D.; Craik, C. S. Biochem. J. 1996, 320, 681. (d) Liao, G.; Zhou,
J.; Wang, H.; Mao, Z.; Xiao, W.; Wang, H.; She, Z.; Zhu, Y. Oncol. Rep.
2010, 23, 387.
(21) Gurjar, M. K.; Cherian, J.; Ramana, C. V. Org. Lett. 2004, 6, 317.
(22) Bobbitt, J. M. J. Org. Chem. 1998, 63, 9367.
1717
dx.doi.org/10.1021/ja110698n |J. Am. Chem. Soc. 2011, 133, 1714–1717