Synthesis of bisbenzannulated spiroketals - Model studies for a modular approach to rubromycins

Article abstract of DOI:10.1021/ol061932w

(Chemical Equation Presented) A highly flexible synthesis of bisbenzannulated spiroketals is described with additions of lithiated methoxyallene to aryl aldehydes and Heck reactions as key steps. Subsequent hydrogenations and ketalizations afforded the de

Full text of DOI:10.1021/ol061932w

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4875-4878
Synthesis of Bisbenzannulated
Spiroketals Model Studies for a
Modular Approach to Rubromycins
s
Sebastian So1rgel, Cengiz Azap, and Hans-Ulrich Reissig*
Institut fu¨r Chemie und Biochemie, Freie UniVersita¨t Berlin, Takustr. 3, D-14195
Berlin, Germany
hans.reissig@chemie.fu-berlin.de
Received August 4, 2006
ABSTRACT
A highly flexible synthesis of bisbenzannulated spiroketals is described with additions of lithiated methoxyallene to aryl aldehydes and Heck
reactions as key steps. Subsequent hydrogenations and ketalizations afforded the desired spiroketals in good yields and with predominating
trans-configuration. With model compound 30, already bearing the fully substituted naphthyl core of rubromycins, the ketalization proceeded
efficiently providing the expected product 31 and the isopropoxy compound 32. Both products are advanced model compounds of heliquinomycin.
Rubromycins, such as γ-rubromycin 1,1 purpuromycin 2,2
and heliquinomycin 3,3 are structurally related pigments,
which display a broad range of biological activity (Figure
1). While γ-rubromycin 1 is a potent inhibitor of DNA
and is a potential topical agent for vaginal infections.5 In
contrast, heliquinomycin 3 proved to be a selective inhibitor
of DNA helicase.3
The basic structure of the rubromycins combines a
naphthoquinone moiety with a 5,6-spiroketal fused to an
isocoumarin unit. Despite the interesting biological properties
and the intriguing molecular architecture of these natural
products, apart from several model studies6 and preliminary
(2) (a) Coronelli, C.; Pagani, H.; Bardone, M. R.; Lancini, G. C. J.
Antibiot. 1974, 27, 161. (b) Coronelli, C.; Zerilli, L. F.; Bardone, M. R.;
Martinelli, E. Tetrahedron 1974, 30, 2747.
(3) (a) Chino, M.; Nishikawa, K.; Umekita, M.; Hayashi, C.; Yamazaki,
T.; Tsuchida, T.; Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1996,
49, 752. (b) Chino, M.; Nishikawa, K.; Tsuchida, T.; Sawa, R.; Nakamura,
H.; Nakamura, K.; Muraoka, Y.; Ikeda, D.; Naganawa, H.; Sawa, T.;
Takeuchi, T. J. Antibiot. 1997, 50, 143. (c) Chino, M.; Nishikawa, K.; Sawa,
R.; Hamada, M.; Naganawa, H.; Sawa, T.; Takeuchi, T. J. Antibiot. 1997,
50, 781. (d) Chino, M.; Nishikawa, K.; Yamada, A.; Ohsono, M.; Sawa,
T.; Hanaoka, F.; Ishizuka, M.; Takeuchi, T. J. Antibiot. 1998, 51, 480.
(4) Goldman, M. E.; Salituro, G. S.; Bowen, J. A.; Williamson, J. M.;
Zink, L.; Schleif, W. A.; Emini, E. A. Mol. Pharmacol. 1990, 38, 20.
(5) Trani, A.; Dallanoce, C.; Panzone, G.; Ripamonti, F.; Goldstein, B.
P.; Ciabatti, R. J. Med. Chem. 1997, 40, 967.
(6) (a) Greul, V. Ph.D. Dissertation, Universita¨t Go¨ttingen, 1971. (b)
Capecchi, T.; de Koning, C. B.; Michael, J. P. Tetrahedron Lett. 1998, 39,
5429. (c) Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc.,
Perkin Trans. 1 2000, 2681. (d) Tsang, K. Y.; Brimble, M. A.; Bremner, J.
B. Org. Lett. 2003, 5, 4425. (e) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R.
Org. Lett. 2006, 8, 2365.
Figure 1. Compounds of the rubromycin family.
polymerase (a reverse transcriptase of HI-virus type 1),4
purpuromycin 2 displays activity against bacteria and fungi2
(1) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Tetrahedron
Lett. 1966, 3525.
10.1021/ol061932w CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/16/2006

investigations toward the synthesis of purpuromycin,7 only
the synthesis of racemic heliquinomycinone 48 (the aglycon
of heliquinomycin 3) has so far been reported.
Scheme 3
Herein we present our investigations regarding the con-
struction of bisbenzannulated spiroketals suitable for a
modular approach to rubromycins. Our retrosynthetic analysis
(Scheme 1) envisages enones 6 to serve as precursors for
Scheme 1
Compounds 13 and 14 were then used in the Pd-catalyzed
coupling with aryl iodides 15/16 (MOM-protected) or 17/
18 (Bn-protected) employing a modified Jeffery protocol
(Scheme 3).11 The corresponding R,â-unsaturated enones
19-22 were obtained in good yields. However, a side
reaction partially oxidized the R-hydroxy group to the
corresponding diketone in varying amounts which made this
transformation less efficient. For the conversion of 13 and
16 into enone 20, the corresponding diketone 23 was isolated
in an almost equal yield of 26% (Scheme 3). During synthesis
of 21 and 22, the corresponding diketones were obtained in
7% yield and trace amounts, whereas 19 gave no side product
at all. Although we applied various conditions, we were not
able to completely suppress this side reaction.
Thus, we slightly modified our sequence by protecting the
R-hydroxy function of enone 14 prior to the Heck coupling.
Among the protecting groups examined,12 the TES group
proved to be most suitable. Subsequent coupling of protected
enone 24 with iodobenzene derivatives 17 and 18 smoothly
afforded the corresponding enones 25 and 26 in good yield
(Scheme 4) without formation of side products.
the synthesis of model spiroketals 5. These highly substituted
enones would be accessible via Heck reactions of iodinated
benzene derivatives 7 (acting as isocoumarin model com-
pounds)9 with R-hydroxy enone derivatives 8. The synthesis
of the required enones 8 should be accomplished by addition
of lithiated methoxyallene 9 to functionalized benz- or
naphthaldehyde derivatives 10 (Scheme 1) followed by acidic
hydrolysis of the alkoxyallene moiety.10
Substituted R-hydroxy enones 13 and 14 were prepared
by addition of lithiated methoxyallene to the corresponding
aryl aldehydes 11 or 12 (Scheme 2). Subsequent hydrolysis
Scheme 2
Scheme 4
of the intermediate allene adducts with acid furnished the
required enones 13 and 14 in excellent overall yields.
(7) (a) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Tetrahedron
Lett. 2006, 47, 5409. (b) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C.
Org. Lett. 2006, 8, 3243.
(8) (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4709. (b) Siu, T.; Qin, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4713.
(9) For a synthesis of an appropriate isocoumarin building block, see:
(a) Brasholz, M.; Reissig, H.-U. Synlett 2004, 2736. (b) Brasholz, M.; Luan,
X.; Reissig, H.-U. Synthesis 2005, 3571.
We then turned our attention toward the final construction
of the desired spiroketals. Hydrogenation of the precursor
4876
Org. Lett., Vol. 8, No. 21, 2006

compounds should result in both saturation of the double
bond, as well as the benzyl protecting group removal.
Subsequent acidic treatment should then induce cyclization.
For MOM-substituted precursors, the removal of the protect-
ing group should only occur under treatment with acid. As
shown in Table 1, hydrogenation followed by treatment with
With these promising model reactions in hand, we studied
the more complex enone 29 which was analogously acces-
sible by addition of lithiated methoxyallene to 3-benzyloxy-
1,4,5,6,8-pentamethoxynaphthalene-2-carbaldehyde followed
by acid treatment and protection.15 Pd-catalyzed coupling
with iodobenzene derivative 17 afforded the required spiroket-
al precursor 30 in 75% yield (Scheme 5). Hydrogenation of
Table 1. Formation of Spiroketals 27 and 28 from Enone
Precursors
Scheme 5
entry enone
Pg
R1
R2
product [%]e trans:cis
1a
2b
3c
4a
5d
6c
19
21
25
20
22
26
MOM
Bn
Bn
MOM
Bn
Bn
H
H
TES
H
H
H
H
H
OMe
OMe
27
27
27
28
28
28
51
83
76
43
54
65
59:41
62:38
100:0
100:0
100:0
100:0
TES OMe
a (1) Pd/C, H2, EtOAc, rt, 2 h; (2) cat. concn HCl, iPrOH, 50 °C, 16-
24 h. b Pd/C, H2, MeOH/CHCl3, rt, 2 days. c (1) Pd(OH)2/C, H2, C6H10,
EtOH, rt, 18-23 h; (2) cat. concn HCl, iPrOH, 50 °C, 1-3 days. d Pd(OH)2/
C, H2, C6H10, EtOH, rt, cat. concn HCl, 24 h. e Yields refer to isolated
material after column chromatography.
enone 30 and treatment with acid at 50 °C led to formation
of trans-configured spiroketals. However, not only the
expected product 31 was obtained in 23% yield but also
isopropoxy-substituted compound 32 was isolated in 42%
yield. Its formation may be explained by a SN1-type
solvolysis via a carbenium ion which is highly stabilized due
to the very electron-rich naphthalene core. This transforma-
tion has to be taken into consideration in further studies
dealing with the synthesis of heliquinomycin. However, the
naphthalene moiety of both spiro compounds 31 and 32
already fully corresponds to a protected version of the
naphthoquinone moiety present in rubromycins (Figure 1).
acid worked well in most cases, resulting in the formation
of the corresponding spiroketals in good to excellent yields.
The TES-protected compounds (Table 1, entries 3 and 6)
were desilylated under these reaction conditions.
Diastereomeric mixtures13 of spiro compound 27 were
obtained for precursors with substituent R2 ) H when
ketalization was performed at room temperature or with
insufficient exposure to higher temperatures (Table 1, entries
1 and 2). However, elevated temperatures (50 °C) and longer
reaction times exclusively led to the formation of trans-
spiroketal 27,14a probably due to thermodynamic control
(Table 1, entry 3). With substituent R2 ) OMe, only trans-
configured product 28 was obtained even at room temper-
ature (Table 1, entries 4-6).14b
In conclusion, a novel protocol for the diastereoselective
formation of functionalized bisbenzannulated spiro[4.5]-
ketals has been presented, applying the addition of lithiated
methoxyallene to suitably substituted aryl aldehydes as
well as a Heck coupling reaction as key steps. This protocol
could also be successfully employed using naphthyl-
substituted enone 30, thus giving rise to more complex
spiroketals. Our strategy not only places the 3′-hydroxy
function in the benzo- or naphthofuran moiety but also will
enable further functionalization of the pyran ring by taking
(10) (a) Clinet, J. C.; Linstrumelle, G. Tetrahedron Lett. 1978, 19, 1137.
(b) Clinet, J. C.; Linstrumelle, G. Tetrahedron Lett. 1980, 21, 3987. For
reviews, see: (c) Zimmer, R. Synthesis 1993, 165. (d) Zimmer, R.; Reissig,
H.-U. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; p 425.
(11) Jeffery, T. Tetrahedron 1996, 52, 10113.
(12) The following protecting groups were tested: TMS, TES, TIPS,
TBDMS, TBDPS, THP.
(13) The trans describes the configuration of the 3′-hydroxy group
relative to the C-O bond of the pyran ring. This configuration is also found
in natural occurring heliquinomycin.
(14) For X-ray analyses of compounds trans-27 and trans-28, see: (a)
Azap, C.; Luger, P.; Reissig, H.-U.; Wagner, A. Z. Kristallogr. NCS 2004,
219, 492. (b) Azap, C.; Luger, P.; Reissig, H.-U.; Wagner, A. Z. Kristallogr.
NCS 2004, 219, 495.
(15) So¨rgel, S.; Azap, C.; Reissig, H.-U. Eur. J. Org. Chem. 2006, 4405.
Org. Lett., Vol. 8, No. 21, 2006
4877

advantage of the enone function in spiroketal precursors 6
(see Scheme 1). Furthermore, the use of chiral alkoxyal-
lenes16 will allow for the preparation of enantiomerically
enriched or pure intermediates of type 8. Studies toward the
synthesis of heliquinomycin and other members of the
rubromycin family are currently underway and will be
reported in due course.
Acknowledgment. Support of this work by the Fonds
der Chemischen Industrie (Kekule´ fellowship for S.S.) is
gratefully acknowledged. We also thank the Schering AG
for general support.
Supporting Information Available: Detailed description
of typical experimental procedures and characterization data
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) (a) Rochet, P.; Vate`le, J.-M.; Gore´, J. Synlett 1993, 105. (b) Surivet,
J.-P.; Gore´, J.; Vate`le, J.-M. Tetrahedron 1996, 52, 14877. (c) Hausherr,
A.; Orschel, B.; Scherer, S.; Reissig, H.-U. Synthesis 2001, 1377. (d) Kaden,
S.; Brockmann, M.; Reissig, H.-U. HelV. Chim. Acta 2005, 88, 1826.
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