Synthesis of 6,6-bisbenzannulated spiroketals related to the rubromycins using a double intramolecular hetero-Michael addition (DIHMA)

Article abstract of DOI:10.1016/j.tetlet.2009.02.030

The synthesis of a series of 6,6-bisbenzannulated spiroketals using a novel microwave-assisted DIHMA approach is reported. Coupling of an aryl acetylene and an aryl aldehyde via acetylide anion addition resulted in the formation of an alkynol which was followed by oxidation to the desired ynone. Spirocyclization using the DIHMA protocol afforded the desired bisbenzannulated spiroketal in good yield.

Full text of DOI:10.1016/j.tetlet.2009.02.030

Tetrahedron Letters 50 (2009) 3245–3248
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Synthesis of 6,6-bisbenzannulated spiroketals related to the rubromycins
using a double intramolecular hetero-Michael addition (DIHMA)
*
Peter J. Choi, Dominea C. K. Rathwell, Margaret A. Brimble
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of 6,6-bisbenzannulated spiroketals using a novel microwave-assisted DIHMA
approach is reported. Coupling of an aryl acetylene and an aryl aldehyde via acetylide anion addition
resulted in the formation of an alkynol which was followed by oxidation to the desired ynone. Spirocyc-
lization using the DIHMA protocol afforded the desired bisbenzannulated spiroketal in good yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 December 2008
Revised 23 January 2009
Accepted 3 February 2009
Available online 8 February 2009
Spiroketals are important subunits present in a broad range of
bioactive natural products and are considered a ‘privileged scaf-
fold’ for drug discovery programs.1 The rubromycin family of nat-
ural products (Fig. 1) are benzannulated spiroketals that have
reverse transcriptase of human immunodeficiency virus-1.3 Purp-
uromycin 44 is a potential topical agent for vaginal infections,5
whereas heliquinomycin 76 with a rare
L-cymarose sugar attached
to the 30-hydroxy functionality is a selective inhibitor of human
DNA helicase. The rubromycin family of antibiotics have also been
proposed to act as bioreductive alkylating agents.7 The unique aro-
matic spiroketal core present in this class of compounds has been
attracted considerable attention.
cin
exhibit potent inhibition of human telomerase2 (IC50
2.64 0.09
c-Rubromycin 1 and b-rubromy-
2
l
M and 3.06 0.85
l
M) and are active against the
O
O
HO
O
O
HO
O
OH
O
O
OH
OH
CO 2Me
CO2Me
CO2Me
CO2Me
MeO
MeO
MeO
O
(S)
O
O
O
(S)
OH
O
O
O
O
β-Rubromycin 2
γ-Rubromycin 1
O
O
HO
O
HO
OH
Me O
MeO
O
O O
O
OH
O
O
OH
OH
O
O
OH
OH
Purpuromycin 4
δ-Rubromycin 3
O
O
HO
O
HO
O
Me
CO2Me
MeO
O
O
O
O
O
(R)
R
OH
OH
OH
O
OH
O
OH
OMe
Griseorhodin C 5: R = OH
Griseorhodin G 6: R = H
O
HO
Heliquinomycin 7
Figure 1. The rubromycin family of antibiotics containing aromatic spiroketal units.
* Corresponding author. Tel.: +64 9 373 7422.
E-mail address: m.brimble@auckland.ac.nz (M.A. Brimble).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.030

3246
P. J. Choi et al. / Tetrahedron Letters 50 (2009) 3245–3248
established as the pharmacophore responsible for the observed
biological activity.2 To date, only a single racemic total syntheses
OH
O
OH
ii
i
of the aglycon of heliquinomycin 78 and
c
-rubromycin 19 have
been reported. Despite the recent advances in the synthesis of frag-
ments of these natural products,10 their total synthesis remains a
considerable challenge.
R1
R1
R1
12 R1 = H
13 R1 = OMe
14 R1 = H
15 R1 = OMe
16 R1 = H
17 R1 = OMe
Our interest in the synthesis of spiroketal natural products,11 in
particular the spiroketal core of the rubromycins,12 has prompted
the synthesis of aryl-fused spiroketals. Although several syntheses
of 5,6-bisbenzannulated13 and 6,6-bisbenzannulated14 spiroketals
related to the rubromycins have been reported, syntheses of bis-
benzannulated spiroketals are less common than their aliphatic
counterparts. The synthesis of aliphatic spiroketals using a double
intramolecular hetero-Michael addition (DIHMA) strategy, in
which double conjugate addition of a diol to an ynone system pro-
vides an effective method to generate 5,6-spiroketals, has been
explored by various research groups.15 To our knowledge, the
use of a DIHMA approach for the synthesis of a bisbenzannulated
spiroketal core has not previously been reported. Therefore, we
OEOM
R1
OEOM
iii
iv
OH
R1
20 R1 = H
18 R1 = H
21 R1 = OMe
19 R1 = OMe
OEOM
OEOM
v
vi
O
herein propose that bisbenzannulated spiroketal
8 could be
assembled via DIHMA of dihydroxy ynone 9 (Fig. 2). In turn,
access to the spiroketal precursor 9 is readily achieved by addition
of the acetylide anion generated from acetylene 11 to aldehyde
10. The efficient synthesis of several bisbenzannulated 6,6-spiro-
ketals using a novel microwave-assisted DIHMA protocol is then
realized.
Acetylenes 24 and 25 were prepared from commercially avail-
able phenols 12 and 13 via Claisen rearrangement of the derived
allyl ethers 14 and 15 (Scheme 1). Protection of the allylphenols
as ethoxymethyl (EOM) ethers followed by hydroboration with
borane-dimethylsulfide complex afforded the primary alcohols
20 and 21. Subsequent oxidation using 2-iodoxybenzoic acid
(IBX) produced the desired aldehydes 22 and 23 that were readily
converted to their respective acetylenes using the Ohira–Bestmann
reagent.16
R1
R1
22 R1 = H
23 R1 = OMe
24 R1 = H
25 R1 = OMe
Scheme 1. Reagents, conditions, and yields: (i) allyl bromide, K2CO3, acetone,
reflux, 14, 97%; 15, 92%; (ii) neat, microwave, 210 °C, 300 W, 16, 92%; 17, 90%; (iii)
ethoxymethyl chloride, iPr2NEt, CH2Cl2, 0 °C, 18, 85%; 19, 86%; (iv) BH3–SMe2,
NaOH, H2O2, 20, 81%; 21, 80%; (v) IBX, DMSO, 22, 84%; 23, 78%; (vi) diethyl 1-diazo-
2-oxopropylphosphonate, K2CO3, MeOH, 24, 94%; 25, 90%.
R2
R3
R2
i
R3
TBDMSO
Aldehydes 29–31 were easily prepared by tert-butyldimethylsi-
lyl chloride protection of the readily available salicylaldehydes
26–28 (Scheme 2).
OH
O
O
26 R2 = H; R3 = H
29 R2 = H; R3 = H
27 R2 = OMe; R3 = H
28 R2 = H; R3 = OMe
30 R2 = OMe; R3 = H
31 R2 = H; R3 = OMe
With acetylenes 24–25 and aldehydes 29–31 in hand, cou-
pling of the two subunits was undertaken (Scheme 3). Generation
of the acetylide anions of 24-25 using n-BuLi and reaction with
aldehydes 29–31 gave the desired alkynols 32–36. Subsequent
oxidation of the secondary alcohols 32–36 to the desired ynones
37–41 was achieved in good yields using IBX. Addition of dieth-
ylamine to a dichloromethane solution of ynones 37–41 led
to the deprotection of the TBDMS group with concomitant forma-
tion of the isolable enamino-ketone intermediate after 30 min.
Intramolecular 6-endo-dig cyclization of this intermediate can
lead to the formation of the desired benzopyrone intermediate
via an addition–elimination sequence.17 The crude enamino-ke-
tones were, therefore, heated under reflux for 16 h, resulting
Scheme 2. Reagents, conditions, and yields: (i) TBDMSCl, imidazole, DMAP, CH2Cl2,
29, 85%; 30, 88%; 31, 90%.
in formation of the desired benzopyrones 42–46 in excellent
yields.
Benzopyrones 44, 45, and 46 underwent deprotection of the phe-
nolic EOM ether with carbon tetrabromide in isopropanol with con-
comitant spirocyclization affording spiroketals 51, 52 and 53,
respectively (Scheme 3). However, in the case of benzopyrones 42
and 43 final spirocyclization to the desired 6,6-spiroketal ring sys-
tem proved challenging, only furnishing the deprotected phenols
47 and 48 upon treatment with carbon tetrabromide. Attempts to
effect the efficient conversion of deprotected phenol 47 to spiroketal
49 were conducted using various reaction conditions (Table 1). After
intense experimentation, cyclization of 47–49 using microwave
irradiation in the presence of potassium carbonate proved to be
the most reliable method.18 This procedure was, therefore, applied
to benzopyrone 48 affording the desired bisbenzannulated 6,6-spi-
roketal 50.
In conclusion, an efficient method for the construction of bis-
benzannulated 6,6-spiroketals related to the rubromycin family
of antibiotics has been developed. The methodology involves the
union of an aryl acetylene with an aryl aldehyde followed by oxi-
dation to an ynone intermediate in preparation for DIHMA to form
a bisbenzannulated spiroketal. Application of this DIHMA protocol
DIHMA
P2O
Cyclisation
R
OP1
R
O
O
R
R
O
acetylide addition
9
O
8
OP1
H
R
+
P1 = TBDMS
OP2
11
R
P
2 = EOM (CH2OCH2CH3)
O
10
Figure 2. Retrosynthesis of 6,6-bisbenzannulated spiroketals.

P. J. Choi et al. / Tetrahedron Letters 50 (2009) 3245–3248
3247
R2
R3
R2
R3
R2
R3
EOMO
EOMO
OTBDMS
EOMO
OTBDMS
i
ii
OTBDMS
R1
O
R1
HO
R1
O
29 R2 = H; R3 = H
24 R1 = H
32 R1 = H; R2 = H; R3 = H
37 R1 = H; R2 = H; R3 = H
30 R2 = OMe; R3 = H
31 R2 = H; R3 = OMe
33 R1 = H; R2 = OMe; R3 = H
34 R1 = OMe; R2 = OMe; R3 = H
35 R1 = OMe; R2 = H; R3 = H
36 R1 = H; R2 = H; R3 = OMe
38 R1 = H; R2 = OMe; R3 = H
39 R1 = OMe; R2 = OMe; R3 = H
40 R1 = OMe; R2 = H; R3 = H
41 R1 = H; R2 = H; R3 = OMe
25 R1 = OMe
EOMO
R2
R3
EOMO
R2
R3
HO
R2
R3
OH
iii
iv
O
O
R1
R1
N
R1
O
O
O
42 R1 = H; R2 = H; R3 = H
47 R1 = H; R2 = H; R3 = H
48 R1 = H; R2 = OMe; R3 = H
43 R1 = H; R2 = OMe; R3 = H
44 R1 = OMe; R2 = OMe; R3 = H
45 R1 = OMe; R2 = H; R3 = H
46 R1 = H; R2 = H; R3 = OMe
vi
v
49 R1 = H; R2 = H; R3 = H
R2
R3
50 R1 = H; R2 = OMe; R3 = H
51 R1 = OMe; R2 = OMe; R3 = H
52 R1 = OMe; R2 = H; R3 = H
53 R1 = H; R2 = H; R3 = OMe
O
O
R1
O
Scheme 3. Reagents, conditions, and yields: (i) n-BuLi, THF, ꢀ78 °C to rt, 32, 71%; 33, 75%; 34, 78%; 35, 82%; 36, 81%; (ii) IBX, DMSO, 37, 87%; 38, 88%; 39, 78%; 40, 82%; 41,
84%; (iii) excess Et2NH, CH2Cl2, reflux, 42, 97%; 43, 92%; 44, 85%; 45, 92%; 46, 92%; (iv) CBr4, iPrOH, 47, 97%; 48, 95%; (v) CBr4, iPrOH, 51, 54%; 52, 36% ; 53, 64%; (vi) K2CO3,
microwave, 300 W, 49, 62%; 50, 60%.
Table 1
Spirocyclization of benzopyrone 47 to spiroketal 49
HO
O
O O
O
47
Solvent
O
49
Entry
Reagent
Conditions
Yield (%)
1
2
3
4
5
6
7
8
9
NaH
LDA
DMF
THF
THF
CCl4
CCl4
CCl4
CCl4
None
CH2Cl2
CH2Cl2
0 °C, 3 h then 65 °C, 3 h
ꢀ78 °C, 3 h
No reaction
No reaction
No reaction
15
<10
<10
<10
62
No reaction
No reaction
KHMDS
Neutral Al2O3
Neutral Al2O3
Silica gel
DOWEXÒ
K2CO3
ꢀ78 °C, 3 h
rt, 16 h
65 °C, 16 h
rt, 4 h
rt, 4 h
120 °C, 0.5 h, microwave (300 W)
rt, 4 h then 45 °C, 10 h
rt, 4 h then 45 °C, 10 h
CSA
pTsOH
10
5. Trani, A.; Dallanoce, C.; Pranzone, G.; Ripamonti, F.; Goldstein, B. P.; Ciabatti, R.
J. Med. Chem. 1997, 40, 967–971.
provides an efficient method for the facile construction of a focused
library of bisbenzannulated spiroketals for biological evaluation.
6. (a) Chino, M.; Nishikawa, K.; Umekia, M.; Hayashi, C.; Yamazaki, T.; Tsuchida,
T.; Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1996, 49, 752–757; (b) Chino,
M.; Nishikawa, K.; Tsuchida, T.; Sawa, R.; Nakamura, H.; Nakamura, K. T.;
Muraoka, Y.; Ikeda, D.; Naganawa, H.; Sawa, T.; Takeuchi, T. J. Antibiot. 1997, 50,
143–177.
References and notes
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Mizushina, Y.; Sakaguchi, K.; Hayashi, H. Biochemistry 2000, 39, 5995–6002.
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W. A.; Emini, E. A. Mol. Pharmacol. 1990, 38, 20–25.
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1974, 30, 2747–2754.
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Morita, N.; Kita, Y. Angew. Chem., Int. Ed. 2007, 46, 7458–7461. Angew. Chem.
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P. J. Choi et al. / Tetrahedron Letters 50 (2009) 3245–3248
10. For a review of the synthesis of the rubromycins see: Brasholz, M.; Sorgel, S.;
Azap, C.; Reissig, H. U. Eur. J. Org. Chem. 2007, 3801–3814.
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M. A.; Halim, R.; Merten, J. Org. Biomol. Chem. 2006, 4, 1387–1399; (c) Brimble,
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Bhat, A.; Whetstone, J.; Brueggemeier, R. Tetrahedron Lett. 1999, 40, 2469–
2472.
18. General procedure—Spirocyclization: A solution of benzopyrone (0.067 mmol)
in dichloromethane (10 mL) was added to oven-dried ground potassium
carbonate (14.47 mmol). The solvent was evaporated in vacuo and the
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5583–5896; (c) Brimble, M. A.; Liu, Y.; Trzoss, M. Synthesis 2007, 9, 1392–1402.
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reaction mixture was placed in
a CEM microwave reactor at 300 W for
30 min at 120 °C. The reaction mixture was allowed to cool to room
temperature, then water (10 mL) was added and the mixture extracted with
ethyl acetate (3 ꢁ 10 mL). The combined organic extracts were washed with
brine (8 mL), dried over magnesium sulfate, and concentrated in vacuo. The
resultant residue was purified by flash column chromatography using
hexane-ethyl acetate (9:1) as eluent to give the desired spiroketal. 2,20-
Spirobi[chroman]-4-one 49: Pale yellow oil (11 mg, 0.041 mmol, 62%); IR
(film) (m
max/cmꢀ1) 2923, 1684, 1459; 1H NMR (400 MHz, CDCl3): d 2.03 (1H,
ddd, Jgem 13.6, J3 ax,
13.3, J3 ax,4 eq 6.1, 30 -Hax), 2.43 (1H, ddd, Jgem 13.6, J3 eq,
0
0
0
0
40 ax
6.1, J3 eq,4 eq 1.9, 30 -Heq), 2.79 (1H, ddd, Jgem 16.4, J4 eq,
6.1, J4 eq,3 eq 1.9,
13.3, J4 ax,3 eq 6.1,
0
0
0
0
0
40 ax
30 ax
40-Heq), 3.06 (2H, s, 3-CH2), 3.29 (1H, ddd, Jgem 16.4, J4 ax,
0
0
0
30 ax
40 -Hax), 6.64-7.95 (8H, m, Ar–H); 13C NMR (100 MHz, CDCl3): d 20.4 (40 -CH2),
30.4 (30 -CH2), 47.6 (3-CH2), 100.8 (q, C-2), 117.1, 118.2, 121.5, 121.9, 126.3,
127.4, 129.0, 136.0 (Ar–CH), 121.1 (q, C4a), 121.3 (q, C4a0), 151.3 (q, C8a0),
157.6 (q, C8a), 190.5 (q, C4). HRMS (CI) m/z calcd for C17H14O3 (M+)
266.0946, found 266.0949.