Photoinduced Synthesis of Benzannulated Spiroketals

Article abstract of DOI:10.1055/s-0034-1381038

A range of benzannulated spiroketals were prepared through photoinduced enone isomerization and spiroketalization as key steps. The simple protocol requires no additional reagents or catalyst, and tolerates both moisture and air.

Full text of DOI:10.1055/s-0034-1381038

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2042–2046
letter
2042
X. Chen, S. Wang
Letter
Synlett
Photoinduced Synthesis of Benzannulated Spiroketals
Xinzheng Chen*
Sasa Wang
O
household 40 W
fluorescent light bulb
MeCN, r.t.
O
Key Laboratory of Chemical Genomics, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen University Town, Shenzhen 518055, P. R. of China
xinzheng1943@126.com
OH
O
OH
24 examples
54–99% yield
Received: 24.03.2015
Accepted after revision: 17.05.2015
Published online: 25.06.2015
O
HO
O
OH
O
CO2Me
DOI: 10.1055/s-0034-1381038; Art ID: St-2015-w0202-l
MeO
O
O
Abstract A range of benzannulated spiroketals were prepared
through photoinduced enone isomerization and spiroketalization as key
steps. The simple protocol requires no additional reagents or catalyst,
and tolerates both moisture and air.
OMe
O
β-rubromycin (1)
O
Key words benzannulated spiroketal, catalyst-free, isomerization,
photochemistry, enones
HO
O
O
OH
R4
MeO
O
O
A number of spiroketal-containing natural products are
found in insects, microbes, plants, fungi, and marine organ-
isms. The chemistry of spiroketals had thus been studied
extensively due to their versatile range of biological activi-
ties.1 Less common within this structure family are benzan-
nulated spiroketals, which are present in rubromycin-relat-
ed natural products (Figure 1).2,3 These substances function
as effective antibiotics as well as human immunodeficiency
virus-1 inhibitors.4 Such bioactivities are believed to be as-
sociated with the presence of the [5,6]bisbenzannulated
spiroketal unit.5
R3
R1
R2
O
OH
γ-rubromycin (2): R1 = H, R2 = H, R3 = H, R4 = CO2Me
purpuromycin (3): R1 = H, R2 = H, R3 = OH, R4 = CO2Me
heliquinomycin (4): R1 = O-cymarose, R2 = OH, R3 = H, R4 = CO2Me
griseorhodin C (5): R1 = OH, R2 = OH, R3 = OH, R4 = Me
griseorhodin G (6): R1 = OH, R2 = OH, R3 = H, R4 = Me
Figure 1 The rubromycin family
The unprecedented structures and the impressive bio-
logical activities of rubromycins has triggered the interest
of chemists. To date, the total synthesis of the racemic agly-
cone of heliquinomycin by Danishefsky,6 the total synthesis
of (±)-γ-rubromycin by Kita,7 Pettus,8 and Reissig,9 and the
total synthesis of (±)-δ-rubromycin by Li10 have been re-
ported. Various methodologies have been developed over
the past decades.11
In a program directed towards the preparation and
study of these fascinating substances, we are interested in
utilizing benign photoisomerization protocols to facilitate
the identification of simple and robust synthetic proce-
dures. Photoisomerization of alkenes represents a well-es-
tablished event, but it is usually effected under high-power
mercury lamp and optical filters under inert atmosphere
protection.12
We set out to use structure 7 as a model substrate to ex-
plore suitable conditions. Although both transition metal13
and photocatalyst sensitized14 photoisomerizations are
known, we found that the reaction also proceeds in the
simplest manner; that is, merely irradiation with a direct
household fluorescent light bulb (40 W) under air. A signifi-
cant solvent effect was revealed from initial screening; the
results are summarized in Table 1. MeCN clearly stood out
as the optimal solvent in terms of product yield (up to 97%).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2042–2046

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X. Chen, S. Wang
Letter
Synlett
When the reaction was performed in MeCN under ni-
trogen atmosphere, the product was furnished in high yield
(97%; Table 1, entry 2); when the light was absent, the reac-
tivity was completely inhibited (entry 3). The replacement
of nitrogen with air atmosphere had virtually no influence
on the reaction (93% yield; entry 4). The use of aqueous me-
dia was also feasible (entry 5). Similar experiments in other
solvents, including ethyl acetate, DMF, DMSO, dichloro-
methane, chloroform, diethyl ether, or THF, all led to prod-
uct formation, albeit in varying isolated yields (19–91%; en-
tries 6–12). Interestingly, the use of Ru(bpy)3Cl2 as a photo-
catalyst (entry 1) did not enhance the performance of the
reaction.
The scope of this spiroketalization reaction was investi-
gated with a range of substrates (Scheme 1). A variety of
substrates readily underwent spiroketalization under the
standard reaction conditions. With halogen groups in the
para-position of the phenyl ring, the corresponding mono-
benzannulated spiroketal 8a–11a was obtained in moder-
ate to high yield. Substrates with a more electron-with-
drawing halogen were found to give the product in lower
yield, which might suggest that the acidity of the phenolic
hydroxyl group had a marked influence on ketalization
(strong acidity was found to adversely affect the generation
of ketals). The m-methoxy-substituted substrate gave 12a
in 88% yield, and alkyl-substituted substrates gave the cor-
responding monobenzannulated spiroketal 13a–17a in
good yield. The benzo substrate gave a moderate yield,
whereas phenyl-substituted substrates 18a and 19a gave
high yield. Monobenzannulated [6,6]spiroketal 20a could
be obtained in 90% yield under the standard reaction condi-
tions. Bisbenzannulated [6,6]spiroketal 21b could be
achieved in virtually quantitative yield. The construction of
the benzannulated spiroketal core of the rubromycin family
(22b) was also realized. A variety of bisbenzannulated
[6,6]spiroketal derivatives 23c–31c could be prepared by
using this method. Fluoro-substituted substrate gave the
lowest yield (24c). Other halogenated Bisbenzannulated
[6,6]spiroketals could be prepared in moderate to high yield
(25c–27c). No product was found when a strongly electron-
withdrawing substituent (NO2) was present (28c). This
again demonstrated that the acidity of phenolic hydroxyl
group affects the generation of ketals. Alkyl-substituted
substrates gave bisbenzannulated [6,6]spiroketals 29c–31c
in good to high yield.
We then sought to elucidate the reaction mechanism. To
this end, the UV/Vis absorption spectra of 7 and 7a were
determined (Figure 2). We found that neither reactant 7 nor
product 7a absorbed at the wavelength of visible light. No
spiroketal products were detected under blue LED irradia-
tion (Table 2, entry 1). In contrast, 7a was obtained in 76%
yield by using a 365 nm black light (entry 2). These control
Table 1 Optimization of the Reaction Conditions[a]
O
fluorescent light bulba
solvent
OH
O
O
OH
7
7a
Entry
Time (d)
Solvent
Catalyst
Conditions
Yield (%)b
c
1
2
1
1
1
1
1
1
1
1
1
1
1
1
MeCN
MeCN
MeCN
MeCN
Ru(bpy)3Cl2
N2
N2
N2
air
air
air
air
air
air
air
air
air
76
97
0
–
–
–
–
–
–
–
–
–
–
–
3d
4
93
79
91
87
68
19
21
31
81
5
MeCN–H2Oe
EtOAc
DMSO
DMF
6
7
8
9
CH2Cl2
CHCl3
Et2O
10
11
12
THF
a A household 40 W fluorescent light bulb was used as light source.
b Isolated yield.
c 1 mol% catalyst was used.
d The reaction mixture was stirred in the dark.
e MeCN–H2O (20:1 v/v).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2042–2046

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X. Chen, S. Wang
Letter
Synlett
Table 2 Effect of Irradiation Wavelength on the Reaction
light source
7
7a
MeCN, 1 d
Light source
Entry
Yield (%)a
1
2
blue LED
0
365 nm black light bulb
76
a Isolated yield.
experiments revealed that the near-UV emission from a
fluorescent bulb15 was required to convert 7 into 7a, and
visible light does not induce the spiroketalization.
We proposed a mechanism for this reaction based on
the experimental results discussed above (Scheme 2). The
near-UV radiation emissions from a fluorescent lamp in-
duced carbon–carbon double bond isomerization of reac-
Figure 2 UV/Vis absorption spectra of 7 and 7a
O
OH
fluorescent light bulb
MeCN, r.t.
R
O
O
OH
O
F
Cl
Br
I
O
O
O
O
O
MeO
O
O
O
O
O
O
8a 3 d, 70%
9a 1 d, 74%
10a 2 d, 95%
11a 3 d, 94%
12a 1 d, 88%
13a 1 d, 78%
Et
Cy
t-Bu
O
O
O
O
O
O
O
O
O
O
Ph
O
O
14a 1 d, 92%
15a 1 d, 88%
16a 2 d, 97%
17a 2 d, 97%
18a 1 d, 68%
19a 2 d, 99%
O
O
O
O
O
O
O
O
20a 1 d, 90%
21b 2 d, 100%
22b 2 d, 80%
23c 2 d, 99%
Cl
F
O
O
O
O
Cl
Br
I
I
F
O
O
O
O
Br
25c 2 d, 89%
24c 2 d, 54%
26c 2 d, 81%
27c 2 d, 96%
t-Bu
O
O
t-Bu
Et
Cy
NO2
O
O
O
O
O
O
Et
Cy
O2N
28c 2 d, 0%
Scheme 1 Synthesis of benzannulated spiroketals
29c 2 d, 85%
30c 2 d, 99%
31c 2 d, 85%
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2042–2046

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X. Chen, S. Wang
Letter
Synlett
tant 7 to form intermediate cis-7; intramolecular ketaliza-
tion of cis-7 then leads to product 7a.
(11) For selected reviews, see: (a) Brasholz, M.; Sörgel, S.; Azap, C.;
Reissig, H.-U. Eur. J. Org. Chem. 2007, 3801. (b) Sperry, J.;
Wilson, Z. E.; Rathwell, D. C. K.; Brimble, M. A. Nat. Prod. Rep.
2010, 27, 1117. (c) Mcleod, M. C.; Rathwell, D. C. K.; Wilson, Z.
E.; Yuen, T.-Y.; Brimble, M. A. Pure Appl. Chem. 2012, 84, 1379.
(d) Green, J. C.; Burnett, G. L. IV.; Pettus, T. R. R. Pure Appl. Chem.
2012, 84, 1621. For other reports, see: (e) Tsang, K. Y.; Brimble,
M. A. Tetrahedron 2007, 63, 6015. (f) Wu, K.-L.; Wilkinson, S.;
Reich, N. O.; Pettus, T. R. R. Org. Lett. 2007, 9, 5537. (g) Zhang, Y.;
Xue, J.; Xin, Z.; Xie, Z.; Li, Y. Synlett 2008, 940. (h) Zhou, G.; Zhu,
J.; Xie, Z.; Li, Y. Org. Lett. 2008, 10, 721. (i) Marsini, M. A.; Huang,
Y.; Lindsey, C. C.; Wu, K.-L.; Pettus, T. R. R. Org. Lett. 2008, 10,
1477. (j) Venkatesh, C.; Reissig, H.-U. Synthesis 2008, 3605.
(k) Aitken, H. R. M.; Furkert, D. P.; Hubert, J. G.; Wood, J. M.;
Brimble, M. A. Org. Biomol. Chem. 2013, 11, 5147.
O
double–bond
isomerization
intramolecular
ketalization
OH
7
7a
UV from
fluorescent lamp
HO
cis-7
Scheme 2 Proposed mechanism
In summary, we have developed a simple and practical
method for the construction of benzannulated [5,6]spiroke-
tals and [6,6]spiroketals.16 The protocol employs neither
catalyst nor photosensitizer or other additives, and is readi-
ly implemented in a synthetic setting. It is hoped that the
operational simplicity of this method will find some uses in
the synthesis of spiroketal-bearing bioactive substances.
(12) (a) Waldeck, D. H. Chem. Rev. 1991, 91, 415. (b) Arai, T.;
Tokumaru, K. Chem. Rev. 1993, 93, 23.
(13) Prier, C. K.; Rankic, D. A.; MacMillon, D. W. C. Chem. Rev. 2013,
113, 5322.
(14) Singh, K.; Staig, S. J.; Weaver, J. D. J. Am. Chem. Soc. 2014, 136,
5275.
(15) For the UV radiation emissions from fluorescent lamps, see:
(a) Khazova, M.; O’Hagan, J. B. Radiat. Prot. Dosimetry 2008, 131,
521. (b) Mironava, T.; Hadjiargyrou, M.; Simon, M.; Rafailovich,
M. H. Photochem. Photobiol. 2012, 88, 1497. (c) Arceo, E.;
Montroni, E.; Melchiorre, P. Angew. Chem. Int. Ed. 2014, 53,
12064.
Acknowledgment
We thank the Shenzhen Bureau of Science and Technology for finan-
cial support.
(16) Photoinduced Synthesis of Benzannulated Spiroketals;
General Procedure: To a 5 mL flask was added substrate (0.1
mmol) and MeCN (2 mL). The mixture was stirred under irradi-
ation from a household 40 W fluorescent light bulb at ambient
temperature. The progress of the reaction was monitored by
TLC. Upon consumption of starting materials, the mixture was
concentrated under reduced pressure and the residue was puri-
fied by silica gel column chromatography to afford the spiro
product.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1381038.
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References and Notes
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(2) Brockmann, H.; Renneberg, K. H. Naturwissenschaften 1953, 40,
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(3) Brockmann, H.; Lenk, W.; Schwantj, G.; Zeeck, A. Chem. Ber.
1969, 102, 126.
(4) Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.; Yokoyama, A.;
Goto, Y.; Mizushina, Y.; Sakaguchi, K.; Hayashi, H. Biochemistry
2000, 39, 5995.
4′,5′-Dihydro-3′H-spiro[chromene-2,2′-furan] (7a): Yield:
1
14.8 mg (93%); colorless liquid. H NMR (400 MHz, CDCl3): δ =
7.18 (td, J = 8.0, 1.6 Hz, 1 H), 7.13 (dd, J = 7.2, 1.2 Hz, 1 H), 6.95–
6.90 (m, 2 H), 6.71 (d, J = 9.6 Hz, 1 H), 5.75 (d, J = 9.6 Hz, 1 H),
4.17–4.12 (m, 1 H), 4.00–3.94 (m, 1 H), 2.42–2.32 (m, 2 H),
2.09–2.00 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 151.7, 129.2,
126.9, 126.8, 122.5, 121.2, 120.3, 116.4, 105.3, 68.2, 39.1, 24.5.
HRMS: m/z [M + H]+ calcd for C12H13O2: 189.0916; found:
189.0909.
(5) (a) Li, A. Y.; Piel, J. Chem. Biol. 2002, 9, 1017. (b) Chino, M.;
Nishikawa, K.; Umekita, M.; Hayashi, C.; Yamazaki, T.; Tsuchida,
T.; Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1996, 49, 752.
(6) (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.
(7) Akai, S.; Kakiguchi, K.; Nakamura, Y.; Kuriwaki, I.; Dohi, T.;
Harada, S.; Kubo, O.; Morita, N.; Kita, Y. Angew. Chem. Int. Ed.
2007, 46, 7458.
3′,4′,5′,6′-Tetrahydrospiro[chromene-2,2′-pyran] (20a): Yield:
10 mg (90%); colorless liquid. 1H NMR (400 MHz, CDCl3): δ =
7.21 (td, J = 8.4, 2.0 Hz, 1 H), 7.14 (dd, J = 7.2, 1.2 Hz, 1 H), 7.01
(d, J = 8.0 Hz, 1 H), 6.95 (td, J = 7.6, 1.2 Hz, 1 H), 6.64 (d,
J = 9.6 Hz, 1 H), 5.73 (d, J = 9.6 Hz, 1 H), 4.03–3.965 (m, 1 H),
3.64–3.60 (m, 1 H), 2.17–2.11 (m, 2 H), 1.80–1.63 (m, 4 H). 13C
NMR (100 MHz, CDCl3): δ = 151.4, 129.1, 127.0, 126.0, 125.4,
121.4, 121.2, 116.5, 95.4, 61.7, 35.0, 24.7, 18.5. HRMS: m/z [M +
H]+ calcd for C13H15O2: 203.1072; found: 203.1067.
(8) Wu, K.-L.; Mercado, E. V.; Pettus, T. R. R. J. Am. Chem. Soc. 2011,
133, 6114.
(9) Wilsdorf, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2014, 53, 4332.
(10) Wang, W.; Xue, J.; Tian, T.; Zhang, J.; Wei, L.; Shao, J.; Xie, Z.; Li,
Y. Org. Lett. 2013, 15, 2402.
3H-Spiro[benzofuran-2,2′-chromene] (22b): Yield: 12.8 mg
(80%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.27–7.17 (m,
4 H), 7.00 (td, J = 7.6, 1.2 Hz, 1 H), 6.98–6.91 (m, 2 H), 6.87 (d,
J = 9.6 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 5.97 (d, J = 9.6 Hz, 1 H),
3.58 (d, J = 16.8 Hz, 1 H), 3.48 (d, J = 16.8 Hz, 1 H). 13C NMR (100
MHz, CDCl3): δ = 157.1, 150.9, 129.8, 128.4, 127.5, 127.0, 125.3,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2042–2046

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X. Chen, S. Wang
Letter
Synlett
124.4, 122.0, 121.3, 119.7, 116.7, 109.8, 107.7, 43.7. HRMS: m/z
[M + H]+ calcd for C16H13O2: 237.0916; found: 237.0909.
6,6′-Diethyl-2,2′-spirobi[chromene] (29c): Yield: 20.7 mg
(85%); colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 7.04–7.02
(m, 4 H), 6.81 (d, J = 9.2 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H), 5.96 (d,
J = 9.6 Hz, 2 H), 2.61 (q, J = 7.6 Hz, 4 H), 1.23 (t, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 148.8, 137.5, 129.3, 126.6, 126.1,
121.7, 119.4, 116.5, 95.2, 28.1, 15.8. HRMS: m/z [M + H]+ calcd
for C21H21O2: 305.1542; found: 305.1540.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2042–2046