Total synthesis of (±)-spirobenzofuran

Article abstract of DOI:10.1055/s-0032-1318310

Spirobenzofuran, embracing a cyclopentane-spirofused benzofuran carbon framework, was efficiently assembled via semipinacol rearrangement with Me ₃Al from 2,5-dimethoxy-4-methylacetophenone.

Full text of DOI:10.1055/s-0032-1318310

LETTER
▌615
letter
Total Synthesis of (±)-Spirobenzofuran
Total Synthesis of (±)-Spirobenzofuran
Hang Su,a Ting Zhou,a Bo Liu*a,b
a
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610 064,
P. R. of China
Fax +86(28)85413712; E-mail: chembliu@scu.edu.cn
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road,
Shanghai 200 032, P. R. of China
Received: 12.01.2013; Accepted after revision: 04.02.2013
ported the total synthesis of 3a and 4 in 14 and 13 steps,
respectively, from the known acetophenone 10,8 in which
an intramolecular anionic cyclization strategy was devel-
oped to generate the vicinally substituted cyclopentanes
(Scheme 2).6d In 2005, Srikrishna and coworkers accom-
plished the first racemic synthesis of spirobenzofuran 1 in
14 steps from 10, featuring the key Ireland–Claisen rear-
rangement and ring-closing metathesis (RCM) reaction
(Scheme 3).7 Later, the Srikrishna group also accom-
plished the racemic synthesis of 2a, 3a, and 4 following
the same synthetic strategy.6a Involved in the total synthe-
sis of natural terpenoids,9 we are also allured by the struc-
ture and bioactivity of this family of molecules, especially
spirobenzofuran 1. Herein, we would like to present our
synthetic efforts on spirobenzofuran 1.
Abstract: Spirobenzofuran, embracing a cyclopentane-spirofused
benzofuran carbon framework, was efficiently assembled via semi-
pinacol rearrangement with Me3Al from 2,5-dimethoxy-4-methyl-
acetophenone.
Key words: spirobenzofuran, semipinacol rearrangement, trimeth-
ylaluminium, total synthesis, sesquiterpenoid
An interesting sesquiterpenoid, spirobenzofuran, was iso-
lated from the fungi Acremonium sp. HKI 0230 by Gräfe
and co-workers. It displayed moderate antimicrobial ac-
tivity against Gram-positive bacteria such as Bacilus sub-
tilis ATCC 6623.1 Structurally, spirobenzofurans were
related to lagopodins 2a–c,2 cuparene-1,4-quinone 3a,3
helicobasidins 3b,c,5 and cuparene-1,4-diol 4 (Figure 1).4
These natural products are embedded with a cyclopentane
ring containing two contiguous quaternary centers, and
thus have become interesting synthetic targets since their
isolation and identification.6,7
The retrosynthetic analysis was depicted in Scheme 1.
The aldehyde 5, a key precursor towards our target mole-
cule, could be obtained from compound 6 employing cru-
cial semipinacol rearrangement. Compound 6 should be
available from epoxidation of compound 7, which could
be produced from compound 8 through ketalization and
simultaneous isomerization of the double bond. Com-
pound 8 could be achieved from the acetophenone 9
through the combination of 1,4-addition and Robinson an-
nulation.
O
O
R1
O
OH
HO
O
O
R2
2a R1 = R2 = H
1
O
O
O
2b R1 = OH, R2 = H
2c R1 = R2 = OH
O
O
O
O
O
O
OH
O
R1
OH
O
O
HO
O
O
R2
OH
6
1
5
3a R1 = R2 = H
3b R1 = OH, R2 = H
3c R1 = R2 = OH
4
O
O
O
O
O
O
Figure 1
O
O
O
Among the completed total synthesis, several examples
are impressing. In 2003, Mukherjee and co-workers re-
O
9
8
7
SYNLETT 2013, 24, 0615–0618
Advanced online publication: 20.02.2013
DOI: 10.1055/s-0032-1318310; Art ID: ST-2013-W0039-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 1 Retrosynthetic analysis of spirobenzofuran 1

616
H. Su et al.
LETTER
Mukherjee's approach
Br
COOMe
OMe
OMe
O
OMe
7 steps
LDA, THF, HMPA, –70 °C
MeOOC
LDA, HMPA, THF, 0 °C
MeI, 0 °C
MeO
MeO
MeO
OH
O
4 steps
oxidation
O
OH
3a
4
Scheme 2
Initially, compound 9 was first converted into the corre- might lead to semipinacol rearrangement, demethylation
sponding TBS enol ether, using Et3N and TBSOTf in di- and concomitant acetalation in one pot, resulting in the fi-
chloromethane. Without quenching the reaction, the nal natural product directly. However, to our disappoint-
resultant enol ether was mixed with mesityl oxide in di- ment, most of the epoxide 614 was converted into the
chloromethane at –78 °C to give 10 in 58% yield.10 It is enone 11, although trace of rearrangement product 12 was
notable that all trials to the direct Michael addition of detected. Accordingly, the semipinacol rearrangement
compound 9 to mesityl oxide failed, which were catalyzed was systematically investigated under various conditions.
by different bases, such as KOt-Bu, KHMDS, NaHMDS, In anhydrous dichloromethane, treating 6 with a variety of
and LDA. The steric hindrance of mesityl oxide might ac- Lewis acids, such as BF3·OEt2, SnCl4, AlCl3, FeCl3,
count for the low reactivity under basic environment. TBSOTf, TMSOTf, LiClO4, ZnCl2, LiI, ZnBr2, PdCl2,
Then intramolecular aldol condensation afforded 8 etc.,15 led to decomposition of the substrate 6. Moreover,
smoothly in 95% yield, by treating 10 with PTSA at 100 °C.11 the reaction with different protonic acids, that is, PTSA,
Subsequently, acid-catalyzed dioxolane formation, ac- CSA, TFA, and oxalic acid,16 afforded no desired rear-
companied by isomerization of the double bond, gave rise rangement product either. To minimize the formation of
to compound 7 in 50% yield (or 80% yield based on the byproduct 11, the reaction conditions keeping the ketal in
recovery of the starting material 8).12 In the presence of 6 stable are obviously necessary. Therefore, the reactions
MCPBA, compound 7 was transformed to the epoxy 6 in with various acids in the presence of orthoester were at-
66% yield.13
tempted,17 and the desired aldehyde 5 was formed but still
in an unsatisfactory yield. Fortunately, when we treated 6
with Me3Al, a very mild Lewis acid, compound 518 was
formed in 88% yield.19 To the best of our knowledge, such
Then, to achieve the skeleton of spirobenzofuran, we
turned our attention to the key semipinacol rearrange-
ment. We envisioned that treating epoxide 6 with BBr3
Srikrishna's approach
O
O
MeO
O
MeO
(i) LDA, THF;
TMSCl, Et3N, –70 °C, 30 min;
r.t., 6 h; reflux, 3 h
4 steps
MeO
COOMe
(ii) dil. HCl, 40 min
(iii) CH2N2, Et2O, 0 °C, 30 min
OMe
OMe
OMe
O
Cl2Ru(PCy3)2=CHPh (5 mol%),
CH2Cl2, r.t., 5 h
MeO
HO
8 steps
COOMe
OMe
OH
O
1
Scheme 3
Synlett 2013, 24, 615–618
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (±)-Spirobenzofuran
617
O
O
O
MeO
O
MeO
O
O
MeO
MeO
a
b
c
OMe
OMe
OMe
OMe
10
9
8
7
O
O
O
O
O
OH
O
MeO
d
MeO
g
f
O
O
HO
OMe
OMe
6
( )-1
5
e
O
O
O
O
O
HO
MeO
MeO
+
MeO
OMe
OH
OMe
OMe
12 (trace)
11 (major)
13
Scheme 4 Reagents and conditions: (a) TBSOTf (1.2 equiv), Et3N, CH2Cl2; 0 °C to r.t., 6 h; mesityl oxide, –78 °C, 58%; (b) PTSA, toluene,
100 °C, 5 h, 95% (c) PTSA, HOCH2CH2OH, benzene, Dean–Stark, reflux, 17.5 h, 80% (brsm); (d) MCPBA, NaHCO3, CH2Cl2, –10 °C, 1.5 h,
66%; (e) BBr3, CH2Cl2, –78 °C, 4 min, 86%; (f) Me3Al, CH2Cl2, 0 °C to r.t., 4 h, 88%; (g) (i) CAN, MeCN, H2O, –10 °C, 10 min; (ii) Na2S2O4,
THF, H2O; 0 °C, 1.5 h; then HCl (1 N), 5 h, r.t., 84% over two steps.
a Me3Al-promoted semipinacol rearrangement was sel-
dom.20 The mild nature of this transformation will surely
make it potentially utilized in organic synthesis. It is inter-
esting that compound 13, resulting from Me3Al addition
to aldehyde 5, was not detected in this step, probably due
to the bulky environment adjacent to the aldehyde
group.21 Finally, after a routine oxidative demethylation–
reduction–ketalization sequence,22 we completed the total
synthesis of rac-spiro-benzofuran 1 (Scheme 4).23
References
(1) Kleinwachter, P.; Schlegel, B.; Dorfelt, H.; Gräfe, U.
J. Antibiot. 2001, 54, 526.
(2) (a) Thomson, R. H. Naturally Occurring Quinones 1971.
(b) Bu’Lock, J. D.; Darbyshire, J. Phytochemistry 1976, 15,
2004. (c) Bottom, C. B.; Siehr, D. J. Phytochemistry 1975,
14, 1433.
(3) Asakawa, Y.; Kondo, K.; Tori, M. Phytochemistry 1991, 30,
325.
(4) Toyota, M.; Koyama, H.; Asakawa, Y. Phytochemistry
1997, 46, 145.
In summary, we have developed a concise synthesis of
spirobenzofuran 1 with 21% overall yield in seven steps.
The synthesis features a Me3Al-promoted semipinacol re-
arrangement and paves the way towards other structurally
related natural product.
(5) Natori, S.; Inouye, Y.; Nishikawa, H. Chem. Pharm. Bull.
1967, 15, 380.
(6) (a) Srikrishna, A.; Lakshmi, B. V.; Ravikumar, P. C.
Tetrahedron Lett. 2006, 47, 1277. (b) Srikrishna, A.; Babu,
R. R.; Ravikumar, P. C. Synlett 2007, 655. (c) Srikishna, A.;
Rao, M. S. Synlett 2004, 374. (d) Paul, T.; Pal, A.; Gupta, P.
D.; Mukherjee, D. Tetrahedron Lett. 2003, 44, 737.
(e) Asakawa, Y.; Matsuda, R.; Tori, M.; Sono, M. J. Org.
Chem. 1988, 53, 5453. (f) Srikrishna, A.; Srinivasa, R. M.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2010, 49, 1363. (g) Srikrishna, A.; Ravikumar, P. C.
Tetrahedron Lett. 2005, 46, 6105. (h) Pal, A.; Dutta, G. P.;
Mukherjee, D. J. Indian Chem. Soc. 2003, 80, 989.
(7) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett. 2005, 46,
7029.
Acknowledgment
We appreciate the financial support from NSFC (21021001,
21172154, 21290180, J1103315) and National Basic Research Pro-
gram of China (973 Program, 2010CB833200).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(8) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1 2000,
3758.
(9) (a) Chen, Y.-X.; Huang, J.-F.; Liu, B. Tetrahedron Lett.
2010, 51, 4655. (b) Huang, C.; Liu, B. Chem. Commun.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 615–618

618
H. Su et al.
LETTER
2010, 46, 5280. (c) Huang, C.; Zhang, W. H.; Liu, B. Sci.
China: Chem. 2011, 54, 43. (d) Liu, Y.-J.; Huang, C.; Liu, B.
Tetrahedron Lett. 2011, 52, 5802. (e) Yue, G.-Z.; Yang, L.;
Yuan, C. C.; Jiang, X.-L.; Liu, B. Org. Lett. 2011, 13, 5406.
(f) Yue, G.-Z.; Yang, L.; Yuan, C. C.; Du, B.; Liu, B.
Tetrahedron 2012, 68, 9624. (g) Huang, X.; Song, L.-Q.;
Xu, J.; Zhu, G.-L.; Liu, B. Angew. Chem. Int. Ed. 2013, 52,
952.
(18) Synthesis of Aldehyde 5
To a solution of compound 6 (200 mg, 0.59 mmol) in CH2Cl2
(10 mL) was added Me3Al (0.59 mL, 1.18 mol, 2.0 M in
toluene) dropwise at –10 °C under argon. The reaction was
warmed to r.t. slowly and stirred for 4 h. Then it was
quenched with sat. aq NaHCO3 (2 mL) at 0 °C. Sat. aq
sodium potassium tartrate (10 mL) was added, and the
biphasic mixture was stirred overnight. The aqueous layer
was separated and extracted with CH2Cl2 (3 × 5 mL). The
residue was purified by flash chromatography (silica gel,
PE–EtOAc = 10:1) to give compound 5 as a yellow solid
(176 mg, 88%).1H NMR (400 MHz, CDCl3): δ = 9.87 (s, 1
H), 6.92 (s, 1 H), 6.69 (s, 1 H), 3.93–3.88 (m, 4 H), 3.79 (s,
3 H), 3.67 (s, 3 H), 2.77 (d, J = 15.2 Hz, A of AB, 1 H), 2.31
(d, J = 15.2 Hz, B of AB, 1 H), 2.27 (d, J = 14.0 Hz, A′ of
A′B′, 1 H), 2.20 (s, 3 H), 1.99 (d, J = 13.6 Hz, B′of A′B′, 1
H), 1.27 (s, 3 H), 0.83 (s, 3 H). 13C NMR (100 MHz, CDCl3):
δ = 201.8, 151.8, 150.7, 127.0, 125.8, 114.8, 114.8, 112.3,
64.3, 64.3, 63.3, 56.3, 55.9, 51.9, 44.2, 43.8, 27.0, 23.9, 16.2.
IR (thin film): 2959, 1716, 1213, 858 cm–1.
(10) Lukas, R. J.; Muresan, A. Z.; Damaj, M. I.; Blough, B. E.;
Huang, X.-D.; Navarro, H. A.; Mascarella, S. W.; Eaton, J.
B.; Marxer-Miller, S. K.; Carroll, F. I. J. Med. Chem. 2010,
53, 4731.
(11) Danishefsky, S.; Etheredge, S. J. J. Org. Chem. 1982, 47,
4791.
(12) Payette, J. N.; Honda, T.; Yoshizawa, H.; Favaloro, F. G. Jr.;
Gribble, G. W. J. Org. Chem. 2006, 71, 416.
(13) Cleve, A.; Fritzemeier, K.-H.; Heinrich, N.; Klar, U.;
Müller-Fahrnow, A.; Neef, G.; Ottow, E.; Schwede, W.
Tetrahedron 1996, 52, 1529.
(14) Analytical Data
1H NMR (400 MHz, CDCl3): δ = 6.86 (s, 1 H), 6.67 (s, 1 H),
3.93–3.84 (m, 4 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 2.78 (s, 1 H),
2.37 (d, J = 15.2 Hz, A of AB, 1 H), 2.23 (d, J = 16.0 Hz, B
of AB, 1 H), 2.20 (s, 3 H), 1.65 (d, J = 13.6 Hz, A′ of A′B′,
1 H), 1.42 (d, J = 13.6 Hz, B′ of A′B′ 1 H), 1.24 (s, 3 H), 1.15
(s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 151.6, 150.1,
128.4, 126.6, 114.1, 109.5, 108.2, 68.2, 64.0, 63.9, 61.1,
56.1, 56.0, 41.2, 39.2, 32.0, 27.9, 26.2, 16.4. IR (thin film):
2955, 1506, 1296, 1093, 823 cm–1.
(19) Keiji, M.; Takashi, O.; Hisashi, Y. J. Am. Chem. Soc. 1989,
111, 6431.
(20) Kingsbury, J. S.; Corey, E. J. J. Am. Chem. Soc. 2005, 127,
13813.
(21) (a) Colucci, J.; Lee, D.; Wilson, M.-C.; Chau, A. Org. Lett.
2002, 4, 4705. (b) Tsuyoshi, I.; Satoru, K.; Makoto, S.;
Tamotsu, F. Chem. Lett. 1997, 11, 1149. (c) Spino, C.;
Granger, M. C.; Tremblay, M. C. Org. Lett. 2002, 4, 4735.
(22) Kostikov, A. P.; Popik, V. V. J. Org. Chem. 2007, 72, 9190.
(23) Analytical Data
(15) (a) Srikrishna, A.; Satyanarayana, G.; Prasad, K. R. Synth.
Commun. 2007, 37, 1511. (b) Xia, W.-J.; Li, D.-R.; Shi, L.;
Tu, Y.-Q. Tetrahedron: Asymmetry 2001, 12, 1459.
(c) Yumiko, Y. Masayoshi I. Org. Biomol. Chem. 2007, 5,
3207. (d) Rickborn, B.; Gerkin, R. M. J. Am. Chem. Soc.
1968, 90, 4193.
(16) (a) Tiberio, C.; Paolo, C.; Maria, F.; Franco, M. J. Chem.
Soc., Perkin Trans. 1 1985, 1607. (b) Song, Z.-L.; Fan,
C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523.
1H NMR (400 MHz, DMSO-d6): δ = 8.66 (s, 1 H), 7.14 (d,
J = 5.6 Hz, 1 H), 6.52 (s, 2 H), 5.79 (d, J = 5.6 Hz, 1 H), 2.83
(d, J = 18.8 Hz, A of AB, 1 H), 2.44 (d, J = 18.8 Hz, B of
AB, 1 H), 2.34 (d, J = 18.4 Hz, A′ of A′B′, 1 H), 2.24 (d,
J = 18.0 Hz, B′ of A′B′, 1 H), 2.07 (s, 3 H), 0.98 (s, 3 H), 0.85
(s, 3 H). 13C NMR (100 MHz, DMSO-d6): δ = 216.2, 150.3,
148.9, 126.5, 123.8, 111.2, 111.0, 102.1, 59.2, 51.9, 42.7,
41.2, 24.6, 23.0, 16.3. IR (thin film): 3395, 1732, 1412,
1085, 923 cm–1. HRMS (ES+): m/z calcd for C15H18O4Na
[M + Na]+: 285.1103; found: 285.1101.
(17) Kita, Y.; Yoshida, Y.; Mihara, S.; Furukawa, A.; Higuchi,
K.; Fang, D. F.; Fujioka, H. Tetrahedron 1998, 54, 14689.
Synlett 2013, 24, 615–618
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.