Total synthesis of furanether b. construction of a hydroazulene skeleton via a novel [5 + 2] cycloaddition reaction of silyloxyallene

Article abstract of DOI:10.1246/cl.2010.630

A new synthetic method for cycloheptanone derivatives was developed on the basis of a novel [5 + 2] cycloaddition reaction using a dicobalt hexacarbonyl propargyl cation species and a silyloxyallene. The method can be applied for constructing functionalized hydroazulene skeletons, and a total synthesis of sesquiterpene furanether B was achieved through the reactions involving transformation of the dicobalt acetylene complex into a maleic anhydride derivative and the crucial oxidative transannular ether ring formation.

Full text of DOI:10.1246/cl.2010.630

doi:10.1246/cl.2010.630
630
Published on the web May 15, 2010
Total Synthesis of Furanether B. Construction of a Hydroazulene Skeleton
via a Novel [5 + 2] Cycloaddition Reaction of Silyloxyallene
Katsuhiko Mitachi,1 Takashi Yamamoto,1 Fumikatsu Kondo,1 Tadashi Shimizu,1 Masaaki Miyashita,2 and Keiji Tanino*1
1Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido 060-0810
2Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, Hachioji, Tokyo 192-0015
(Received March 23, 2010; CL-100279; E-mail: ktanino@sci.hokudai.ac.jp)
A new synthetic method for cycloheptanone derivatives was
a
OTIPS
TIPSO
developed on the basis of a novel [5 + 2] cycloaddition reaction
using a dicobalt hexacarbonyl propargyl cation species and a
silyloxyallene. The method can be applied for constructing
functionalized hydroazulene skeletons, and a total synthesis of
sesquiterpene furanether B was achieved through the reactions
involving transformation of the dicobalt acetylene complex into
a maleic anhydride derivative and the crucial oxidative trans-
annular ether ring formation.
TIPSO
R
EtAlCl
2
+
1
Co
Co
•
R
b
O
O
TIPSO
R
R
Co(CO)
Co(CO)
3
or
3
Co(CO)
Co(CO)
3
3
TIPSO
A
B
Cycloaddition reactions provide a straightforward and
powerful method for constructing a carbocyclic skeleton of
various kinds of natural products. While a significant number of
total syntheses have been accomplished by the use of the Diels-
Alder reaction,1 there are relatively few examples involving a
[5 + 2] cycloaddition reaction as a key step for construction of a
cycloheptane skeleton.2 We have reported a novel method for
cycloheptanone synthesis via an intermolecular [5 + 2] cyclo-
addition reaction using dicobalt acetylene complex 1 as a five-
carbon unit (Scheme 1).3 The reaction proceeds in a stepwise
fashion involving a dicobalt propargyl cation and a silyloxonium
ion intermediate as shown in Scheme 1.
Scheme 2. Intermolecular [5 + 2] cycloaddition reaction of
silyloxyallene and dicobalt acetylene complex 1.
TIPSO
TIPSO
Br
CHBr (2.4 equiv)
3
KO Bu (3 equiv)
TIPSO
Me
MeLi
t
•
(3 equiv)
Br
Me
hexane
ether
Me
2
3
-20 °C
-60 °C
3
83% from 2
O
Me
EtAlCl (2.2 equiv)
2
Co(CO)
+
1
3
CH Cl , 0 °C
2
2
(1.3 equiv)
Co(CO)
3
TIPSO
The efficiency of the cycloaddition reaction as well as the
utility of the products having a dicobalt acetylene complex
moiety led us to explore the reactions with other nucleophilic
olefins. Particularly, we were intrigued by a silyloxyallene
derivative bearing a highly strained sp carbon atom as a
nucleophilic center (Scheme 2). The reaction of a silyloxyallene
with 1 would afford a silyloxonium ion conjugated with a
double bond that in turn might undergo either a cyclization
reaction giving rise to A (path a) or a conjugate addition reaction
leading to B (path b).
4 86% (E:Z = 4:1)
Scheme 3. Preparation and the [5 + 2] cycloaddition reaction
of silyloxyallene 3.
was slightly sensitive to acidic conditions, purification was
performed by flash column chromatography using neutralized
silica gel. In the presence of EtAlCl2, silyloxyallene 3 smoothly
reacted with the five-carbon unit 1 to give cycloheptanone
derivative 4, which indicated that the intramolecular conjugate
addition reaction is much more favorable (path b in Scheme 2).
The preliminary result led us to design a new route for
constructing a hydroazulene skeleton starting from allene
derivative 5 having a terminal iodo group (Scheme 4). The
[5 + 2] cycloaddition reaction of 5 with 1 afforded the desired
cycloheptanone 6 which was subjected to an intramolecular
alkylation reaction mediated by silver(I) trifluoroacetate5 giving
rise to keto aldehyde 7 in high yield. On the other hand,
treatment of the corresponding enol silyl ether 8 with the silver
salt resulted in the selective formation of ketone 9 as a single
product. It is noteworthy that attempts to obtain the ketone 9
through a reaction of 6 with a base led to formation of a complex
mixture.
Silyloxyallene 3 was easily prepared from enol silyl ether 2
via cyclopropanation with a dibromocarbene species followed
by treatment with MeLi (Scheme 3).4 Since the silyloxyallene
OTIPS
O
TIPSO
TIPSO
EtAlCl
2
+
Co(CO)
3
Co(CO)
3
R
CH Cl
R
Co(CO)
3
2
2
Co(CO)
3
BzO
1
OTIPS
OTIPS
TIPSO
TIPSO
R
Co
Co
Co
Co
R
In order to demonstrate the utility of the present method,
total synthesis of furanether B,6,7 a terpenoid isolated from
Lactarius scrobiculetus, was undertaken (Scheme 5). Since
seven-membered dicobalt acetylene complexes are easily trans-
Scheme 1. Lewis acid-promoted intermolecular [5 + 2] cyclo-
addition reaction of dicobalt acetylene complex 1 (TIPSO:
triisopropylsilyloxy).
Chem. Lett. 2010, 39, 630-632
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

631
O
O
I
I
O
I
a
b
c,d
O
EtAlCl
(2.2 equiv)
2
Co(CO)
3
O
CO2Et
O
+
1
Co(CO)
3
CH Cl
2
0 °C
2
13 67%
14 75%
(1.1 equiv)
•
I
I
OTIPS
OTIPS 6 80%
(E:Z = 8:1)
5
g
e,f
O
+
1
Co(CO)
3
(1.2 equiv)
•
CF CO Ag (5 equiv)
2,6-lutidine (1 equiv)
3
2
H
TIPSO
OTIPS
Co(CO)
3
12 quant.
15 53%
CH Cl , -20 °C
2
2
CHO
7 80% (dr = 2:1)
O
I
O
Co(CO)3
Co(CO)3
I
Co(CO)3
Co(CO)3
I
OTMS
Co(CO)
TIPSO
+
3
TMSOTf (3 equiv)
CF CO Ag (5 equiv)
3
2
Et N (6 equiv)
2,6-lutidine (1 equiv)
3
Co(CO)
3
6
(E)
17
OTIPS
OTMS
16
CH Cl , -20 °C
CH Cl , 0 °C
2
2
2
2
OTIPS
H
8 90%
I
O
H
O
Co(CO)3
Co(CO)3
Co(CO)3
H
h
i
O
Co(CO)
3
Co(CO)
Co(CO)3
3
Co(CO)
+
H
3
Co(CO)
3
H
OTIPS
OH
OTIPS 11 74%
18 69%
CHO
(from 12)
OTIPS
9 60%
(single isomer)
7 21%
OH
H
H
j
Co(CO)3
Co(CO)3
Co(CO)3
Scheme 4. Synthesis of hydroazulene 9 via sequential [5 + 2]
cycloaddition and intramolecular alkylation reactions.
+
Co(CO)3
H
H
O
OH
O
H
H
H
OTIPS 19 66%
OTIPS 20 17%
O
O
O
O
O
O
O
O
Scheme 6. Synthesis of hydroazulene derivative 19. Reagents
and conditions: (a) i. NaBH4 (3 equiv), THF, rt, 45 h, ii. p-
TsOH¢H2O (0.1 equiv), benzene, rt, 21 h; (b) TMSI (3 equiv),
CCl4, 80 °C, 9 h, then EtOH, rt, 12 h; (c) DIBAL (1.05 equiv),
hexane, ¹78 °C, 30 min then HCl (aq); (d) TIPSOTf (3 equiv),
Et3N (9 equiv), CH2Cl2, rt, 1 h; (e) CHBr3 (2.4 equiv), KOtBu (3
equiv), hexane, ¹23 °C, 1 h; (f) MeLi (3 equiv), ether, ¹60 °C,
15 min; (g) EtAlCl2 (2 equiv), CH2Cl2, 0 °C, 30 min; (h)
TMSOTf (2.6 equiv), Et3N (5.3 equiv), CH2Cl2, 0 °C, 30 min;
(i) CF3CO2Ag (2 equiv), 2,6-lutidine (1 equiv), CH2Cl2, 0 °C,
30 min; (j) DIBAL (2 equiv), ether, ¹78 °C, 30 min.
H
H
OHC
H
10
furanether B
H
OTIPS
I
Co(CO)
3
Co(CO)
3
•
H
OTIPS
12
OTIPS
11
Scheme 5. Retrosynthetic analysis of furanether B.
formed into the corresponding maleic anhydrides under the
influence of ceric ammonium nitrate (CAN),3,8 we planned to
construct the furan moiety by reduction of the corresponding
maleic anhydride. The cyclic ether was designed to be
constructed via an intramolecular oxidative cyclization reaction
of alcohol 10, which could be prepared from ketone 11 by
selective reduction from the convex face followed by treatment
with CAN.
16 and its isomer 17 (Scheme 6). Fortunately, the treatment
of the inseparable mixture with TMSOTf and triethylamine
effected selective conversion of ketone 16 to enol silyl ether 18
in 69% overall yield. The cyclization reaction of 18 mediated by
silver(I) trifluoroacetate resulted in selective formation of the
desired ketone 11 with no by-product corresponding to the keto
aldehyde 7 in Scheme 4. Stereoselective reduction of 11 was
performed by using DIBAL in ether to afford alcohol 19 in 66%
yield along with its stereoisomer 20.
It is noteworthy that the bulkiness of the allene 12 having a
quaternary carbon atom affected the selectivity of the [5 + 2]
cycloaddition reaction in which a small amount of ketone 17
was produced. When the R group in Scheme 2 is bulky, the
steric repulsion between the enol silyl ether moiety and the R
group slows down path b, which enhances formation of 17
through path a. On the other hand, the bulkiness of the side
chain brought about site-selective cyclization of 18 at the less
hindered enol silyl ether moiety to afford ketone 11 in good
yield.
Allene 12 was synthesized from lactone 13,9 which was
prepared from commercially available 2,2-dimethylglutaric
anhydride (Scheme 6). The reaction of lactone 13 with TMSI
followed by treatment with ethanol afforded iodo ester 14 via
cleavage of the C-O bond.10 Ester 14 was then reduced with
DIBAL, and the resulting aldehyde was treated with TIPSOTf
and triethylamine giving rise to enol silyl ether 15. Trans-
formation of 15 into allene 12 was achieved by applying a
similar reaction sequence in Scheme 3.
The key [5 + 2] cycloaddition reaction11 of the allene 12
with 1 afforded an 84:16 mixture of the desired cycloheptanone
Chem. Lett. 2010, 39, 630-632
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

632
OH
O
References and Notes
H
H
H
1
K. Takao, R. Munakata, K. Tadano, Chem. Rev. 2005, 105,
4779, and referenses cited there in.
Co(CO)3
Co(CO)3
a
b
O
O
O
2
For examples: a) P. A. Wender, C. D. Jesudason, H. Nakahira,
N. Tamura, A. L. Tebbe, Y. Ueno, J. Am. Chem. Soc. 1997,
119, 12976. b) P. A. Wender, K. D. Rice, M. E. Schnute, J.
Am. Chem. Soc. 1997, 119, 7897, and referenses cited there
in.
H
H
H
OHC
OTIPS 19
21
O
H
c
O
O
O
3
K. Tanino, F. Kondo, T. Shimizu, M. Miyashita, Org. Lett.
O
+
O
2002, 4, 2217.
H
O
4
5
W. R. Moore, H. R. Ward, J. Org. Chem. 1962, 27, 4179.
C. W. Jefford, A. W. Sledeski, P. Lelandais, J. Boukouvalas,
Tetrahedron Lett. 1992, 33, 1855.
HO
HO
22 91% from 19
23 57%
H
6
7
Isolation of furanether B: R. Battaglia, M. De Bernardi, G.
Fronza, G. Mellerio, G. Vidari, P. Vita-Finsi, J. Nat. Prod.
1980, 43, 319.
Total synthesis of furanether B: a) M. E. Price, N. E. Schore,
Tetrahedron Lett. 1989, 30, 5865. b) M. E. Price, N. E.
Schore, J. Org. Chem. 1989, 54, 5662. c) G. A. Molander,
J. S. Carey, J. Org. Chem. 1995, 60, 4845. d) R. P. L. Bell, A.
Sobolev, J. B. P. A. Wijnberg, A. de Groot, J. Org. Chem.
1998, 63, 122.
d,e
O
O
furanether B
H
76%
Scheme 7. Total synthesis of Furanether B. Reagents and
conditions: (a) (NH4)2Ce(NO3)6 (12 equiv), CH3CN-H2O, rt,
30 min; (b) NaBH4 (5 equiv), THF-H2O, rt, 30 min then HCl
(aq), rt, 30 min; (c) DIBAL (1.8 equiv), CH2Cl2, ¹78 °C, 10 min
then HCl (aq); (d) Tf2O (1.5 equiv), 2,6-di-tert-butylpyridine (3
equiv), CH2Cl2 ¹78 °C, 45 min; (e) LiBHEt3 (2.1 equiv), THF,
rt, 15 min.
8
9
a) M. J. Schottelius, P. Chen, Helv. Chim. Acta 1998, 81,
2341. b) K. Tanino, T. Shimizu, M. Miyama, I. Kuwajima,
J. Am. Chem. Soc. 2000, 122, 6116.
D. M. Bailey, R. E. Johnson, J. Org. Chem. 1970, 35, 3574.
10 G. A. Olah, S. C. Narang, B. G. B. Gupta, R. Malhotra, J.
Org. Chem. 1979, 44, 1247.
The stage was set for conversion of the dicobalt acetylene
complex moiety to a maleic anhydride derivative. Surprisingly,
treatment of the alcohol 19 with an excess amount of CAN led to
formation of aldehyde 21 having an oxygen bridge in the
cycloheptane ring (Scheme 7). The result indicates that the
secondary hydroxy group of the substrate underwent trans-
annular oxidative coupling with the enol silyl ether moiety.12
The unexpected reaction allowed us to accomplish the total
synthesis in fewer steps.
Thus, the reaction of the aldehyde 21 with NaBH4 followed
by workup under acidic conditions gave rise to hydroxy lactone
22 as a mixture of regioisomers in high overall yield.
Conversion of the unsaturated lactones to the furan ring was
achieved by DIBAL reduction. Finally, the primary hydroxy
group of 23 was removed via reduction of the corresponding
triflate with LiBHEt3. The spectral data of the synthetic
compound were identical with those of furanether B.
In conclusion, a novel synthetic method for functionalized
cycloheptanone derivatives was developed on the basis of a
[5 + 2] cycloaddition reaction using a dicobalt hexacarbonyl
propargyl cation species and a silyloxyallene. The reaction
proceeds through an intermolecular addition followed by an
intramolecular conjugate addition. The method can be applied
for constructing functionalized hydroazulene skeletons, and a
new total synthesis of furanether B was achieved through the
reactions involving transformation of dicobalt acetylene com-
plex into the maleic anhydride derivative and the key oxidative
transannular ether ring formation.
11 The experimental procedure for the [5 + 2] cycloaddition
reaction: To a mixture of siloxyallene 12 (3.8 g, 9.3 mmol)
and cobalt complex 1 (7.2 g, 11 mmol) in CH2Cl2 (22 mL)
was added a 0.96 M hexane solution of EtAlCl2 (19.3 mL,
18.6 mmol) at 0 °C. After stirring for 30 min, the reaction was
quenched with a saturated aqueous solution of Rochelle salt.
The mixture was stirred vigorously for 30 min and separated.
The aqueous layer was extracted with ether and the combined
organic layer was dried over MgSO4. Concentration under
reduced pressure followed by flash column chromatography
using neutral silica gel afforded 6.3 g of a mixture of
cycloadducts 16 and 17. The mixture was dissolved in
CH2Cl2 (41 mL), and to this was added triethylamine
(6.8 mL, 49 mmol) followed by TMSOTf (4.4 mL, 25 mmol)
at 0 °C. After stirring for 30 min, a saturated aqueous solution
of NaHCO3 was added, and the mixture was separated. The
aqueous layer was extracted with ether, and the combined
organic layer was dried over MgSO4. Concentration under
reduced pressure followed by purification by flash column
chromatography afforded 5.4 g (69% from 12) of enol silyl
ether 18 and 1.1 g (16% from 12) of cycloadduct 17. Cobalt
complex 18: 1H NMR (500 MHz, CDCl3): ¤ 6.28 (s, 1H),
5.30 (d, J = 8.0 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 3.31 (d,
J = 17.2 Hz, 1H), 3.20 (d, J = 9.7 Hz, 1H), 3.14 (d,
J = 9.7 Hz, 1H), 2.85 (td, J = 8.0, 4.6 Hz, 1H), 1.64 (dd,
J = 14.3, 8.0 Hz, 1H), 1.47 (dd, J = 14.3, 4.6 Hz, 1H), 1.14
(sept, J = 6.3 Hz, 3H), 1.06 (d, J = 6.3 Hz, 18H), 1.04 (s,
6H), 0.24 (s, 9H). 13C NMR (125 MHz, CDCl3): ¤ 199.95
(3C), 199.63 (3C), 147.30, 136.78, 116.88, 115.96, 95.24,
87.81, 44.12, 37.89, 34.27, 29.09, 27.33, 27.30, 24.14, 17.64
(6C), 11.79 (3C), 0.24 (3C). HRMS (EI) m/z; calcd for
C31H45O8Si2Co2I: 846.0362, found: 846.0316.
This work was partially supported by the Global COE
Program (Project No. B01: Catalysis as the Basis for Innovation
in Materials Science) and Grant-in-Aid for Scientific Research
on Innovative Areas (Project No. 2105: Organic Synthesis Based
on Reaction Integration) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
12 A similar cyclization reaction of an alcohol having an
allylsilane moiety was reported: S. R. Wilson, C. E. Augelli-
Szafran, Tetrahedron 1988, 44, 3983.
Chem. Lett. 2010, 39, 630-632
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/