Convenient synthesis of angular triquinane from 4-alkenylfulvene via thermal cycloaddition followed by skeletal rearrangement of the resulting [4 + 2] adduct

Article abstract of DOI:10.1246/cl.2008.454

Alkenylfulvene prepared by the annulation of allylidenetriphenylphosphorane with 1,4-ynedione proceeded thermal cyclo-addition in a highly regio- and stereoselective manner to give [4 + 2] adduct which was then converted into triquinane derivative by the

Full text of DOI:10.1246/cl.2008.454

454
Chemistry Letters Vol.37, No.4 (2008)
Convenient Synthesis of Angular Triquinane from 4-Alkenylfulvene via Thermal Cycloaddition
Followed by Skeletal Rearrangement of the Resulting [4 + 2] Adduct
Sho Inagaki,1 Keisuke Imura,1 Toshio Morita,1 Yasuharu Yoshimi,1 Minoru Hatanaka,ꢀ1 and Tomikazu Kawano2
1Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui,
3-9-1 Bunkyo, Fukui 910-8507
2School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Shiwa-gun, Iwate 028-3694
(Received January 8, 2008; CL-080019; E-mail: hatanaka@acbio2.acbio.fukui-u.ac.jp)
Alkenylfulvene prepared by the annulation of allylidenetri-
EtO
EtO
EtO
EtO
a
b
phenylphosphorane with 1,4-ynedione proceeded thermal cyclo-
addition in a highly regio- and stereoselective manner to give
[4 + 2] adduct which was then converted into triquinane deriv-
ative by the treatment with LHMDS-t-BuOK after hydrolysis of
the enol ether group.
H
H
O
O
OBn
OBn
1
2
O
OH
d
c
t-Bu
Cycloaddition reaction of fulvene is attractive tool to con-
struct various fused ring-systems. Unique 6ꢀ electrons of ful-
vene allow reacting with dienophiles, 1,3-dipolarophiles and di-
enes to produce [4 + 2], [6 + 2], and [6 + 4] cycloaddition
products and competition among these cycloadditions has been
observed in many cases.1 Although intramolecular cycloaddition
of 4-alkenylfulvenes has advantage to control the competition,2
the approach is limited by difficulty of regioselective preparation
of substituted fulvenes.3 We have reported that 4-alkenylfulvene
could be prepared regioselectively by the reaction of allylidene-
triphenylphosphorane with 1,4-ynedione and underwent thermal
[4 + 2] cycloaddition in a highly regio- and diastereoselective
manner.4 The resulting adduct was transformed into the bicy-
clo[3.3.0]octene derivative which possessed proper functionali-
ties to provide an access to triquinane skeleton as found in pen-
talenic acid and pentalenolactone.5 Thus, we set out to study an
access to the triquinanes using this methodology since they have
been still attractive synthetic target of organic chemists in terms
of their unique structural feature and biological activities.
We now disclose that regioselective synthesis and subsequent
thermal cycloaddition of 4-alkenylfulvene provides a good yield
of [4 + 2] adduct which is then converted into angular triqui-
nane via unexpected skeletal rearrangement.
The present investigation commenced by synthesis of t-
butyl-substituted ynedione 4 (Scheme 1) because previous syn-
thesis from the corresponding phenyl-substituted ynedione led
to the formation of a mixture of E/Z isomers (1:2.5) in which
Z isomer proceeded [4 + 2] cycloaddition while E isomer gave
poor results.4b We expected that the bulky t-butyl substituent
would retard E-fulvene formation due to steric repulsion with
the 4-substituent. The monoacetal 1 prepared from 2-methylpro-
panal was treated with vinylmagnesium bromide followed by
benzyl bromide to give 2. Hydrolysis of 2 and ethynylation
of the resulting aldehyde gave 3 which was then converted
into t-butyl-substituted 1,4-ynedione 4 via a sequence consisted
of protection, the Sonogashira reaction, and then the Jones
oxidation. Reaction of the 1,4-ynedione with 2-ethoxyallylide-
netriphenylphosphorane proceeded nicely at 0 ꢁC to give almost
exclusively the Z-fulvene 5 in 94% yield as expected. Thermal
cycloaddition of the fulvene 5 in refluxing toluene followed by
mild acid hydrolysis of the resulting [4 + 2] adduct gave the
OBn
H
O
3
4
t-Bu
t-Bu
H
O
e
OBn
f
O
EtO2C
OBn
O
CO2Et
EtO
5
6
Scheme 1. Reagents and conditions; (a) (i) C6H11NH2,
CH2Cl2, rt, 79%, (ii) (EtO)2CHCH2Br, LDA, HMPA, THF,
ꢂ78 ꢁC, then tartaric acid, H2O, 0 ꢁC, 96%. (b) (i) vinylmagne-
sium bromide, THF, 0 ꢁC, 94%, (ii) BnBr, NaH, TBAI, THF
30 ꢁC, 91%. (c) (i) TsOH, acetone, H2O, 96%, (ii) ethynylmag-
nesium bromide, THF, 0 ꢁC, 80%. (d) (i) TMSCl, Et3N, ether, rt,
(ii) t-BuCOCl, (PPh3)2PdCl2, CuI, Et3N, benzene, rt, (iii) citric
acid, MeOH, H2O, rt, 81% (from 3), (iv) Jone’s reagent, rt,
83%. (e) Ph3P=CHC(OEt)=CHCO2Et, THF, 0 ꢁC, 24 h, 94%.
(f) (i) toluene, 100 ꢁC, 85%, (ii) TFA, THF, H2O, rt, 1 h, 72%.
tricyclic ketone 66 stereoselectively.
Having achieved efficient formation of the tricyclic ketone 6
using t-butyl 1,4-ynedione 4, conversion of 6 into triquinane
skeleton was next investigated (Scheme 2). Treatment of 6 with
NaOMe in MeOH proceeded ring opening even at ꢂ78 ꢁC to
give the methyl ester 7 in 79% yield. When the reaction was
carried out at ꢂ10 ꢁC, the pyrone 10 was generated in 71% yield.
Similarly, treatment of 7 with LDA in THF also gave 10 in 41%
yield and in both cases the expected formation of triquinane by
cyclization between the ꢁ position of ketone and the bridgehead
methyl ester was not observed. The cyclization was achieved
with more reactive phenylthioester 9, which was prepared from
6 by the treatment with DBU in aqueous THF and then conden-
sation of the resulting acid 8 with benzenethiol. Treatment of 9
with LDA in THF gave triquinane 11 but in a low yield (28%).
Finally, we found that the desired triquinane 11 was formed
directly from the ketone 6. When the ketone 6 was treated with
LHDMS in the presence of potassium t-butoxide in THF at
ꢂ78 ꢁC, skeletal transformation occurred to give 11.7 The
reaction underwent only under the above conditions using the
combination of LHDMS and potassium t-butoxide and in the
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.4 (2008)
455
References and Notes
1
OBn
H
OBn
H
a) K. N. Houk, L. J. Luskus, J. Org. Chem. 1973, 38, 3836.
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in Comprehensive Organic Synthesis, ed. by B. M. Trost,
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Chem. 1989, 54, 5148. c) E. Herrmann, H.-J. Gais, B.
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a
O
b
EtO2C
6
O
O
(R=OMe)
t-Bu
COR
CO2Me
t-Bu
7: R=OMe
8: R=OH
9: R=SPh
10
e
c
OBn
H
d
EtO2C
t-Bu
O
O
2
11
Scheme 2. Reagents and conditions; (a) for preparation of 7:
NaOMe, MeOH, THF, ꢂ78 ꢁC, 79%; for the preparation of 8:
DBU, THF, H2O, rt, 94%. (b) NaOMe, MeOH, THF, ꢂ10 ꢁC,
1 h, 71% (from 6). (c) DCC, PhSH, 92%. (d) LDA, THF,
ꢂ78 ꢁC, 28%. (e) LHDMS, t-BuOK, THF, ꢂ10 ꢁC, 4 h, 72%.
3
4
5
Table 1. Reaction conditions of skeletal rearrangementa
Yieldb of
11/%
Entry
Base
Additive (mol amt.)
1
2
3
4
5
6
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
s-BuLi
—
LiCl (1.0)
t-BuOK (1.0)
t-BuOK (1.5)
t-BuOK (3.0)
t-BuOK (1.5)
0
0c
42
72
0
0
aAll reaction were carried out at ꢂ78 ꢁC in THF using
6
Data for 6: 1H NMR (CDCl3, 300 MHz) ꢃ 7.27–7.35 (m, 5H),
6.38 (s, 1H), 4.54 (s, 2H), 4.36–4.25 (m, 2H ꢃ 1/2),
4.10–3.99 (m, 2H ꢃ 1/2), 3.25 (d, J ¼ 9:17 Hz, 2H) 2.48
(dd, J ¼ 21:6 Hz, J ¼ 17:2 Hz, 2H), 2.36 (t, J ¼ 4:49 Hz,
1H), 2.31 (t, J ¼ 4:49 Hz, 1H), 2.24–2.15 (m, 1H), 1.91
(d, J ¼ 14:7 Hz, 1H), 1.70 (d, J ¼ 14:8 Hz, 1H), 1.25
(t, J ¼ 7:15 Hz, 3H), 1.18 (s, 3H), 1.16 (s, 9H), 1.09
(s, 3H). 13C NMR (CDCl3, 75 MHz) ꢃ 207.24, 205.30,
167.72, 159.48, 138.81, 127.65, 127.26, 112.64, 92.10,
73.01, 69.35, 61.12, 52.40, 49.22, 43.82, 43.73, 38.30,
31.59, 29.65, 26.44, 25.33, 14.19, HRMS (TOF) m=z:
[M + Na]þ Calcd for C28H36O5Na 475.2460; Found
475.2447.
b
c
1.1 mol amt. of base. Isolated yield. The acid 8 was ob-
tained in 61% yield.
t-Bu
OBn
H
H
O
EtO2C
11
9
H
OBn
t-Bu
base
7
O
O
O
CO2Et
12
6
Scheme 3. A possible mechanism of skeletal rearrangement.
1
absence of potassium t-butoxide no formation of 11 was ob-
served (Table 1). The best yield (72%) was obtained in the pres-
ence of 1.5 molar amounts of potassium t-butoxide. The struc-
ture of 11 was confirmed by a combination of COSY and HMBC
spectra in the NMR experiments. Thus, the skeletal transforma-
tion may be explained in terms of easiness of the C7–C8 bond
cleavage addressed to release of ring strain and existence of
the two electron-withdrawing groups at the 7 and 10 positions.
Deprotonation at the 9 position of 6 affects the C7–C8 bond
cleavage to generate the ketene 12 (Scheme 3). Recyclization
of 12 and successful double bond migration gives rise 11 which
has stable ꢂ-oriented ethoxycarbonyl group.
7
Data for 11: mp 146–147 ꢁC; H NMR (CDCl3, 500 MHz)
ꢃ 7.38–7.29 (m, 5H), 4.62 (dd, J ¼ 15:0, 11.9 Hz, 2H),
4.13 (bq, J ¼ 7:0 Hz, 2H), 3.65 (dd, J ¼ 12:2, 7.9 Hz, 2H),
3.33 (d, J ¼ 6:4 Hz, 1H), 2.79 (d, J ¼ 16:5 Hz, 1H), 2.62
(d, J ¼ 16:5 Hz, 1H), 2.47 (bt, J ¼ 7 Hz, 1H), 2.34–2.27
(m, 1H), 2.21–2.17 (m, 1H), 1.66 (d, J ¼ 13:4 Hz, 1H),
1.45 (d, J ¼ 13:4 Hz, 1H), 1.30 (bt, J ¼ 7:0 Hz, 3H), 1.19
(s, 9H), 1.12 (s, 3H), 1.06 (s, 3H); 13C NMR (CDCl3,
125 MHz) ꢃ 207.69, 204.258, 185.86, 170.92, 138.46,
137.65, 128.41, 127.65, 127.21, 95.07, 72.61, 61.38,
56.05, 54.51, 51.9, 50.27, 44.39, 43.99, 43.60, 37.62,
37.62, 31.57, 27.10, 25.81, 22.64, 21.01, 14.05; ꢄmax (neat):
In summary, stereoselective synthesis of triquinane skeleton
was achieved via thermal intramolecular [4 + 2] cycloaddition
of 4-alkenylfulvenes followed by skeletal rearrangement.
1734, 1706, 1669, 1623 cmꢂ1
; HRMS (TOF) m=z:
[M + Na]þ Calcd for C28H36O5Na 475.2460, found
475.2448.
Published on the web (Advance View) March 15, 2008; doi:10.1246/cl.2008.454