Facile synthesis of enantiopure tricyclic furanyl derivatives via tungsten-mediated cycloalkenation reactions and Diels-Alder reactions

Article abstract of DOI:10.1016/S0040-4039(02)01815-4

Chiral furanyl diene 1 is easily prepared from cycloalkenation of chiral tungsten alkynol with acetaldehyde, followed by demetalation with Me₃NO. This diene bears a chiral 1,3-dioxolane group to control diastereoselective Diels-Alder reactions

Full text of DOI:10.1016/S0040-4039(02)01815-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7983–7985
Facile synthesis of enantiopure tricyclic furanyl derivatives via
tungsten-mediated cycloalkenation reactions and
Diels–Alder reactions
Heh-Lung Huang, Heh-Chang Huang† and Rai-Shung Liu*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC
Received 5 July 2002; revised 19 July 2002; accepted 23 August 2002
Abstract—Chiral furanyl diene 1 is easily prepared from cycloalkenation of chiral tungsten alkynol with acetaldehyde, followed
by demetalation with Me3NO. This diene bears a chiral 1,3-dioxolane group to control diastereoselective Diels–Alder reactions
with electron-deficient olefins. The chiral 1,3-dioxolane substituent of the cycloadducts was degraded to a hydrogen atom to make
these molecules possess a common furanyl functionality. © 2002 Elsevier Science Ltd. All rights reserved.
Enantiopure tricyclic furanyl derivatives with frame-
work A are commonly encountered in many naturally
occurring compounds, particularly in the family of
terpenoids.1 Scheme 1 shows several representatives
that show interesting biological activities.1 The bicyclic
ether framework A is also a useful building block for
complex bioactive molecules.2 A short synthesis of these
ether derivatives has attracted considerable attention.2,3
The synthetic methods are quite diverse and require
long procedures. Furthermore, most investigation
focused on synthesis of racemic forms.2,3 [4+2]-Cycload-
dition of heterocyclic dienes with electron-deficient
olefins is a useful synthetic method for many compli-
cated molecules.4 Previously, we reported that treat-
ment
of
alkynyltungsten
compounds
with
RCH3CHO/BF3·Et2O complex formed oxacarbenium
salts6 (Scheme 1, Eq. (2)), further yielding a tungsten–
furanyl diene7 efficiently. In this work, we report a
facile synthesis of enantiomeric bicyclic ethers A based
on this tungsten-mediated cyclization with the protocol
shown in Scheme 1. The oxacyclic diene is designed to
bear a chiral dioxolane group to control diastereoselec-
tivity of [4+2]-cycloaddition, and such a chiral sub-
stituent is readily removed from the resulting
cycloadducts.
Scheme 2 shows the synthesis of chiral tungsten–
alkynol 5 for the cyclization, The starting chiral diol 1
Scheme 1.
* Corresponding author. Tel.: +886-3-5715131-3385; fax: +886-3-5711082; e-mail: rsliu@mx.nthu.edu.tw
† The undergraduate research program from Department of Chemistry, Chung Yuan Christian University, Chungli 32023, Taiwan, ROC.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01815-4

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H.-L. Huang et al. / Tetrahedron Letters 43 (2002) 7983–7985
was prepared in two steps from L(+)-diethyl tartrate
according to the literature.8 Alkylation of 1 with benzyl
bromide, followed by Swern oxidation, afforded alde-
hyde 3 in an overall yield 58%. Propargylation of chiral
aldehyde 3 proceeded with excellent diastereoselectivity
(dr >25) on treatment with propargyl zinc bromide in
DMF/ether and anti-alcohol 4 was obtained in 86%
yield.5 Treatment of alkynol 4 with CpW(CO)3Cl (1.0
equiv.) and CuI catalyst (11 mol%) in Et2NH effected
metallation,6,7 yielding tungsten–alkynol species 5 in
71% yield. Treatment of complex 5 with excess acetal-
dehyde in the presence of BF3·Et2O in cold diethyl ether
(−78°C) produced a yellow oil, presumably tungsten–
oxacarbenium salt B. Subsequent treatment of this salt
with Et3N (2.0 equiv.) afforded tungsten–furanyl diene
6 in 64% overall yield. Hydrodemetalation of dienyl
complex 6 with Me3NO in CH3CN yielded the desired
chiral diene 7 in 60% yield.9
The dioxolane group of diene 7 effects diastereoselec-
tive Diels–Alder reaction upon treatment with various
electron-deficient olefins under ambient conditions; the
results are shown in Scheme 3. The reaction of diene 7
with maleic anhydride, maleimide and N-phenyl
maleimide proceeds smoothly at 23°C to afford one
diastereomeric product 8–10 exclusively (dr >20). In the
presence of Zn(OTf)2 (3.0 equiv.), 1,4-benzoquinone
and 1,4-naphthoquinone reacted with diene 7 at 23°C
to afford cycloadducts 11 and 12 efficiently. Structural
elucidation of these cycloadducts relies on proton NOE
spectra that show the H3 proton to be cis to H2 and H4
protons but trans to the H1-proton, respectively. This
information indicates that the olefin approaches the
diene in an endo mode and opposite the chiral dioxo-
lane group.
Scheme 3. Diels–Alder reaction of diene 7 with olefins.
Scheme 4 shows a convenient method for degradation
of the dioxolane group of cycloadducts 8–10 into an
aldehyde or a hydrogen atom. Hydrolysis of com-
pounds 8–10 with HCl (3.0 M)/MeOH mixtures at 23°C
for 4 h led to formation of the corresponding diols that
were subsequently oxidatively cleaved with NaIO4/silica
to afford aldehyde derivatives 13–15 in 66–68% yields
after purification on a silica column. Column chro-
matography of these samples also led to epimization of
the aldehyde carbon to form two diastereomers (ca. 3:1
ratio). Treatment of compounds 13–15 with
RhCl(PPh3)3 catalyst (1.0 equiv.) in CH2Cl2 (23°C) led
to decarbonylation to form tricyclic furan derivatives
16–18 efficiently.10 HPLC-analysis of compounds 16–18
shows the ee values of these compounds to exceed
98%.11,12
In summary, we present a facile synthesis of chiral
furanyl diene 1 based on tungsten-mediated cycloalke-
Scheme 2.
Scheme 4.

H.-L. Huang et al. / Tetrahedron Letters 43 (2002) 7983–7985
7985
nation. Synthesis of furanyl diene requires a long proce-
dure according to literature methods.3 The diene bears
a dioxolane group to control diastereoselectivity of
Diels–Alder reactions. This stereodirecting group is
readily removed using conventional method. This syn-
thetic approach provides a short synthesis of enantio-
pure tricyclic furan.
6. Liang, K.-W.; Li, W.-T.; Lee, G.-H.; Peng, S.-M.; Liu,
R.-S. J. Am. Chem. Soc. 1997, 119, 4404.
7. Li, W.-T.; Lai, F.-C.; Lee, G.-H.; Peng, S.-M.; Liu,
R.-S. J. Am. Chem. Soc. 1998, 120, 4520.
8. (a) Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.;
Linden, A. J. Org. Chem. 2001, 66, 4180; (b) Inouye,
M.; Fujimoto, K.; Furusyo, M.; Nakazumi, H. J. Am.
Chem. Soc. 1999, 121, 1452.
9. Pei, C.-C.; Liu, R.-S. Org. Lett. 2001, 3, 1295.
10. Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99.
11. Determination of the ee values of compounds of 16–18
is performed on a Merck Chiralsphere column (diiso-
propyl ether/hexane=1/15–1/5).
References
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12. Spectral data: Spectral data for compound 16: [h]=
1
−13.7 (c 1.0, CHCl3); H (CDCl3, 400 MHz): l 5.68 (br
s, 1H), 4.52 (m, 1H), 4.18 (m, 1H), 3.98 (m, 1H), 3.37 (t,
J=8.8 Hz, 1H), 3.02 (m, 1H), 2.70 (m, 1H), 2.55 (m,
1H), 2.03 (m, 1H); 13C NMR (CDCl3, 100 MHz): l
177.7, 174.8, 131.7, 117.3, 79.9, 73.7, 42.7, 38.3, 31.3,
22.9; MS (70 eV, m/e): 194 (M+). Anal. calcd for
C10H10O4: C, 61.85; H, 5.19; Found: C, 61.78; H, 5.17.
Compound 17: [h]=−15.2 (c 1.0, CHCl3); 1H (CDCl3,
400 MHz): l 5.80 (br s, 1H), 4.67 (m, 1H), 4.42 (t,
J=6.8 1 Hz, 1H), 3.74 (t, J=7.2 Hz, 1H), 3.53 (m, 1H),
3.18 (m, 1H), 2.79 (s, 1H), 2.63 (m, 1H), 2.34 (m, 1H),
2.10 (m, 1H); 13C NMR CDCl3, 100 MHz: l 178.7,
174.1, 137.3, 117.4, 79.0, 75.9, 43.0, 40.0, 32.2, 24.9; MS
(70 eV, m/e): 193 (M+). Anal. calcd for C10H11NO3: C,
62.17; H, 5.74; Found: C, 62.12; H, 5.79. Compound 18:
[h]=−23.7 (c 1.0, CHCl3); 1H (CDCl3, 400 MHz): l
7.17–7.48 (m, 5H), 5.78 (m, 1H), 4.65 (m, 1H), 4.50 (m,
1H), 3.72 (m, 1H), 3.66 (q, J=8.8 Hz, 1H), 3.52 (t,
J=7.2 Hz, 1H), 3.24 (m, 1H), 2.91 (m, 1H), 2.61 (m,
1H), 2.18 (m, 1H); 13C NMR (CDCl3, 100 MHz): l
179.0, 175.0, 137.9, 131.9, 128.3, 127.6, 126.6, 117.3,
79.0, 75.4, 42.4, 39.4, 32.2, 25.0; MS (70 eV, m/e): 269
(M+). Anal. calcd for C16H15NO3: C, 71.36; H, 5.61;
Found: C, 71.32; H, 5.60%.
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