Intramolecular Diels-Alder reactions of masked p-benzoquinones: A novel methodology for the synthesis of highly functionalized cis-decalins

Article abstract of DOI:10.1039/b000248h

Tethering of dienols to hydroquinones under Mitsunobu conditions followed by oxidation with diacetoxyiodobenzene in methanol resulted in the development of highly functionalized cis-decalins via intramolecular Diels- Alder reactions of in situ generated m

Full text of DOI:10.1039/b000248h

Intramolecular Diels–Alder reactions of masked p-benzoquinones: a novel
methodology for the synthesis of highly functionalized cis-decalins
Yow-Fu Tsai, Rama Krishna Peddinti and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300. E-mail: ccliao@mx.nthu.edu.tw
Received (in Cambridge, UK) 4th January 2000, Accepted 25th January 2000,
Published on the Web, 2nd March 2000
Tethering of dienols to hydroquinones under Mitsunobu
conditions followed by oxidation with diacetoxyiodobenzene
in methanol resulted in the development of highly function-
alized cis-decalins via intramolecular Diels–Alder reactions
of in situ generated masked p-benzoquinones.
Because of their widespread occurrence in a large variety of
natural products of biological importance, decalins remain a
focus of attention for synthetic organic chemists.1–3 Function-
alized decalins with proper stereochemistry are possible
intermediates for several terpenoids possessing biological
activity. Not surprisingly, there has been a great deal of interest
in developing methodologies for their synthesis, as evidenced
by the growing number of reports in this area.4–8 Most recently,
we have shown that masked o-benzoquinones (MOBs), i.e.
Scheme 1 Reagents and conditions: i, DAIB, solvent, room temp., 2 h.
Scheme 2 Reagents and conditions: i, PPh3, DEAD, THF.
Attempts to improve the yields by changing the reaction
conditions were not successful. The use of DIAD in place of
DEAD produced slightly better yields. However, we have
conveniently produced the required phenols 13b–27b by
choosing selectively protected hydroquinones 10–12 as starting
materials for Mitsunobu reaction followed by saponification in
very good yields (Scheme 3, Table 1).
Masked p-benzoquinones 13c–27c generated via oxidation of
phenols 13b–27b (0.5 mM) in MeOH (50 ml) using DAIB (0.75
mM) as oxidant underwent intramolecular cyclization at room
temperature (Method A), or at reflux temperature in benzene
(Method B) or in toluene (Method C) to afford the cycloadducts
13d,e–27d,e in 78–90% yield (Scheme 3). Table 2 illustrates
typical results of the IMDA reactions of MPBs.
6,6-dialkoxycyclohexa-2,4-dienones, are efficient intermedi-
ates for the stereoselective synthesis of highly functionalized
cis-decalins.9 Herein, we report a novel method for the synthesis
of highly functionalized decalins via the intramolecular Diels–
Alder (IMDA) reactions of in situ generated masked p-
benzoquinones (MPBs), a class of cross-conjugated cyclohexa-
dienones. To the best of our knowledge this is the first detailed
study of IMDA reactions of MPBs.10
Over the past ten years we have been investigating the inter-
and intra-molecular Diels–Alder reactions of MOBs11 and their
synthetic potential has been exploited.12 In contrast to the case
of MOBs, the Diels–Alder chemistry of MPBs is less ex-
plored.13 This may be due to the fact that the lesser reactivity of
MPBs often requires harsh reaction conditions like high
pressure13a or high temperature13c,d with prolonged reaction
times. We envisioned that this problem could possibly be
overcome by performing these reactions in an intramolecular
fashion14 via the in situ generation of MPBs by oxidizing p-
methoxyphenols with diacetoxyiodobenzene (DAIB) in the
presence of a dienol in a tandem oxidative acetalization process
that would furnish stereoselective and highly functionalized cis-
decalins.
The gross structures of all the IMDA adducts were deter-
1
mined by their IR, H and 13C NMR, DEPT, low- and high-
resolution mass spectral analyses. The stereochemistries of
As a prelude to this objective, we have carried out the
reactions of p-methoxyphenols 1 and 2 with 10 equiv. of sorbic
alcohol (6) in the presence of DAIB in different solvents, such
as THF, CF3CH2OH and CH2Cl2. We have isolated the adducts
3 formed via IMDA reaction of in situ generated MPBs in rather
poor yields (Scheme 1). Although the reasons for the lower
reactivity of 1 and 2 with 6 are not known at this point, it is
apparent that, unlike 2-methoxyphenols,11b 4-methoxyphenols
cannot undergo facile tandem IMDA reactions. Consequently,
we have switched our attention to tethering15 the diene moiety
to the hydroquinones via Mitsunobu reaction with dienols prior
to oxidation by DAIB. For this purpose, we have performed the
reactions of hydroquinone 4 and dienols 5–6 under Mitsunobu
conditions to obtain the products in 38–55% yields (Scheme 2).
Scheme 3 Reagents and conditions: i, PPh3, DIAD, THF, 5–9; ii, K2CO3,
MeOH, 0 °C; iii, DAIB, MeOH; iv, Methods A–C.
DOI: 10.1039/b000248h
Chem. Commun., 2000, 475–476
This journal is © The Royal Society of Chemistry 2000
475

Table 1 Synthesis of phenols 13b–27b
Phenols
Dienols
Dienyl ethers
Phenols
10–12
5–9
13a–27a (% yield)
13b–27b (% yield)
10
11
12
5
6
7
8
9
5
6
7
8
9
5
6
7
8
9
13a (82)
14a (86)
15a (84)
16a (87)
17a (78)
18a (87)
19a (85)
20a (85)
21a (83)
22a (74)
23a (85)
24a (83)
25a (85)
26a (83)
27a (75)
13b (98)
14b (98)
15b (97)
16b (99)
17b (99)
18b (81)
19b (85)
20b (85)
21b (88)
22b (76)
23b (98)
24b (96)
25b (97)
26b (97)
27b (99)
Fig. 2 Diels–Alder transition states.
transformation of transoid to cisoid conformation of the diene
units in MPBs 16c, 21c and 26c (R1 = R2 = H, R3 = Me)
required for Diels–Alder reaction needs more energy as
reflected by the reaction conditions employed (entries 4, 9 and
14). Owing to the disfavored interactions in their exo-transition
states (Fig. 2), endo-adducts 16d, 21d and 26d were formed
exclusively in these reactions.
In summary, we have shown for the first time that masked p-
benzoquinones tethered to a diene moiety undergo efficient
intramolecular cyclization to produce highly functionalized cis-
decalins in very good yields. Our methodology provides an easy
access to a series of stereoselective cis-decalins attached to five-
membered oxygen heterocycles which may otherwise be
difficult to synthesize. Further applications of MPBs in organic
synthesis are under investigation in our laboratory.
Table 2 IMDA reactions of MPBs 13c–27c generated from phenols 13b–
27b
Yield
(%)
Entry
Phenol
MPB
Methoda DA adduct
endo+exob
We thank the National Science Council (NSC) of the
Republic of China for financial support. R. K. P. thanks the NSC
for a post-doctoral fellowship.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
13c
14c
15c
16c
17c
18c
19c
20c
21c
22c
23c
24c
25c
26c
27c
B
A
B
C
A
B
A
B
C
A
A
A
A
Cc
A
13d + e
14d
15d + e
16d
17d
18d + e
19d
20d + e
21d
22d
23d + e
24d + e
25d + e
26d
88
90
85
80
78
85
84
88
79
79
83
87
88
83
82
1+1
1+0
3+1
1+0
1+0
1+1
1+0
Notes and references
1 J. R. Hanson, Nat. Prod. Rep., 1999, 16, 209 and references therein.
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109.
3 A. T. Merritt and S. V. Ley, Nat. Prod. Rep., 1992, 9, 243.
4 R. B. Grossman, R. M. Rasne and B. O. Patrick, J. Org. Chem., 1999,
64, 7173.
5 K. Ohrai, K. Kondo, M. Sodeoka and M. Shibasaki, J. Am. Chem. Soc.,
1994, 116, 11 737.
6 O. Z. Pereira and T. H. Chan, J. Org. Chem., 1994, 59, 6710.
7 H.-J. Liu and Y. Han, Tetrahedron Lett., 1993, 34, 423.
8 G. Müller and G. Jas, Tetrahedron Lett., 1992, 33, 4417.
9 P. D. Rao, C.-H. Chen and C.-C. Liao, Chem. Commun., 1998, 155;
P.-Y. Hsiu and C.-C. Liao, Chem. Commun., 1997, 1085; T.-H. Lee,
C.-C. Liao and W.-C. Liu, Tetrahedron Lett., 1996, 37, 5897.
10 A. E. Fleck, J. A. Hobart and G. W. Morrow, Synth. Commun., 1992, 22,
179.
2.5+1
1+0
1+0
1+1
1.2+1
2.5+1
1+0
27d + e
1+1
a All MPBs were generated at 0 °C and after usual workup, the crude residue
was used as such for Methods B and C. Method A: room temp., 15 min;
Method B: benzene, reflux, 4 h; Method C: toluene, reflux, 40 h.
b Determined by 1H NMR. c Reaction time: 18 h.
11 (a) C.-C. Liao, C.-S. Chu, T.-H. Lee, P. D. Rao, S. Ko, L.-D. Song and
H.-C. Shiao, J. Org. Chem., 1999, 64, 4102 and references therein;
(b) C.-S. Chu, T.-H. Lee, P. D. Rao, L.-D. Song and C.-C. Liao, J. Org.
Chem., 1999, 64, 4111; (c) M.-F. Hsieh, P. D. Rao and C.-C. Liao,
Chem. Commun., 1999, 1441; (d) C.-H. Chen, P. D. Rao and C.-C. Liao,
J. Am. Chem. Soc., 1998, 120, 13 254.
12 W.-C. Liu and C.-C. Liao, Chem. Commun., 1999, 117.
13 (a) E. R. Jarvo, S. R. Boothroyd and M. A. Kerr, Synlett, 1996, 897; (b)
R. A. Russel, D. A. C. Evans and R. N. Warrener, Aust. J. Chem., 1984,
37, 1699; (c) M. C. Carreno, F. Farina, A. Galan and J. L. G. Ruano,
J. Chem. Res., 1981 (S) 370; (M) 4310; (d) M. C. Carreno, F. Farina, A.
Galan and J. L. G. Ruano, J. Chem. Res., 1979, (S) 296; (M) 3443.
14 W. R. Roush, Combining C–C p-bonds, in Comprehensive Organic
Synthesis, ed. B. M. Trost, I. Fleming and L. A. Paquette, Pergamon,
Oxford, 1991, vol. 5, ch. 4.1.
Fig. 1 Reactivity series for the diene moiety.
endo-adducts 14d, 16d, 17d, 19d, 21d, 22d and 26d were
established by NOE studies. The endo-adduct 25d and the exo-
adduct 25e were separated from their mixture 25d + e by
recrystallizing from hexane–Et2O to afford the former as an oil
and the latter as crystals, and their stereochemistry was deduced
from NOE studies. The stereochemistry of 25e was further
confirmed from its single crystal X-ray structure.16 The endo
and exo ratios of cycloadducts from entries 1, 3, 6, 8, 11–13 and
15 were determined from their 1H NMR (400 MHz) spectra.
In the IMDA reactions of unsymmetrical MPBs 18c–22c and
23c–27c, the double bond with less electron density, i.e. the
unsubstituted double bond in 18c–22c and the CO2Me-
substituted double bond in 23c–27c, behaved as a dienophile.
The IMDA reactions of MPBs 23c–27c bearing an additional
electron-withdrawing group (CO2Me) (entries 11–15) are faster
than those of 13c–22c (entries 1–10), where such a group is not
present. The two sets of MPBs 13c–22c and 23c–27c show
comparable reactivities. It appears that the reactivity pattern
mainly depends on the tethered diene unit and could be
explained on the basis of the position of the substituents
attached to the diene moiety,17 as shown in Fig. 1.
15 D. R. Gauthier Jr., K. S. Zandi and K. J. Shea, Tetrahedron, 1998, 54,
2289; M. Bols and T. Skrydstrup, Chem. Rev., 1995, 95, 1253.
16 Crystal data for 25e: C15H18O5, M = 278.3. monoclinic, a = 9.1424(4),
b = 11.5049(5), c = 13.4460(6) Å. b = 101.281(1)°, V = 1387.0(4)
Å3, T = 296 K, space group P21/n, Z = 4, m(Mo-Ka) = 0.100 mm21
.
8056 reflections measured, 3010 unique (Rint = 0.0325), final R indices
[I ! 3s(I)] R1 = 0.0436, wR2 = 0.0492. CCDC 182/1531. See http://
www.rsc.org/suppdata/cc/b0/b000248h/ for crystallographic files in .cif
format.
17 R. Sustmann and R. Schubert, Angew. Chem., Int. Ed. Engl., 1972, 11,
840.
In most of the cases studied, the endo-adduct was obtained as
either the sole product or the predominant product. The
Communication b000248h
476
Chem. Commun., 2000, 475–476