Cycloadditions of o-quinone dimethides with p-quinol derivatives: Regiocontrolled formation of anthracyclic ring systems

Article abstract of DOI:10.1016/j.tetlet.2003.12.114

Regioselective cycloadditions between the cyclohexadienones 12-14 and the ortho-quinone dimethide 19, which is thermally generated from the corresponding 1,3-dihydro-1-methoxy-2,2-dioxide benzo[c]thiophene 27, are reported. The synthetic sequence provides

Full text of DOI:10.1016/j.tetlet.2003.12.114

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1793–1796
Cycloadditions of o-quinone dimethides with p-quinol derivatives:
regiocontrolled formation of anthracyclic ring systemsq
Junhua Wang, Liping H. Pettus and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106-9510 USA
Received 2 October 2003; revised 5 December 2003; accepted 5 December 2003
Abstract—Regioselective cycloadditions between the cyclohexadienones 12–14 and the ortho-quinone dimethide 19, which is
thermally generated from the corresponding 1,3-dihydro-1-methoxy-2,2-dioxide benzo[c]thiophene 27, are reported. The synthetic
sequence provides rapid access to highly substituted anthracyclic system and may be of use for construction of the natural product
(+)-rishirilide B.
Ó 2003 Elsevier Ltd. All rights reserved.
O
The most obvious disconnection for a synthesis of
rishirilide B (1) results in the highly oxidized cyclohex-
enone 4 and the isobenzofuran-4-ol 3 (Fig. 1). Unfor-
δ–
CH3
δ+
O
CO2H
HO
OH
tunately, the alcohol functional group present on the
isobenzofuran-4-ol 3 would determine the regiochemical
outcome of this hypothetical union and lead to the
undesired regioisomer 2.1 A variety of other natural
products containing anthracyclic ring systems pose a
similar regiochemical challenge.
fgdr
OH
4
3
O
OH
O
CH3
CH3
Several elegant solutions to this regiochemical dilemma
have recently appeared. Hauser and Xu use the iso-
benzofuranone enolate 5 with the enone 7 to ensure the
desired regiochemical outcome of 8 despite the influence
of the aryl methoxy residue (Scheme 1).2 Swenton and
co-workers3 and Baker and co-workers4 have indepen-
dently utilized this strategy with the related nitrile 6 in
highly efficient syntheses of hydroxypthalides and hong-
conin, respectively.
CO2H
CO2H
HO
HO
preferred 2
OH
OH
OH
1: (-)-rishirilide B
fgdr = functional group directing regiochemistry
Figure 1. Regiochemical challenge posed by rishirilide B (1).
fgdr
red
overrides
blue
O
OH
O
However, use of the isobenzofuranone enolates 5 and 6
introduce several problems if applied in the synthesis of
1. First, erasure of the hydroquinone functionality in 8
requires many synthetic manipulations. Second, the
preparation of the methoxy-substituted isobenzofura-
none 5 and 6 proves tedious.5 A recent Suzuki synthesis
of these derivatives, which involves an efficient desym-
OLi
CH3
CH3
+
δ+
O
δ–
Z
CO2Me
CO2Me
-78 ˚C
OMe OAc
7
OMe
then Ac2O
8
5: Z = -SO2Ph
6: Z = -CN
Scheme 1. Hauser assembly of tricycle used in synthesis of rishirilide B
(1).
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.12.114
metrization of 2-iodo-resorcinol (Fig. 2), is perhaps the
most efficient assembly process leading to enolates 5 and
6.6
* Corresponding author. Tel.: +1-805-893-5531; fax: +1-805-893-5690;
e-mail: pettus@chem.ucsb.edu
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.114

1794
J. Wang et al. / Tetrahedron Letters 45 (2004) 1793–1796
MeO
n-BuLi
OMe
OMe
cis-cyclobutene product divert material from the syn-
thetic stream.
OTf
I
1) Tf2O, i-PrNEt
2) Cs2CO3
OH
I
1)
TMSO
2) KF
3) (MeO)2SO2, K2CO3
With knowledge of the factors responsible for regio-
chemical control and the difficulty of associated with
construction of the prospective coupling partners, we
began investigating similar reactions with regards to the
novel p-quinol derivatives 12–14 (Scheme 3). Initially,
we were concerned that 12–14 might not readily undergo
a [4+2] cycloadditions with o-quinone dimethides,
because similar systems proved sluggish in their cyc-
loadditions.9 Therefore, we first investigated the reac-
tivity of these p-quinol derivatives with the
furanoenolates 15 and 16. While the isobenzofuranone
enolate 15 failed to undergo addition to 12, the less
encumbered nitrile derivative 16 participates in the
desired Michael–Dieckman process. Instead of the
anticipated tautomer 17, however, the anthraquinone 18
emerges as the sole product. Because this ring forming
process destroyed the stereocenter intended to direct the
creation of subsequent stereocenters, other annulation
reactions were investigated.
OMe
OH
OMe
O
OMe
1) MMPP, Na2HPO4
1) NaBH4 then HCl
2) Ac2O, DMAP
2) Z-H
O
O
OAc
OMe
OMe
Z = –CN
O
Z = –SPh
Z = –SO2Ph
m-CPBA
Z
OMe
Figure 2. Suzuki synthesis of precursors to furanoenolates 5 and 6.
Danishefsky and co-workers demonstrated another
solution to the regiochemical problem presented by
rishirilide B (1).7 In their total synthesis of ())-(1), the
(E,Z)-o-quinone dimethide 9 undergoes an endo oriented
[4+2] cycloaddition with 10. Because the directing effects
of the methide siloxy residues cancel-out, the siloxy
substituent on the benzene ring of 9 determines the
regiochemical preference with regards to the o-quinone
dimethide 9, while an internal hydrogen bond attenuates
the electrophilicity and determines the regiochemical
preference with regards to the cyclohex-2-ene-1,4-dione
10 (Scheme 2). The cycloaddition between compounds 9
and 10 results almost exclusively in the regioisomer 11;
the methine stereocenter adjacent to the protonated
carbonyl most likely arises from a post cycloaddition
epimerization.
While the combination of 9 and any of our p-quinol
derivatives 12–14 would likely lead to the undesired
regiochemistry, we speculated the cycloaddition of the
p-quinol derivatives 12–14 with the unknown o-quinone
fgdr
OH
OH
O
OLi
O
O
O
Z
Y
–
δ
This elegant strategy, however, is not without problems.
The trans-substituted cyclobutene precursor to 9 is dif-
ficult to prepare and its synthesis results in some of the
corresponding cis-substituted cyclobutene (Fig. 3).
Because cyclobutenes thermally open by a conrotary
motion and the fact that only trans-substituted cyclo-
butenes afford geometrically disposed o-quinone dimet-
hide capable of cycloaddition,8 the long route and
O
O
X
O
15 X = –SO2Ph
16 X = –CN
O
O
not
17
12 Y= -Me, Z = -H
13 Y = Z = -Br
14 Y = –Br, Z = -H
isolated
O
OH
O
O
OH
18 (82% from 12+16)
O
Scheme 3. Anthraquinone emerges upon our addition of 16–12.
O
O
OTBS
TBSO
TBSO
O
O
(E)
H
+
–
Me
δ
δ
90 ˚C
+
CO2TSE
O
CO2TSE
O
(Z)
H
TBSO
OTBS
TBSO
H
H
11
9
fgdr
10
fgdr
Scheme 2. Danishefsky assembly of the rishirilide B core.
OMe
OMe
Br
NaI
AgBF4
MeOH
NBS, hν
DMF
AIBN
Br
OMe
OMe
OMe
1) AgOAc, HOAC, H2O
2) NaOMe
X
X
3) Swern
4) 48% HBr
5) TBSOTf
X
OR
X
6:1 / trans:cis
OTBS
OR
O
geometric isomers of o-quinone
dimethides reported to be unproductive
in [4+2] cycloadditions
1) NaBH4
2) TBSOTf
O
OTBS
OTBS
OTBS
Figure 3. Danishefsky preparation of cyclobutene precursor to 9.
Scheme 4. Our revised strategy for rishirilide B core.

J. Wang et al. / Tetrahedron Letters 45 (2004) 1793–1796
1795
O
O
OMe
H
identity of enone 21, compound 20 is converted into 21
(80% yield) by the addition of PPh3 in MeOH.10 Inde-
pendent treatment of 21 and 22 with DDQ in benzene
affords compounds 23 and 24 in 87% and 91% yield,
respectively.11
X
X = –Br or –CH3
chromatography
14 + 27
12 + 27
ZnO, 110˚
toluene
O
H
on silica gel
or CF3CO2H
OMe
DDQ
O
O
O
O
X
X
O
When compared with the two previous strategies, sev-
eral benefits of our approach become apparent. First, an
o-quinone dimethide masked as a 1,3-dihydro-1-meth-
oxy-2,2-dioxide benzo[c]thiophene can be generated
under milder conditions (0.5 M in toluene, 1 equiv ZnO,
reflux 110 °C).12 Second, a Durst–Charlton o-quinone
dimethide is more accessible than 9 or the isobenzof-
uranone enolates 5 and 6. As illustrated in Scheme 6,
a three-pot method provides the previously unknown
o-quinone dimethide precursor 27. The route begins
with a Comins process for in situ protection of the com-
mercially available aldehyde 25 followed by subsequent
ortho- directed aryl lithiation and methylation to afford
the benzaldehyde 26 in >87% yield.13 Photolysis of 26
(0.1 M benzene, 2.5 equiv SO2, 450 W Hg lamp, 0 °C,
8 h) produces the corresponding hemi-hydrate, which
upon addition of MeOH and p-TsOH generates 27 in a
75% overall yield. Lastly, because the o-quinone
dimethide precursor 27 is not a diastereomeric mixture,
all of it enters the synthetic stream as 19 leading to 1.
H
O
OMe
OMe
O
O
O
21: X=Br (84%)
22: X=Me (72%)
23: X=Br (87%)
24: X=Me (91%)
Scheme 5. Our cycloadditions of o-DM 19 with p-quinols 12 and 14.
OMe
N
CHO
CHO
Li
N
1) SO2, 450W Hg-hν
SO2
3 eq PhLi
MeI 87%
2) MeOH, pTSA
75% overall
OR
25 R=Me
OR
26 R=Me
OR
27 R=Me
ZnO, 110 ˚C
fgdr
OR
OR
19 R=Me
Scheme 6. Our synthesis of the Durst–Charlton type of precursor to
19.
With regards to the preparation of the p-quinol deriva-
tives 12–14 were used in this study, these are available in
>68% yield by oxidation of the corresponding phenols
34–36 [0.01 M in CH3NO2, 1.1 equiv of PhI(OCOCF3)2,
0 °C] (Scheme 7). We find the presence of a substituent
larger than a hydrogen atom at the [Y] position in
the phenol precursor greatly improves the yields of the
dearomatization–lactonization protocol by >20%.9 The
phenols 34–36 are constructed from 32 to 33 by intro-
duction of the amide side chain 37 via a Finkelstein
dimethide 19 might prove fruitful (Scheme 4). The out-
come, however, was by no means certain as the directing
effects of the methoxy residues in 19 opposed one
another. We anticipated that the methide methoxy res-
idue would play a greater role because of its proximity
to the reaction sites.
The cycloaddition of the bis-bromide 13, presumably the
most reactive among the three p-quinol derivatives, was
the first we investigated. Gratifyingly, the reaction
between 13 and 19, which is thermally generated from 27
(Scheme 6), proceeds smoothly and affords 20 in 80%
yield (Scheme 4). None of undesired regioisomer is evi-
dent upon inspection of the crude NMR spectra for the
reaction. The structure of the product 20 was unequiv-
ocally established by X-ray analysis. Similar conditions
for cycloaddition are almost equally effective with the
p-quinols 14 and 12 (Scheme 5). These latter two com-
pounds were initially expected to be somewhat less
reactive than the bis-bromoenone 13. Fortunately, both
14 and 12 are smoothly annulated by 19. However, upon
chromatography on silica gel the initial cycloadducts
undergo b-elimination of their respective methoxy resi-
dues resulting in the corresponding enones, 21 (84%
yield) and 22 (72% yield).à To further substantiate the
procedure and subsequent cleavage of the –OBoc resi-
14e
due by action of aq HCl in dioxane.
Bromination of
35 affords 36. The phenols 32–33 are available from the
bis-Boc aldehydes 30–31 through a process that involves
OBOC
OH
X
Y
X
Y
BOC2O, Hünig's Base
DMAP
OBOC
OH
H
O
H
O
30: X = –H, Y = –CH3
31: X = –H, Y = –Br
28: X = –H, Y = –CH3
29: X = –H, Y = –Br
1) NaBH4
2) 2.3 eq. (CH3)2CH2MgBr
OH
OBOC
1) K2CO3
X
Y
N
X
Y
37
Cl
n-Bu4NI
N
O
O
OH
O
2) HCl dioxane
Br2/HOAc
34: X = –H, Y = –CH3
35: X = –H, Y = –Br
36: X = –Br, Y = –Br (65% from 35)
Data for compound 20 has been filed with the Cambridge Crystal-
lographic Data Centre and can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk).
32: X = –H, Y = –CH3
33: X = –H, Y = –Br
PhI(OCOCF3)2
CH3NO2
then H2O
O
X
Y
12: X = –H, Y = –CH3 (72% from 34)
13: X = –Br, Y = –Br (42% from 33)
14: X = –H, Y = –Br (68% from 35)
O
à
The ratio of the adduct containing the methoxy residue and the
O
enone elimination product varies among reactions. However, the
former can be transformed into the latter by addition of CF3COOH
upon completion of the cycloaddition.
O
Scheme 7. Our synthesis of p-quinol derivatives 12–14.

1796
J. Wang et al. / Tetrahedron Letters 45 (2004) 1793–1796
an o-quinone methide intermediate.14 The benzaldehy-
des 28 and 29 and amide 37 are known compounds.15;16
5. Bates, M. A.; Sammes, P. G.; Thomson, G. A. J. Chem.
Soc., Perkin Trans. 1 1988, 3037.
6. Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama, Y.;
Tanabe, M.; Miyamoto, M.; Yasui, Y.; Matsumoto, T.;
Suzuki, K. Helv. Chim. Acta 2002, 85, 3589.
7. (a) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001,
123, 351–352; (b) Yamamoto, K.; Hentemann, M. F.;
Allen, J. G.; Danishefsky, S. J. Chem. Eur. J. 2003, 9,
3242–3252.
A method for the enantioselective preparation of com-
pounds resembling 23 and 24 will be reported shortly.9b
The conversion of these compounds into 1 will be
reported in due course.
8. Sammes, P. G. Tetrahedron 1976, 32, 405.
9. (a) Van De Water, R. W.; Hoarau, C.; Pettus, T. R. R.
Tetrahedron Lett. 2003, 44, 5109–5113; (b) Mejorado, L.;
Pettus, T. R. R. Unpublished results.
10. Borowitz, I. J.; Kibby, K. C., Jr., Virkhalls, R. J. Org.
Chem. 1966, 31, 4031.
Supplementary information
Key spectroscopic data and experimental procedures for
the construction of 27, 28–37, 12–14, and 20–24 are
reported and are available for download.
11. Zimmerman, H. E.; Cassel, J. M. J. Org. Chem. 1989, 54,
3800.
12. Durst, T.; Kozma, E. C.; Charlton, J. L. J. Org. Chem.
1985, 50, 4829–4833.
Acknowledgements
13. (a) Comins, D. L.; Brown, J. D. J. Org. Chem. 1989, 54,
3730–3732; (b) Compound 26 can also be constructed
according to: Leeds, A. R.; Boettger, S. D.; Ganem, B. J.
Org. Chem. 1980, 45, 1098.
Research Grants from NIH (GM-64831) and UC-AIDS
(K00-SB-039) are greatly appreciated.
14. (a) Pettus, T. R. R.; Van De Water, R. W.; Magdziak, D.;
Chau, J. J. Am. Chem. Soc. 2000, 122, 6502–6503; (b)
Jones, R. M.; Van De Water, R. W.; Lindsey, C.; Hoarau,
C.; Ung, T.; Pettus, T. R. R. J. Org. Chem. 2001, 66, 3435–
3441; (c) Tuttle, K.; Rodriguez, A. A.; Pettus, T. R. R.
Synlett 2003, 2234–2237; (d) Hoarau, C.; Pettus, T. R. R.
Synlett 2003, 127–137; (e) Lindsey, C.; Gomez-Diaz, C.;
Villalba, J. M.; Pettus, T. R. R. Tetrahedron 2002, 58,
4559–4565.
References and notes
1. Brizzi, R. S.; Roos, G. H. P. S. Afr. J. Chem. 1985, 38,
150–152.
2. Hauser, F. M.; Xu, Y.-J. Org. Lett. 1999, 1, 335–336.
3. Freskos, J. N.; Morrow, G. W.; Swenton, J. S. J. Org.
Chem. 1985, 50, 805–810.
15. Chen, W.-M. Indian J. Chem., Sect. B 1996, 35B, 1085–
1087.
16. Bui, E.; Bayle, J. P.; Perez, F.; Liebert, L.; Courtieu J. Liq.
Cryst. 1990, 8, 513–526.
4. Deshpande, P. P.; Price, K. N.; Baker, D. C. J. Org. Chem.
1996, 61, 455.