Convergence in [2+2+2] synthesis of β-phenylnaphthalene motif in polyaromatic natural products

Article abstract of DOI:10.1016/j.tetlet.2006.06.078

Two optional routes to β-phenylnaphthalene structure are developed by introducing α- and β-styryl groups onto different positions in the benzocyclobutene ring followed by ring enlargement.

Full text of DOI:10.1016/j.tetlet.2006.06.078

Tetrahedron Letters 47 (2006) 6673–6676
Convergence in [2+2+2] synthesis of b-phenylnaphthalene motif
in polyaromatic natural products
Isao Takemura, Koreaki Imura, Takashi Matsumoto and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and SORST, Japan Science and Technology Agency (JST),
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Received 27 April 2006; revised 12 June 2006; accepted 15 June 2006
Available online 18 July 2006
Abstract—Two optional routes to b-phenylnaphthalene structure are developed by introducing a- and b-styryl groups onto different
positions in the benzocyclobutene ring followed by ring enlargement.
Ó 2006 Elsevier Ltd. All rights reserved.
b-Phenylnaphthalene is a structure commonly found in
various polyketide-derived polyaromatic natural prod-
ucts (Fig. 1).1 We previously reported an approach to
this motif by assembling three two-carbon units, benz-
yne I, olefin II, and a styryl group IV (Scheme 1), by
which the above structure is accessible as its dihydro
form.2,3 Thanks to the inherent selectivities of the reac-
tions and also by proper choice of reaction partners, one
could not only divergently construct various related
structures, but also devise optional routes convergent
to a single skeleton, albeit with subtle differences in sub-
stitution or oxidation patterns.
This letter focuses the latter aspect of the approach;
introduction of a- and b-styryl groups onto different
positions in the benzocyclobutene ring leads, after
ring expansion stage, to the same skeleton, VIIa and
VIIb.
step 1
+
[2 + 2]
I
II
III
step 2
HO
OMe
O
IV
Me
OH
OMe
OMe
O
O
HO
O
O
Me
OH
OH
Va
Vb
AcO
Me2N
ravidomycin
celebaquinone
step 3
step 3
O
OH
OH
HO
HO
HO
O
O
OH
MeO
VIa
VIb
OH
MeO
O
HO
O
OH
OH
pradimicinone
PD116704
Figure 1.
VIIa
VIIb
*
Corresponding author. Tel.: +81 5734 2228; fax: +81 3 5734 2788;
email: ksuzuki@chem.titech.ac.jp
Scheme 1. Convergence in [2+2+2] approach.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.078

6674
I. Takemura et al. / Tetrahedron Letters 47 (2006) 6673–6676
OMe
Me3Si
OMe
OMe
To address such scenario, we examined two optional
synthetic routes to a model tetracyclic lactone 1, remi-
niscent of the gilvocarcin–ravidomycin class antibiotics.4
The routes differ in the initial connectivity of the benzo-
cyclobutenedione unit A and the styryl unit B as shown
by two arrows, a and b (Fig. 2).
HO
Br
a, b
c, d
MeO2C
MeO2C
MeO2C
2
3
4
h–k
OMe
e–g
OMe
H
For the selective bond connection at the two carbonyls
in unit A, we used a set of mono-protected benzocyclo-
butenediones, A1 and A2, available via the regioselective
[2+2] cycloaddition of a-alkoxybenzynes and ketene
silyl acetals.5 Thus, the question was centered at their
partners, that is, the styryl anion equivalents B1 and
B2, suitable for coupling with A1 and A2, for the pro-
jected ring enlargement to phenylnaphthalenes A1B1
and A2B2 (Scheme 2). Note that two routes, if viable,
lead to the same skeleton, but with different protection
patterns for phenols (R, R0).
Br
O
O
O
O
6
5
Scheme 3. Reagents and conditions: (a) Tf2O, (i-Pr)2NEt, CH2Cl2,
ꢀ78 °C (97%); (b) Me3SiC„CH, cat. (Ph3P)2PdCl2, DMF, 90 °C
(85%); (c) K2CO3, MeOH (quant.); (d) Et4N+(HBr2)ꢀ, CH2Cl2 (95%);
(e) LiAlH4, THF, ꢀ78 ! 0 °C (98%); (f) MnO2, CHCl3, reflux (94%);
(g) 1,3-propanediol, cat. TsOH, toluene, reflux (89%); (h) LiAlH4,
THF, ꢀ78 ! ꢀ20 °C (97%); (i) MnO2, CHCl3, reflux (86%); (j)
K2CO3, MeOH (98%); (k) 1,3-propanediol, cat. TsOH, toluene, reflux
(98%).
Herein, we report the realization of both of these routes,
and their comparison within the synthesis of model lac-
tone 1.
after desilylation of 3, selective addition of hydrogen
bromide to the triple bond was achieved by using
Et4N+(HBr2)ꢀ,8 giving vinyl bromide 4 in excellent
yield. Conversion of 4 to styryl bromide 5 was effected
by reduction with LiAlH4, oxidation of the resulting
benzyl alcohol followed by acetalization.
Scheme 3 shows divergent preparation of styryl bromide
5 and acetylene 6, which were used as precursors of an-
ions B1 and B2 (as its equivalent, vide infra) for intro-
ducing a styryl group at the internal or the terminal
position, respectively. Phenol 26 was converted to the
corresponding triflate, which was subjected to Sono-
gashira reaction7 with Me3SiC„CH to give acetylene
3, which served as the divergent point to 5 and 6. Thus,
On the other hand, acetylene 6 was also prepared from 3
in high yield by desilylation and conversion of the ester
moiety into acetal in a similar manner as above.
Scheme 4 shows route a by the A1–B1 combination.
Halogen–lithium exchange of styryl bromide 5 (t-BuLi,
Et2O, ꢀ78 °C, 10 min) followed by addition of ketone
A1 (ꢀ78 °C, 5 min) gave adduct 7 in 90% yield. Upon
heating (toluene, reflux, 7.5 h), benzocyclobutenol 7
underwent clean ring expansion, giving naphthol 8 in
96% yield. Thus, the expected sequential ring opening
of the benzocyclobutene ring and the 6p-electrocycliza-
tion occurred smoothly, which was followed by in situ-
elimination of an equivalent of methanol to complete
MeO
OMe
MeO
O
O
b
or
a
OMe
OMe
A
O
O
OHC
B
1
Figure 2.
MeO
MeO
OMe
OMe
MeO
OMe
O
OMe
MeO
OMe
OMe
OMe
A2
O
O
OMe
A1
A1
MeO
MeO
O
HO
Br
OMe
O
a
b
t
-BuLi, Et2O
—78 °C
O
OMe
O
O
O
O
O
7 90%
B1
B2
5
MeO
OR
MeO
OMe
OMe
OMe
toluene
110 °C
R'O
7.5 h
96%
HO
O
O
O
O
A1B1: R = Me, R' = H from a
A2B2: R = H, R' = Me from b
8
Scheme 2.
Scheme 4. Combination of units A1–B1.

I. Takemura et al. / Tetrahedron Letters 47 (2006) 6673–6676
6675
MeO
OMe
the aromatization. It should be noted that full aromati-
zation at the final stage is the long-term reflection of
high oxidation state of the starting material A1.
1
OMe
8
MeO
O
O
O
OMe
Scheme 5 shows another unit combination, A2–B2. Intro-
duction of the styryl unit at its terminal position was ef-
fected in an indirect way by using an acetylide addition
followed by hydroalumination. Thus, lithiation of acet-
ylene 6 (n-BuLi, THF, ꢀ78 °C, 5 min) followed by treat-
ment with ketone A2 (ꢀ78 ! 0 °C, 75 min) cleanly gave
propargyl alcohol 9 in 89% yield. Hydroalumination of
9 (LiAlH4, THF, ꢀ78 ! 0 °C, 4 h) gave benzocyclo-
butenol 10 with an (E)-styryl group,9 ready for the key
ring expansion reaction. Again, upon heating compound
10 in toluene for 2.5 h, the ring enlargement smoothly
proceeded, which was accompanied by in situ-elimina-
tion of methanol to give arylnaphthalene 11 in 94%
yield.
OH
12
HC
13
O
Scheme 6.
ification of the resulting carboxylic acid with TMS–dia-
zomethane gave methyl ester 15 in high overall yield.
Finally, removal of the acetyl group in basic methanol
followed by acidification gave lactone 1 in 80% yield.
By contrast, the conversion of the isomeric arylnaphthal-
ene 11 (see Scheme 5) into lactone 1 appeared to be less
straightforward in view of its protection pattern. One
can, nevertheless, devise an effective route by using a
‘trick’ prior to the ring expansion: replacement of the di-
methyl acetal in 9 by a 1,3-dioxane acetal (Scheme 8).
Both approaches proved to work fine, giving a pair of
isomeric phenylnaphthalenes 8 and 11 in high yields.
The semi-convergence should be noted in the fact that
isomeric starting materials converged to two arylnaph-
thalenes 8 and 11, which share the same oxygenation pat-
tern, but with different protection pattern.
MeO
OMe
MeO
OMe
Our attention was turned to test their conversion to the
model target 1. Upon simple comparison of the protec-
tion pattern of 8 and 11, it seemed that 8 would be more
easily convertible to 1, as only two steps would be for-
mally necessary: the acetal hydrolysis and oxidation,
which turned out to be not the case.
OMe
OMe
c,d
a,b
HO
AcO
HC
O
O
O
8
14
MeO
OMe
MeO
OMe
Although acetal 8 was hydrolyzed (3 M aq HCl, THF,
77% yield) without event, the resulting lactol 12 failed
to be oxidized under various conditions. For example,
treatment of 12 with PCC (CH2Cl2, 8 h) gave none of
lactone 1, but instead gave quinone 13 in quantitative
yield (Scheme 6).
OMe
OMe
e
AcO
MeO2C
O
O
15
1
Scheme 7. Reagents and conditions: (a) Ac2O, 4-DMAP, pyridine
(97%); (b) 80% aq AcOH (97%); (c) NaClO2, NaH2PO4, 2-methyl-2-
butene, H2O, acetone; (d) Me3SiCHN2, MeOH, benzene (89%, two
steps); (e) K2CO3, MeOH, reflux; then 2 M aq HCl, 0 °C (80%).
This detour was solved as in Scheme 7. Acetylation of
phenol 8 and hydrolysis of the acetal gave aldehyde
14. Oxidation of 14 was effected by NaClO2, and ester-
MeO
O
MeO
O
MeO
MeO
MeO
OH
MeO
OMe
MeO
MeO
a–c
OH
OMe
OMe
A2
O
O
O
LiAlH4, THF
83%
OMe
O
O
OMe
H
OMe
9
16
O
OMe
n
-BuLi, THF
O
–78 ˚C
MeO
OMe
MeO
OMe
9 89%
O
OMe
OMe
d
e
O
6
MeO
OH
MeO
OH
HO
O
O
HO
O
MeO
OMe
O
O
toluene
110 ˚C
17
8
2.5 h
OMe
MeO
O
O
94%
OMe
Scheme 8. Reagents and conditions: (a) 1,3-propanediol, cat. CSA,
THF, 50 °C (87%); (b) LiAlH4, THF, ꢀ78 °C ! rt (95%); (c) n-BuLi,
Et2O, ꢀ78 °C; then MeOTf, ꢀ78 °C ! rt (90%); (d) toluene, 110 °C,
2.5 h (97%); (e) SO3Æpyridine, Et3N, DMSO, rt, 8 h (64%).
O
O
10
11
Scheme 5. Combination of units A2–B2.

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I. Takemura et al. / Tetrahedron Letters 47 (2006) 6673–6676
Ishikawa, Y.; Tsuruta, H.; Suzuki, K. Angew. Chem., Int.
Ed. 2004, 43, 3167–3171.
Hydroalumination and methylation gave the modified
substrate 16 in high yield. Thermal reaction of 16 (tolu-
ene reflux, 2.5 h) proceeded smoothly to give naphthal-
ene 17 in 97% yield. Treatment of alcohol 17 with
SO3Æpyridine (Et3N, DMSO) effected oxidation of the
c-(aryloxy)propanol moiety and the b-elimination to
provide 8, which was identical with the sample shown
in Scheme 4, convertible by the same sequence of reac-
tions (Scheme 7) into the model lactone 1.
3. For reviews on the related reactions, see: (a) Moore, H. W.;
Yerxa, B. R. Chemtracts 1992, 5, 273–313; Liebeskind, L. S.
Tetrahedron 1989, 45, 3053–3060; For leading references,
see: (b) Jackson, D. K.; Narasimhan, L.; Swenton, J. S. J.
Am. Chem. Soc. 1979, 101, 3989–3990; Liebeskind, L. S.;
Iyer, S.; Jewell, C. F., Jr. J. Org. Chem. 1986, 51, 3065–
3067; Hickman, D. N.; Wallace, T. W.; Wardleworth, J. M.
Tetrahedron Lett. 1991, 32, 819–822; Perri, S. T.; Foland, L.
D.; Decker, O. H. W.; Moore, H. W. J. Org. Chem. 1986,
51, 3067–3068; For our contribution in this area, see: (c)
Matsumoto, T.; Hamura, T.; Miyamoto, M.; Suzuki, K.
Tetrahedron Lett. 1998, 39, 4853–4856; Hamura, T.;
Miyamoto, M.; Matsumoto, T.; Suzuki, K. Org. Lett.
2002, 4, 229–232; Hamura, T.; Miyamoto, M.; Imura, K.;
Matsumoto, T.; Suzuki, K. Org. Lett. 2002, 4, 1675–1678.
4. For reviews on the gilvocarcin–ravidomycin-type antibiot-
ics, see: (a) Hua, H. H.; Saha, S. Recl. Trav. Chim. Pays-Bas
1995, 144, 341–355; For the total synthesis of gilvocarcin M
and V, see: (b) Matsumoto, T.; Hosoya, T.; Suzuki, K. J.
Am. Chem. Soc. 1992, 114, 3568–3570; Hosoya, T.; Taka-
shiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc.
1994, 116, 1004–1015; For the total synthesis of ravidomy-
cin, see: (c) Futagami, S.; Ohashi, Y.; Imura, K.; Ohmori,
K.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41,
1063–1066.
In conclusion, two viable, complementary routes have
been described for the synthetic approach to the b-phen-
ylnaphthalene structure motifs embedded in various
polyaromatic natural products.
Acknowledgement
Partial financial support by 21st Century COE Program
is gratefully acknowledged.
References and notes
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