Synthetic study of aquayamycin. Part 1: Synthesis of 3-(phenylsulfonyl)phthalides possessing a β-C-olivoside

Article abstract of DOI:10.1016/S0040-4039(00)01478-7

An efficient synthetic route to 3-(phenylsulfonyl)phthalides possessing a β-C-olivoside was developed by exploiting the regioselective [2+2] cycloaddition of benzyne with ketene silyl acetal. The compounds are useful in the total synthesis of the angucyclines, including aquayamycin. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01478-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8383–8387
Synthetic study of aquayamycin. Part 1: Synthesis of
3-(phenylsulfonyl)phthalides possessing a b-C-olivoside
Takashi Matsumoto, Hiroki Yamaguchi, Toshiyuki Hamura, Mitsujiro Tanabe,
Yokusu Kuriyama and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST,
Japan Science and Technology Corporation (JST), O-okayama, Tokyo 152-8551, Japan
Received 3 August 2000; accepted 28 August 2000
Abstract
An efficient synthetic route to 3-(phenylsulfonyl)phthalides possessing a b-C-olivoside was developed by
exploiting the regioselective [2+2] cycloaddition of benzyne with ketene silyl acetal. The compounds are
useful in the total synthesis of the angucyclines, including aquayamycin. © 2000 Elsevier Science Ltd. All
rights reserved.
Among the angucycline class of antibiotics,1 aquayamycin (1)2 holds a special status because
of two salient structural features: (1) the C-glycoside at C9, and (2) the hydroxy groups at the
A/B ring junction. Since the structure elucidation of 1 in 1970, the congeners that share these
two structural features are increasing in number, thereby now constituting the largest subclass,
the aquayamycin-type angucyclines.1
However, no total synthesis of an aquayamycin-type compound has appeared, in contrast to
those of the structurally simpler non-aquayamycin-type compounds lacking the angular oxygens,
such as urdamycinone B and C104 (Fig. 1).3,4 We now wish to record the first total synthesis of
aquayamycin (1) in three consecutive papers.5
O
1
O
HO
O
OH
O
OH
O
HO
A
12
7
12a
D
C
B
OH
O
O
O
9
HO
HO
HO
HO
RO
HO
5
6a
HO
O
HO
O
HO
O
Aquayamycin (1)
Urdamycinone B
C104
(R = n-C5H11CH=CHCH=CHCO-)
Figure 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01478-7

8384
In planning the synthesis of 1, we envisioned the Hauser reaction between the phthalide anion
I and a cyclohexenone II, followed by cyclizing the A ring (Fig. 2).5b,6,7
A ring cyclization
CHO
O
O
+
O
Aquayamycin (1)
O
O
O
OBn
BnO
BnO
SO2Ph
RO
I
II
Figure 2.
Along these lines, described herein is the synthesis of the phthalide 2 (Scheme 1) by utilizing
the [2+2] cycloaddition of benzyne and ketene silyl acetal (KSA) followed by the Baeyer–Villiger
oxidation. The method is flexible enough to allow also the synthesis of the regioisomeric
phthalide 3.
The b-C-olivoside 4, previously reported,8 served as the common starting material for these
regioisomeric phthalides. The [2+2] cycloaddition of the benzyne A, generated from 4, with
KSAs proceeded in a regiospecific manner as we previously found for the simple a-alkoxybenzy-
nes (see B).9,10 The regiospecific conversion of the benzocyclobutenone via the Baeyer–Villiger
oxidation gave the corresponding phthalide.11
X
Y
OTf
I
O
O
BnO
BnO
BnO
BnO
MeO
OSiR3
OMe
OMe
OR
B
(X, Y: H or OMe)
4
A
1. Synthesis of phthalide 3 (series A)
A mixture of the triflate 48 (1 equiv.) and the KSA 5 (1.5 equiv.) in THF was treated with
n-BuLi (1.2 equiv.) at −78°C.10 The benzyne A, thus generated, underwent rapid [2+2] cycload-
dition with 5 at this temperature. The cycloadduct 6, obtained as a single regioisomer as
expected, was hydrolyzed with aqueous HF in CH3CN to give the ketone 7.12,13 The Baeyer–
Villiger oxidation of 7 with MMPP (magnesium monoperoxyphthalate) in the presence of
Na2HPO4 gave the phthalide 8 in 93% yield.11 The regioselectivity was perfect in that the
regioisomer, the 2(3H)-benzofuranone, was not observed. This was in line with our previous
finding that benzocyclobutenones undergo an oxygen insertion at the C1ꢀC2 bond upon
Baeyer–Villiger reaction,11 which proved valid for this more oxidized congener 7. Treatment of
8 with thiophenol under acidic conditions, followed by oxidation of the resulting sulfide with
mCPBA, afforded the 3-(phenylsulfonyl)phthalide 3 in high yield.12,14

8385
2. Synthesis of phthalide 2 (series B)
The synthesis of the phthalide 2 started with the cycloaddition of the benzyne A with the KSA
9, which has an additional oxygen function. Gratifyingly, the reaction also proceeded regio-
OTf
O
BnO
BnO
I
OMe
MeO
H
MeO
MeO
OMe
Sugar
4
Series B
Series A
TBDMSO
OMe
OTMS
5
a
9
f
H
OMe
OMe
OMe
OTMS
OMe
OMe
Sugar
Sugar
OTBDMS
MeO
MeO
g
6
10
b
OMe
OMe
OMe
O
Sugar
Sugar
Sugar
Sugar
O
MeO
MeO
h
7
11
c
OMe
O
O
Sugar
OR
j
O
MeO
MeO
k
12: R=H
13: R=Ac
i
8
d,e
13': R=TBDMS
SO2Ph
O
O
3
1
3
l,m
O
O
O
Sugar
Sugar
1
7
4
O
SO2Ph
OR
MeO
MeO
MeO
14: R=Ac
3
2
14': R=TBDMS
Scheme 1. Series A (synthesis of 3): (a) 5, n-BuLi, THF, −78°C, 20 min; (b) HF aq., MeCN, 2 h, 93% (two steps from
4); (c) MMPP, Na2HPO4, DMF, H2O, 40°C, 2 h, 93%; (d) PhSH, p-TsOH, benzene, reflux, 3 h, 78%; (e) mCPBA,
CH2Cl2, 7 h, 90%. Series B (synthesis of 2): (f) 9, n-BuLi, Et2O, −78°C, 15 min; (g) KF aq., (n-Bu)4NCl, MeCN, 40
min, 73% (two steps from 4); (h) NaBH4, MeOH, THF, 0°C, 15 min; then 4 M HCl aq., 2 h, 98%; (i) Ac2O, DMAP,
pyridine, 0°C, 15 min, 93%; (j) TBDMSCl, imidazole, DMF, 1.5 h, 98%; (k) (for 13) mCPBA, Na2HPO4, CH2Cl2,
0°C, 15 min, 95%; (for 13%) mCPBA, Na2HPO4, CH2Cl2, 2 h, 88%; (l) (for 14) PhSH, p-TsOH, benzene, reflux, 1 h,
97%; (m) mCPBA, CH2Cl2, 0°C, 2 h, 93%

8386
specifically to give the adduct 10,10c,13 which was treated with aqueous KF in the presence of
(n-Bu)4NCl in CH3CN to give the ketone 11 as a single product.10c,12 Reduction of the ketone
11 with NaBH4 followed by acid hydrolysis gave the hydroxy ketone 1212,13 in quantitative yield,
which was converted to the corresponding acetate 13 and the tert-butyldimethylsilyl ether 13%.
Significantly, the Baeyer–Villiger oxidation again proceeded with rigorous regioselectivity for
both compounds, 13 and 13%. For these cases, mCPBA (1.2 equiv.) was the oxidant of choice,
thereby giving a better yield of the phthalide, 14 and 14%, respectively.11 Unfortunately,
replacement of the tert-butyldimethylsiloxy group in the phthalide 14% by a phenylthio group
proved to be very slow under the conventional conditions (PhSH, p-TsOH, benzene, reflux), and
was not reproducible (the yield <65%) because of a competing deprotection at the sugar hydroxy
group(s). On the other hand, the reaction of the phthalide 14 proceeded smoothly under similar
conditions, and oxidation of the resulting sulfide with mCPBA afforded the 3-(phenyl-
sulfonyl)phthalide 2 in high yield.12,14
In summary, an isomeric pair of 3-(phenylsulfonyl)phthalides possessing a b-C-olivoside, 2
and 3, was synthesized in a divergent manner. Based on these findings, we successfully
accomplished the first total synthesis of aquayamycin (1), which will be described in the
following papers.
Acknowledgements
Financial support from ‘Uehara Memorial Foundation’ is gratefully acknowledged.
References
1. Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 103. Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127.
2. Sezaki, M.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M. Tetrahedron 1970, 26, 5171.
3. (a) Total syntheses of angucyclines possessing the C-glycoside: (urdamycinone B) Yamaguchi, M.; Okuma, T.;
Horiguchi, A.; Ikeura, C.; Minami, T. J. Org. Chem. 1992, 57, 1647. Sulikowski, G. A.; Boyd, V. A. J. Am.
Chem. Soc. 1995, 117, 8472. Matsuo, G.; Miki, Y.; Nakata, M.; Matsumura, S.; Toshima, K. Chem. Commun.
1996, 224. (C104) Matsumoto, T.; Sohma, T.; Yamaguchi, H.; Kurata, S.; Suzuki, K. Tetrahedron 1995, 51, 7347.
4. For synthetic studies on the aquayamycin-type skeleton, see: Kraus, G. A.; Wan, Z. Tetrahedron Lett. 1997, 38,
6509. Krohn, K.; Micheel, J. Tetrahedron 1998, 54, 4827.
5. (a)Yamaguchi, H.; Konegawa, T.; Tanabe, M.; Nakamura, T.; Matsumoto, T.; Suzuki, K. the following paper.
(b) Matsumoto, T.; Yamaguchi, H.; Tanabe, M.; Yasui, Y.; Suzuki, K. the third paper in this series.
6. Hauser, F. M.; Prasanna, S. J. Org. Chem. 1982, 47, 383. Hauser, F. M.; Prasanna, S. J. Am. Chem. Soc. 1981,
103, 6378. Review: Mitchell, A. S.; Russell, R. A. Tetrahedron 1995, 51, 5207.
7. For an example of application of the Hauser reaction in aryl C-glycoside synthesis, see: Tatsuta, K.; Ozeki, H.;
Yamaguchi, M.; Tanaka, M.; Okui, T. Tetrahedron Lett. 1990, 31, 5495.
8. Matsumoto, T.; Sohma, T.; Yamaguchi, H.; Suzuki, K. Chem. Lett. 1995, 677.
9. We previously reported the Diels–Alder reaction of benzyne A with furan derivatives. Matsumoto, T.;
Yamaguchi, H.; Suzuki, K. Synlett 1996, 433. Matsumoto, T.; Yamaguchi, H.; Suzuki, K. Tetrahedron 1997, 53,
16533.
10. For the [2+2] addition of a-alkoxybenzyne with ketene silyl acetal, see: (a) Hosoya, T.; Hasegawa, T.; Kuriyama,
Y.; Matsumoto, T.; Suzuki, K. Synlett 1995, 177. (b) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Suzuki, K.
Tetrahedron Lett. 1995, 36, 3377. (c) Hosoya, T.; Hamura, T.; Kuriyama, Y.; Miyamoto, M.; Matsumoto, T.;
Suzuki, K. Synlett 2000, 520.
11. Hosoya, T.; Kuriyama, Y.; Suzuki, K. Synlett 1995, 635.

8387
12. The regioisomers were assigned by the comparison of the 13C NMR spectra with those of the congeners lacking
the sugar moiety, whose structures have been unambiguously determined. The chemical shifts of the carbonyl
carbons (l, CDCl3) are shown for compounds 2, 3, 7, 11, 12, and 15–22 in the table below.
13. The sugar moiety, not surprisingly, induced virtually no stereochemical bias on the reaction, thereby giving a ca.
1:1 mixture of the diastereomers. We used the diastereomer mixture in the following reaction, although the
separation was possible by careful chromatography.
14. The phthalide 3 underwent facile partial epimerization at C3 during the silica-gel chromatography, which was not
the case for 2.
.
.