A new enantioselective total synthesis of Al-77-B

Article abstract of DOI:10.1021/ol990102y

(formula presented) An enantioselective total synthesis of Al-77-B (1), a gastroprotective substance isolated from a culture broth of Bacillus pumilus Al-77, was performed in high overall yield. In this synthesis, the dihydroisocoumarin part 14 and the di

Full text of DOI:10.1021/ol990102y

ORGANIC
LETTERS
1999
Vol. 1, No. 3
499-502
A New Enantioselective Total Synthesis
of AI-77-B
Hiyoshizo Kotsuki,* Tomohiro Araki, Aya Miyazaki, Mitsuhiro Iwasaki, and
Probal K. Datta
Department of Material Science, Faculty of Science, Kochi UniVersity,
Akebono-cho, Kochi 780-8520, Japan
kotsuki@cc.kochi-u.ac.jp
Received May 24, 1999
ABSTRACT
An enantioselective total synthesis of AI-77-B (1), a gastroprotective substance isolated from a culture broth of Bacillus pumilus AI-77, was
performed in high overall yield. In this synthesis, the dihydroisocoumarin part 14 and the dihydroxyamino acid part 20 were both assembled
from D-ribose as the common chiral source. For the construction of 14 a bromobenzofuran derivative was used as a novel salicylic acid
synthon. Finally, DEPC-mediated condensation of 14 and 20 yielded AI-77-B (1).
The AI-77s are a group of 3,4-dihydroisocoumarin antibiotics
that have been isolated from a culture broth of Bacillus
pumilus AI-77.1,2 The major component, AI-77-B (1), has
been found to exhibit potent gastroprotective activity without
anticholinergic, antihistaminergic, or central suppressive
effects.3 Due to its unique structure and its characteristic
biological activity, AI-77-B (1) has attracted a great deal of
attention from synthetic chemists. To date, four syntheses
of this compound have been reported by Hamada/Shioiri,4
Thomas,5 Procter,6 and Vogel.7 Several approaches to the
partial synthesis of 1 have also been reported.8
Our own enantioselective synthesis of 1 uses two seg-
ments, the dihydroisocoumarin (part A) and the dihy-
droxyamino acid (part B), which were both assembled from
D-ribose as the common chiral source.9 To construct part A,
* To whom correspondence should be addressed. Tel: +81-888-44-8298.
Fax: +81-888-44-8360.
(1) (a) Shimojima, Y.; Hayashi, H.; Ooka, T.; Shibukawa, M. Agric. Biol.
Chem. 1982, 46, 1823. (b) Shimojima, Y.; Hayashi, H.; Ooka, T.;
Shibukawa, M.; Iitaka, Y. Tetrahedron Lett. 1982, 23, 5435. (c) Shimojima,
Y.; Hayashi, H.; Ooka, T.; Shibukawa, M. Iitaka, Y. Tetrahedron 1984,
40, 2519.
(2) Okazaki, H.; Kishi, T.; Beppu, T.; Arima, K. J. Antibiot. 1975, 28,
717. Itoh, J.; Omoto, S.; Shomura, T.; Nishizawa, N.; Miyado, S.; Yuda,
Y.; Shibata, U.; Inoue, S. J. Antibiot. 1981, 34, 611. Itoh, J.; Shomura, T.;
Omoto, S.; Miyado, S.; Yuda, Y.; Shibata, U.; Inouye, S. Agric. Biol. Chem.
1982, 46, 1255. Itoh, J.; Omoto, S.; Nishizawa, N.; Kodama, Y.; Inouye,
S. Agric. Biol. Chem. 1982, 46, 2659.
compound 14, our earlier approach relied on novel carbon-
carbon bond-forming reactions10 of triflate 9 with an aryl
Grignard reagent and subsequent regioselective metalation/
(4) (a) Hamada, Y.; Kawai, A.; Kohno, Y.; Hara, O.; Shioiri, T. J. Am.
Chem. Soc. 1989, 111, 1524. (b) Hamada, Y.; Hara, O.; Kawai, A.; Kohno,
Y.; Shioiri, T. Tetrahedron 1991, 47, 8635.
(3) Shimojima, Y.; Hayashi, H. J. Med. Chem. 1983, 26, 1370.
Shimojima, Y.; Shirai, T.; Baba, T.; Hayashi, H. J. Med. Chem. 1985, 28,
3. Inouye, S.; Kondo, S. In NoVel Microbial Products for Medicine and
Agriculture; Demain, A. L., Somkuti, G. A., Hunter-Cevera, J. C.,
Rossmoore, H. W., Eds.; Elsevier: Amsterdam, 1989; Chapter 21.
(5) Broady, S. D.; Rexhausen, J. E.; Thomas, E. J. J. Chem. Soc., Chem.
Commun. 1991, 708.
(6) (a) Ward, R. A.; Procter, G. Tetrahedron Lett. 1992, 33, 3359. (b)
Ward, R. A.; Procter, G. Tetrahedron 1995, 51, 12301.
(7) Durgnat, J.-M.; Vogel, P. HelV. Chim. Acta 1993, 76, 222.
10.1021/ol990102y CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/25/1999

carboxylation.9a However, the latter step did not prepare
enough of the product, and we elected to adopt a completely
different strategy using benzofuran 5 for the Grignard partner
as a novel salicylic acid synthon, such as 6. The requisite 5
was prepared by CsF-mediated rearrangement11 of m-
bromophenyl propargyl ether (2) in good regioselectivity
(Scheme 1). Since 3 and 4 were inseparable at this stage,12
the corresponding Grignard reagent was prepared as a
mixture.
Conversion of 11 to 14 was straightforward.9a Thus, protec-
tion of 11 as its benzyl ether followed by deprotection of an
acetonide function gave a diol (present as a form of
hemiacetal), which was further oxidized with NaClO2/
NaHSO3/30% H2O2 under carefully controlled conditions15
to afford hydroxylactone 12. Compound 12 was then
transformed to 14, [R]22 ) -55.4° (c 1.01, MeOH) (lit.6b
D
[R]D ) -55.6° (c 1.08, MeOH)) and mp 203-205 °C (lit.6b
mp 209-212 °C), via azidation with SN2 inversion and
catalytic hydrogenation (three steps, 96% overall yield).
As illustrated in Scheme 3, the optically pure 20 (part B)
was also assembled from D-ribose.9c Treatment of 1517 with
p-methoxybenzylamine followed by acetylation gave lactam
16. Stereoselective alkylation of 16 with allyltrimethylsilane
by the assistance of BF3‚OEt2 proceeded quantitatively to
afford 17 via a well-known N-acylpyrrolidinium ion inter-
mediate.18 Deprotection of the PMB group in 17 by CAN-
oxidation produced 18 (57%) along with its p-methoxy-
benzoyl derivative (38%); the latter compound could be
hydrolyzed smoothly to 18 under basic conditions, and hence
18 was obtained in an overall yield of 85%. Reprotection of
Scheme 1
18 with Boc2O/cat. DMAP gave the N-Boc lactam 19, [R]25
D
) +89.5° (c 0.98, CHCl3) and mp 65.5-67 °C, quantita-
tively.
The final steps of our AI-77-B (1) synthesis are shown in
Scheme 4. Since our initial attempts to realize the uncatalyzed
condensation of 14 with 19 at high pressure were all
unsuccessful due to the undesired isomerization of 14,9b,c,19
we applied Hamada’s conditions.4 Accordingly, DEPC-
mediated condensation of 14 with 20 at 0 °C (DMF, Et3N,
12 h) was achieved in 77% yield.19 In situ generation of acid
20 from 19 and also gradual addition of Et3N were essential
to increase the yield of this step. Oxidative cleavage of the
An efficient copper-catalyzed coupling reaction of the
triflate 9 derived from 713 with the Grignard reagent 5 was
achieved at room temperature to afford 10 in 93% yield
(Scheme 2). Ozonolysis of 10 followed by hydrolysis of the
resulting acetate gave the salicylaldehyde 11 (82.7% for two
steps).14 At this stage, it became possible to chromatographi-
cally separate 11 from its regioisomer originating from 4.
20
terminal double bond with RuCl3 and NaIO4 followed by
deprotection of an acetonide as well as an N-Boc function
under mildly acidic conditions (3% HCl in MeOH) yielded
AI-77-B (1) (two steps, 85% overall yield), [R]23D ) -76.1°
(8) Kawai, A.; Hara, O.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1988,
29, 6331. Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1989, 37, 1087. Gesson,
J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron Lett. 1989, 30, 6503.
Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T. Tetrahedron 1990,
46, 4823. Bertelli, L.; Fiaschi, R.; Napolitano, E. Gazz. Chim. Ital. 1993,
123, 669. Ward, R.; Procter, G. Tetrahedron 1995, 51, 12821. Shinozaki,
K.; Mizuno, K.; Masaki, Y. Heterocycles 1996, 43, 11. Superchi, S.;
Minutolo, F.; Pini, D.; Salvadori, P. J. Org. Chem. 1996, 61, 3183.
Shinozaki, K.; Mizuno, K.; Wakamatsu, H.; Masaki, Y. Chem. Pharm. Bull.
1996, 44, 1823. Mukai, C.; Miyakawa, M.; Hanaoka, M. J. Chem. Soc.,
Perkin Trans. 1 1997, 913. Ghosh, A. K.; Cappiello, J. Tetrahedron Lett.
1998, 39, 8803.
(c 0.09, MeOH) (lit.4b [R]22 ) -78.2° (c 0.08, MeOH))
D
and mp 147.5-148.0 °C (lit.1c mp 139.5-140.0 °C). The
(15) NaClO2 oxidation was best achieved by using H2O2 as the HOCl
scavenger.16 When the oxidation was performed in the absence of H2O2,
12 was obtained in only 50% yield, along with 48% of the aromatic
chlorinated compounds.
(16) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567. See
also: Hase, T.; Wa¨ha¨la¨, K. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, p 4533.
(17) Ali, S. M.; Ramesh, K.; Borchardt, R. T. Tetrahedron Lett. 1990,
31, 1509.
(9) (a) Kotsuki, H.; Miyazaki, A.; Ochi, M. Chem. Lett. 1992, 1255. (b)
Kotsuki, H.; Iwasaki, M.; Nishizawa, H. Tetrahedron Lett. 1992, 33, 4945.
(c) Kotsuki, H.; Iwasaki, M.; Ochi, M. Heterocycles 1994, 38, 17.
(10) Review: Kotsuki, H. J. Synth. Org. Chem. Jpn. 1999, 57, 334.
(11) Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.; Suzuki, M. Chem.
Pharm. Bull. 1992, 40, 1148. Ishikawa, T.; Nagai, K.; Ohkubo, N.; Ishii,
H. Heterocycles 1994, 39, 371. Ishikawa, T.; Mizutani, A.; Miwa, C.; Oku,
Y.; Komano, N.; Takami, A.; Watanabe, T. Heterocycles 1997, 45, 2261.
(12) These isomers could be separated by JAI Recycling Preparative
(18) Zaugg, H. E. Synthesis 1984, 85, 181. Speckamp, W. N.; Hiemstra,
H. Tetrahedron 1985, 41, 4367. Hiemstra, H.; Speckamp, W. N. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, U.K., 1991; Vol. 2, pp 1047-1082.
(19) As mentioned by Shimojima et al.,1c the free amine of 14 was readily
isomerized to the corresponding seven-membered lactam 14a. This tendency
significantly decreased the product yield when the condensation of 14 with
20 was conducted at room temperature.
1
HPLC LC-908, and each structure was determined unambiguously by H
NMR (400 MHz). 3: δ 2.46 (3H, s), 6.42 (1H, t, J ) 1.0 Hz), 7.06 (1H,
t, J ) 8.1 Hz), 7.32, 7.34 (each 1H, dd, J ) 8.1, 1.0 Hz). 4: δ 2.42 (3H,
s), 6.32 (1H, d, J ) 0.7 Hz), 7.28 (1H, ddd, J ) 8.3, 1.4, 0.7 Hz), 7.30
(1H, d, J ) 8.3 Hz), 7.55 (1H, dd, J ) 1.4, 0.7 Hz).
(13) Kotsuki, H.; Miyazaki, A.; Ochi, M. Tetrahedron Lett. 1991, 32,
4503.
(14) Ishii, H.; Ohta, S.; Nishioka, H.; Hayashida, N.; Harayama, T. Chem.
Pharm. Bull. 1993, 41, 1166.
(20) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
500
Org. Lett., Vol. 1, No. 3, 1999

Scheme 2a
a Legend: (a) (i) (CH3)2CdPPh3, THF, -30 °C to room temperature, 96%, (ii) H2, 10% Pd/C, K2CO3, AcOEt, quantitative; (b) Tf2O,
pyridine, CH2Cl2, -15 °C, quantitative; (c) CuBr (0.3 equiv), THF, 0 °C to room temperature, 12 h, 93%; (d) (i) O3, CH2Cl2, -78 °C, then
Me2S, 88%, (ii) aqueous K2CO3, MeOH, 94%; (e) (i) BnBr, K2CO3, acetone, reflux, 94%, (ii) 60% HClO4 (cat.), aqueous CH3CN, 0 °C,
96%, (iii) NaClO2, NaHSO3, 30% H2O2, KH2PO4, aqueous CH3CN, 95%; (f) (i) MsCl, Et3N, CH2Cl2, (ii) NaN3 (10 equiv), 18-crown-6,
DMF, 80 °C, 22 h, 98% in two steps; (g) H2, 10% Pd(OH)2/C, 3% HCl in MeOH, 98%.
Scheme 3a
a Legend: (h) 4-MeOC6H4CH2NH2, EtOH, 0 °C, 1 h, then Ac2O, pyridine, DMAP, quantitative; (i) CH2dCHCH2SiMe3, BF3‚OEt2,
CH2Cl2, 0 °C to room temperature, quantitative; (j) (i) CAN, aqueous CH3CN, 0 °C, (ii) 0.23 M KOH, THF/H2O (5:4), room temperature,
overall 85%; (k) Boc2O, cat. DMAP, THF, room temperature, quantitative; (l) 1.0 M LiOH, aqueous THF.
Scheme 4a
a Legend: (m) DEPC, Et3N, DMF, 0 °C, 12 h, 77%; (n) RuCl3, NaIO4, CCl4/CH3CN/H2O (2:2:3), room temperature, 3 h; (o) (i) 3% HCl
in MeOH, 11 h, (ii) 0.1 M NaOH (pH 9), 3 h, (iii) 0.1 M HCl (pH 6.5), 85% from 21.
spectroscopic data of the synthesized product were identical
in all respects with those provided for the natural substance.21
In conclusion, an efficient, enantioselective total synthesis
of AI-77-B (1) has been accomplished using a 12-step
sequence from chiral triflate 9, with an overall yield of
41.5%. The average yield per step is 93%, and this constitutes
the most efficient synthesis to date. In addition, this route
provides a new rapid entry to an 8-hydroxydihydroisocou-
marin framework using bromobenzofuran 3 as the salicylic
acid synthon. This may be useful for deriving a wide variety
of dihydroisocoumarin families of natural products.
(21) Our synthetic 1 was consistent with the published data.1c We also
thank Professor Y. Hamada (Chiba University) for providing proton and
carbon NMR spectra of authentic 1.
Org. Lett., Vol. 1, No. 3, 1999
501

Acknowledgment. This work was supported in part by
Scientific Research Grants from the Ministry of Education,
Science, Sports and Culture of Japan and a Grant-in-Aid for
Special Scientific Research from Kochi University. We are
grateful to Prof. Y. Fukuyama of Tokushima Bunri Univer-
sity for the MS/HRMS measurements. We also thank Central
Glass Co., Ltd., for generously supplying Tf2O.
Supporting Information Available: Text giving experi-
mental procedures and figures giving NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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