Synthetic studies on bengazoles of marine sponge origin. Synthesis of the core bis-oxazole fragments

Article abstract of DOI:10.1055/s-1998-1852

The core bis-oxazole fragment 3 was constructed by the coupling of the aldehyde (6) with the lithiated oxazoles (7), oxidation of the resulting bis-oxazolyl methanol (11), followed by the asymmetric reduction with (R)-(+)-BINAL-H as key steps. Preparation of another bis-oxazole fragment (4) was accomplished by the Barton-McCombie radical deoxygenation reaction of 11.

Full text of DOI:10.1055/s-1998-1852

September 1998
SYNLETT
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Synthetic Studies on Bengazoles of Marine Sponge Origin. Synthesis of the Core Bis-oxazole
Fragments
a
b
a
Pabba Chittari, Yasumasa Hamada, Takayuki Shioiri *
a
Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
(Fax: +81-52-834-4172; E-mail: shioiri@phar.nagoya-cu.ac.jp
b
Faculty of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 17 June 1998
Abstract: The core bis-oxazole fragment 3 was constructed by the
coupling of the aldehyde (6) with the lithiated oxazoles (7), oxidation of
the resulting bis-oxazolyl methanol (11), followed by the asymmetric
reduction with (R)-(+)-BINAL-H as key steps. Preparation of another
bis-oxazole fragment (4) was accomplished by the Barton-McCombie
radical deoxygenation reaction of 11.
Bengazoles are a growing family of natural products isolated from
marine sponges and characteristic of bis-oxazoles containing
1
carbohydrate-like polyol side chains, as shown in Fig. 1. They exhibit
interesting biological profiles such as anthelminthic, antifungal, or
1
cytotoxicity.
Scheme 2
to the O-silyl derivatives (7a : R=TBS (tert-butyldimethylsilyl); 7b :
R=TBDPS (tert-butyldiphenylsilyl)), as shown in Scheme 2.
Formation of the bis-oxazoles (11a and 11b) in their racemic
modifications was achieved by the coupling of the aldehyde (6) with the
5
lithiated derivatives of the silylated alcohols (7) in moderate yield.
Attempts to improve the reaction efficiency by the addition of borane as
6
a Lewis acid to complex the oxazole nitrogen failed to increase the
yield, and changing bases or addition of co-solvents resulted in either
decomposition or recovery of the starting materials. The racemic bis-
oxazoles (11) were used as the central building block to obtain the chiral
oxazoles (11*) and the de-oxygenated bis-oxazole (4), as shown in
Scheme 3.
Figure 1
As continuation of our interests on the synthesis of biologically active
and structurally interesting marine natural products, we have embarked
on the total synthesis of bengazoles (1 and 2), the overall strategy of
which is shown in Scheme 1. The recent report of Molinski and co-
7
Oxidation of 11 with chemical manganese dioxide (CMD) afforded the
bis-oxazolyl ketones (12). The asymmetric reduction of the oxazole
carbonyl group in 12 was carried out with various reagents, as
summarized in Table 1. The initial trial with Brown’s (+)-DipCl
2
workers prompted us to record our preliminary results on the synthesis
of bis-oxazole fragments (3 and 4) toward the total synthesis of
bengazoles.
3
8
(diisopinocamphenylchloroborane, A) failed to produce the desired
product and the reaction mixture turned to black color (run 1). The
oxazaborolidine-catalyzed reduction with the Itsuno-Corey reagent (B)
9
using catecholborane (CB) as a reducing agent did not give any
reduced product (run 2). Similarly, the Lewis acid (boron trifluoride
etherate) assisted reduction (hoping to suppress the possible
10
complexation of catechol borane with the oxazole nitrogen ) resulted
in the recovery of the starting material. Then, we used the methoxy-
11
oxazaborolidines (C and D) which were developed in our group to
increase the reactivity as well as selectivity due to higher Lewis acidity
of boron because of the more electron donating methoxy group, which
revealed to have a suitable property for coordination with heterocyclic
carbonyl group for the asymmetric reduction. As expected, these
oxazaborolidine reagents provided better yield and higher selectivity
compared to the corresponding B-methyl analog (B). Use of a
stoichiometric amount of chiral auxiliary C with borane dimethyl
sulfide (BMS), followed by slow addition of the bis-oxazolyl ketone
(12b) at 0° C afforded the desired bis-oxazolyl alcohol (11*b) in 48%
yield with 37% enantiomeric excess (run 5). It might be accompanied by
parallel achiral reduction due to proximal arrangement of the complexed
Scheme 1
First, 5-formyloxazole (6) was quantitatively obtained by acidic
hydrolysis of the corresponding acetal (8), which was prepared in 86%
yield from ethyl diethoxyacetate and lithiated methyl isocyanide. On
4a
12
borane with the oxazole nitrogen. To overcome the competing achiral
the other hand, ethyl oxazole-4-carboxylate (9), prepared in 70% yield
reduction, the same reaction was carried out with prior addition of boron
trifluoride etherate to suppress the complexation of borane but it
resulted in low yields. The oxazaborolidine D derived from α-pinene
from ethyl isocyanoacetate and formic acid according to the
Schöllkopf’s procedure, underwent the reduction with sodium
borohydride to give the alcohol (10) in 80% yield, which was converted
4
11

1023
LETTERS
SYNLETT
conditions by use of tributyltin hydride-azobisisobutyronitrile (AIBN)
16b
to ensure complete deoxygenation, giving the desired bis-oxazole (4)
in 54% yield, as shown in Scheme 3.
In summary, we have achieved the synthesis of the core bis-oxazole
fragments (3 and 4) of the bengazole family. Further coupling of the side
chain and generalization of the novel synthetic route for bengazoles are
actively under investigation in our laboratories.
Acknowledgments: One of the authors (P.C.) is grateful to the Japan
Society for the Promotion of Science for the fellowship. This work was
partially supported by Grant-in-Aids for Scientific Research from the
Ministry of Education, Science, Sports and Culture, Japan.
Scheme 3
did not give any good results (run 4) compared to the proline based
chiral auxiliary (C). Our attention now focused the use of the aluminum
13
References and Notes
complex (E) of binaphthol, (R)-(+)-BINAL-H. When 5 equivalents of
E was used for the reduction, the best result (78% yield with 68% ee)
was obtained. The configuration of the major isomer (11*b) was found
to be (S) by the modified Mosher method. The asymmetric reduction
1. a) Adamczeski, M.; Quinoà, E.; Crews, P. J. Am. Chem. Soc. 1988,
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Schleyer, M. J. Nat. Prod. 1994, 57, 829.
14
with (R)-(+)-BINAL-H will proceed via the six-membered chair
transition state by the chelation between the oxazole nitrogen and the
15
BINAL oxygen atom. The synthesis of the required aldehyde 3 was
accomplished by the reactions, outlined in Scheme 3. The hydroxyl
function in 11*b was protected with methoxymethyl (MOM) chloride,
followed by deprotection of the TBDPS group with
tetrabutylammonium fluoride (TBAF) to give the alcohol. The resulting
2. Shafer, C. M.; Molinski, T. F. Tetrahedron Lett. 1998, 39, 2903.
3. Presented in part at the 117th Annual Meeting of the
Pharmaceutical Society of Japan (Tokyo), March 26-28, 1997,
Abstracts 2, p.16 and at the 118th Annual Meeting of the
Pharmaceutical Society of Japan (Kyoto), March 31-April 2,
1998, Abstracts 2, p.47.
7
16a
alcohol was oxidized with CMD afforded the aldehyde (3).
For the construction of another bis-oxazole fragment (4), the
Clemmensen reduction of the bis-oxazole ketone (12) or catalytic
hydrogenation over palladium-carbon resulted in the partial reduction to
give the oxazole alcohol (11). Transfer hydrogenation of the ketone
(12a) with palladium carbon-ammonium formate gave the formyl imino
derivative (13). The successful formation of 4 was finally achieved by
4. (a) Schöllkopf, U.; Schröder, R. Angew. Chem. Int. Ed. Engl.
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5. Hodges, J. C.; Patt, W. C.; Connolly, C. J J. Org. Chem. 1991, 56,
17
the Barton-McCombie radical deoxygenation reaction of 11b,
449 and references therein.
involving the xanthate formation either with carbon disulfide-methyl
iodide-sodium hydride or phenyl thionochloroformate. Surprisingly, the
xanthate intermediate was accompanied by the deoxygenated product
(4). This might be due to the active benzylic carbon of the bis-oxazole
xanthate leading to the generation of free radical species in the presence
of light. Thus, the reaction mixture was subjected to radical catalyzed
6. Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192.
7. Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai, M.;
Ando, A.; Shioiri, T. Synlett 1998, 35.

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SYNLETT
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o
16. a) 3: oil; [α] = +1.4 (c 0.3, CHCl ); IR (CHCl ): 1700, 1585,
D
3
3
-1
1558, 1506, 1471, 1396, 1330, 1213, 1151, 1103, 1028 cm
H NMR (CDCl , 270 MHz): 3.41(s, 3H, CH ), 4.77 (s, 2H,
;
12. Quallich, G. J.; Woodall, T. M. Tetrahedron Lett. 1993, 34, 4145.
1
3
3
13. a) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709. b) Noyori, R.; Tomino, I.; Yamada, M.;
Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717.
CH ), 6.05 (s, 1H, CH), 7.27 S, 1H, CH), 7.93 (s, 1H, CH), 8.31
2
(s, 1H, CH), 9.96 (s, 1H, CHO). b) 4: oil, IR (CHCl ): 1587, 1576,
3
-1
1
1487, 1471, 1427, 1361, 1213 cm ; H NMR (CDCl , 270 MHz):
3
1.07 (s, 9H, 3CH ), 4.17 (s, 2H, CH ), 4.66 (s, 2H, CH ), 6.99 (s,
1H, CH), 7.34-7.43 (m, 6H, ArH), 7.47 (s, 1H, CH), 7.65 (m, 4H,
ArH), 7.83 (s, 1H, CH).
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Soc. 1991, 113, 4092.
3
2
2
13
15. Possible transition state will be as follows:
17. (a) Barton, D. H. R.; McCombie, S.W, J. Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Barton, D. H. R.; Jang D. O.; Jaszberenyi,
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