Asymmetric synthesis of aerothionin, a marine dimeric spiroisoxazoline natural product, employing optically active spiroisoxazoline derivative

Article abstract of DOI:10.1016/j.tetlet.2005.11.097

Successful first synthesis of optically pure (+)- and (-)-aerothionins (1) from the racemic spiroisoxazoline derivative 8 has been accomplished. The absolute configuration of natural (+)-1 was determined by comparison of (+)- and (-)-8 with related deriva

Full text of DOI:10.1016/j.tetlet.2005.11.097

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 727–731
Asymmetric synthesis of aerothionin, a marine dimeric
spiroisoxazoline natural product, employing optically active
spiroisoxazoline derivative
Takahisa Ogamino, Rika Obata and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 17 October 2005; revised 17 November 2005; accepted 21 November 2005
Available online 6 December 2005
Abstract—Successful first synthesis of optically pure (+)- and (ꢀ)-aerothionins (1) from the racemic spiroisoxazoline derivative 8 has
been accomplished. The absolute configuration of natural (+)-1 was determined by comparison of (+)- and (ꢀ)-8 with related
derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
Up to now, several spiroisoxazoline natural products
have been isolated from marine origins (Fig. 1). Among
tiomerical difference. We describe herein the synthesis of
optically active spiroisoxazoline 8 and its synthetic
access to optically pure (+)- and (ꢀ)-1.
1
them, dimeric natural products carrying two spiroisox-
2
azoline units, such as aerothionin (1), homoaerothionin
3
4
5
(
2), caissarin B (3), fisturalin 3 (4), calafianin (5), and
As reported previously, synthesis of the racemic spirois-
oxazoline compound (± )-8 was efficiently achieved by
electrochemical oxidation of 9, followed by Zn(BH )
6
their congeners, were reported to show significant bio-
activity, mainly antimicrobial and cytotoxic activities. In
addition, antihistamine activity of archerine (6) and K,
4
2
7
12
reduction of 10 (Scheme 1).
8
Na-ATPase inhibitory activity of ianthesin C (7) were
reported.
The coupling reaction of (± )-8 with several chiral
reagents was attempted to produce a chromatographically
separable diastereomeric mixture. After repeated inspec-
tion, it was observed that camphanic acid esters 11 and
12, produced by esterification with (ꢀ)-camphanic chlo-
ride, were easily separable by silica gel chromatography
Synthetic studies on these natural products have been
carried out by several groups. The first total synthesis
of aerothionin (1), produced by the amidation of (± )-8
9
with the corresponding diamine, was reported by our
1
0
13
group, although diastereomeric separation of natural
and its diastereoisomer was unsuccessful. Asymmetric
synthesis of the spiroisoxazoline unit 8 (70–80% ee) was
(Scheme 2).
1
The optically active spiroisoxazoline compounds (+)-
and (ꢀ)-8 were successfully obtained by solvolysis of
11 and 12 under basic conditions (Scheme 3). Their
optical purity was confirmed by chiral HPLC analysis
(Daicel CHIRALPAK AD-H: 100% EtOH) of (+)-
and (ꢀ)-10, which were produced by the Dess–Martin
oxidation of (+)- and (ꢀ)-8 (Scheme 4). No observation
of the corresponding enantiomeric isomers on the
HPLC chart indicated that both enantiomers possess
1
1
reported by Hoshino et al., although separation of dia-
stereomers derived from 8 carrying insufficient optical
purity was unsuccessful. From the viewpoint of biolog-
ical investigation, acquisition of completely pure dimeric
spiroisoxazoline compounds without contamination of
their diastereoisomer is essential for evaluation of enan-
1
4
complete optical purity. To determine their absolute
stereochemisty, (+)- and (ꢀ)-8 were submitted to acid
hydrolysis, followed by cyclization to yield (+)- and
Keywords: Spiroisoxazoline; Bromotyrosine; Diastereomeric separa-
tion; Aerothionin.
*
Corresponding author. Tel./fax: +81 45 566 1717; e-mail:
nisiyama@chem.keio.ac.jp
23
(ꢀ)-13, optical rotations {½aꢁ +322.8 (c 1.0, CHCl3)
D
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.097

728
T. Ogamino et al. / Tetrahedron Letters 47 (2006) 727–731
Figure 1. Structures of dimeric spiroisoxazoline natural products.
Scheme 1. Synthesis of spiroisoxazoline (± )-8.
Scheme 2. Esterification of (± )-8 by (ꢀ)-camphanic chloride.
2
D
3
and ½aꢁ ꢀ320.6 (c 1.0, CHCl )} of which were com-
the absolute configuration of (+)- and (ꢀ)-13 might be
3
2
D
0
pared with the reported data {½aꢁ +202.8 (c 0.64,
as depicted in Scheme 3.
1
5
16,17
CHCl )} (Scheme 3).
Although the reported abso-
3
lute value of optical rotation was different from our
To obtain further structure proof, a synthesis of aerop-
data, the plus sign of the reported 13 indicated that
lysinin-1 (14), the absolute configuration of which was

T. Ogamino et al. / Tetrahedron Letters 47 (2006) 727–731
729
Scheme 3. Synthesis of optically active spiroisoxazoline 8.
Scheme 4. Derivation of 8–10 for optically purity analysis.
determined by X-ray crystallographic analysis, was per-
Scheme 5. Synthesis of optically active aeroplysinin-1 (14).
formed by using (+)- and (ꢀ)-8, according to the same
1
2b
procedure as described previously (Scheme 5).
Con-
2
3
sequently, their optical rotations {(ꢀ)-14: ½aꢁ ꢀ199.1
D
2
D
3
(
c 0.5 acetone); (+)-14: ½aꢁ +192.9 (c 0.5 acetone)}
22
were identical with the reported data {(ꢀ)-14: [a]
MeOH) and ½aꢁ +203.8 (c 0.5, MeOH)} and the abso-
D
D
ꢀ
198 (c 0.5 acetone); (+)-14: [a] +182 (c 0.5
lute configuration of 1 should be as described in
Scheme 6, which definitely supported the report by
Rinehart.
D
1
8
acetone)}.
Finally, optically pure (+)- and (ꢀ)-1 were successfully
synthesized by condensation of (+)- and (ꢀ)-8 with 1,4-
In conclusion, the optically active spiroisoxazoline units
(+)- and (ꢀ)-8 were produced, and the synthesis of (+)-
and (ꢀ)-1 without contamination of its diastereomer
was unambiguously achieved. By this investigation, the
absolute configuration of 1 was synthetically deter-
mined. This investigation will open up a synthetic access
to other dimeric spiroisoxazoline natural products, and
their biological profiles.
1
0
1
diaminobutane (Scheme 6). The H NMR data of the
2
synthetic 1 was superimposable to the reported data.
Previously, Rinehart reported the absolute configura-
2
c
tion of natural 1 {[a]D +210 (c 1.7, MeOH)} by
means of an X-ray crystallographic analysis, together
1
9
with its circular dichroism. Our synthetic samples
22
exhibited the optical rotations {½aꢁD ꢀ205.2 (c 0.5,

730
T. Ogamino et al. / Tetrahedron Letters 47 (2006) 727–731
Scheme 6. Synthesis of optically active aerothionin (1).
Acknowledgments
7. Ciminiello, P.; Aversano, C. D.; Fattorusso, E.; Magno, S.
Eur. J. Org. Chem. 2001, 55–60.
8
9
. Okamoto, Y.; Ojika, M.; Kato, S.; Sakagami, Y. Tetra-
hedron 2000, 56, 5813–5818.
. (a) Wasserman, H. H.; Wahng, J. J. Org. Chem. 1998, 63,
This work was supported by Grant-in-Aid for the 21st
Century COE program ÔKeio Life Conjugate Chemis-
try,Õ as well as Scientific Research C from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan. The authors are grateful to the COE program
and JSPS Research Fellowships for Young Scientists
for financial support to T.O.
5
581–5586; (b) Goldenstein, K.; Fendert, T.; Proksch, P.;
Winterfeldt, E. Tetrahedron 2000, 56, 4173–4185; (c)
Boehlow, T. R.; Jonathan Harburn, J.; Spilling, C. D. J.
Org. Chem. 2001, 66, 3111–3118.
10. (a) Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1983,
4, 3351–3352; (b) Nishiyama, S.; Yamamura, S. Bull.
2
Chem. Soc. Jpn. 1985, 58, 3453–3456.
1
1. (a) Murakata, M.; Yamada, K.; Hoshino, O. J. Chem.
Soc., Chem. Commun. 1994, 443–444; (b) Murakata, M.;
Yamada, K.; Hoshino, O. Tetrahedron 1996, 52, 14713–
14722; (c) Murakata, M.; Tamura, M.; Hoshino, O. J.
Org. Chem. 1997, 62, 4428–4433; (d) Murakata, M.;
Yamada, K.; Hoshino, O. Heterocycles 1998, 47, 921–931.
References and notes
1
2
. Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48, and
references cited therein.
. (a) Fattorusso, E.; Minale, L.; Sodano, G.; Moody, K.;
Thomson, R. H. J. Chem. Soc., Chem. Commun. 1970,
52–753; (b) Moody, K.; Thomson, R. H.; Fattorusso, E.;
Minale, L.; Sodano, G. J. Chem. Soc., Perkin Trans. 1
972, 18–24; (c) McMillan, J. A.; Paul, I. C.; Goo, Y. M.;
12. (a) Ogamino, T.; Ishikawa, Y.; Nishiyama, S. Heterocycles
2003, 61, 73–79; (b) Ogamino, T.; Nishiyama, S. Tetra-
hedron 2003, 59, 9419–9423.
7
ꢀ
1
1
1
13. Compound 11: IR (film) 1795, 1749 cm
;
H NMR
Rinehart, K. L., Jr.; Krueger, W. C.; Pschigoda, L. M.
Tetrahedron Lett. 1981, 22, 39–42.
(400 MHz, CDCl ) d 0.97 (3H, s), 1.09 (3H, s), 1.11 (3H,
s), 1.71 (1H, m), 1.93 (1H, m), 2.11 (1H, m), 2.38 (1H, m),
3
3
. Saeki, B. M.; Granato, A. C.; Berlinck, R. G. S.;
Magalh a´ es, A.; Schfer, A. B.; Ferreira, A. G.; Pinheiro,
U. S.; Hajdu, E. J. Nat. Prod. 2002, 65, 796–799.
. Gopichand, Y.; Schmits, F. J. Tetrahedron Lett. 1979, 41,
3.03 (1H, d, J = 18.0 Hz), 3.67 (1H, d, J = 18.0 Hz), 3.78
1
3
(3H, s), 3.91 (3H, s), 6.12 (1H, s), 6.42 (1H, s); C NMR
(100 MHz, CDCl ) d 9.7, 16.6, 16.8, 29.0, 31.3, 39.2, 53.2,
3
4
5
6
54.5, 54.8, 60.2, 60.3, 74.3, 90.9, 107.2, 120.7, 130.8, 149.8,
3921–3924.
151.5, 159.8, 166.3, 177.5. HRMS found m/z 574.9778,
+
. Encarnaci o´ n, R. D.; Sandoval, E.; Malmstrøm, J.; Chris-
tophersen, C. J. Nat. Prod. 2000, 63, 874–875.
calcd for C21
H23Br
NO
: M , 574.9790. Compound 12:
2
8
ꢀ
1
1
IR (film) 1792, 1747 cm ; H NMR (400 MHz, CDCl ) d
3
. (a) Kernan, M. R.; Canbie, R. C.; Bergquist, P. R. J. Nat.
Prod. 1990, 53, 615–622; (b) Acosta, A. L.; Rodr ´ı guez, A.
D. J. Nat. Prod. 1992, 55, 1007–1012; (c) Grunasekera, S.
P.; Cross, S. S. J. Nat. Prod. 1992, 55, 509–512; (d) K o¨ nig,
G. M.; Wright, A. D. Heterocycles 1993, 36, 1351–1358;
1.02 (3H, s), 1.05 (3H, s), 1.12 (3H, s), 1.68 (1H, m), 1.93
(1H, m), 2.06 (1H, m), 2.45 (1H, m), 3.06 (1H, d,
J = 18.5 Hz), 3.60 (1H, d, J = 18.5 Hz), 3.78 (3H, s),
1
3
3.91 (3H, s), 6.07 (1H, s), 6.40 (1H, s); C NMR
(100 MHz, CDCl ) d 9.7, 16.6, 16.9, 29.0, 31.0, 39.5,
3
(
e) Mancini, I.; Guella, G.; Laboute, P.; Debitus, C.;
Pietra, F. J. Chem. Soc., Perkin Trans. 1 1993, 3121–3125;
f) Compagnone, R. S.; Avila, R.; Su a´ rez, A. I.; Abrams,
53.1, 54.6, 55.0, 60.2, 60.3, 74.7, 90.8, 106.8, 121.2, 130.6,
150.1, 151.6, 160.0, 166.5, 177.8. HRMS found m/z
+
(
574.9780, calcd for C21
H23Br
2
NO
8
: M , 574.9790.
O. V.; Rangel, H. R.; Arvelo, F.; Pi n˜ a, I. C.; Merentes, E.
J. Nat. Prod. 1999, 62, 1443–1444; (g) El Sayed, K. A.;
Bartyzel, P.; Shen, X.; Perry, T. L.; Zjawiony, J. K.;
Hamann, M. T. Tetrahedron 2000, 56, 949–953.
14. Optical purity analysis of 10 by chiral HPLC showed large
difference in the retention times (10R: 18 min, 10S:
26 min), although the enantiomers of
separated.
8 were not

T. Ogamino et al. / Tetrahedron Letters 47 (2006) 727–731
731
5
1
5. Goldenstein, K.; Fendert, T.; Proksch, P.; Winterfeldt, E.
Tetrahedron 2000, 56, 4173–4185.
6. (a) Ogamino, T.; Nishiyama, S. Tetrahedron Lett. 2005,
reported. In addition, comparison with the wave length
of the CD spectra reported indicated the absolute
structure of calafianin (5) might be as depicted in
Figure 1.
1
4
6, 1083–1086; (b) Ogamino, T.; Obata, R.; Tomoda,
H.; Nishiyama, S. Bull. Chem. Soc. Jpn., in press.
18. (a) Cosulich, D. B.; Lovell, F. M. J. Chem. Soc., Chem.
Commun. 1971, 397–398; (b) Fulmor, W.; Van Lear, G. E.;
Morton, G. O.; Mills, R. D. Tetrahedron Lett. 1970, 11,
4551–4552.
2
2
1
7. (+)- and (ꢀ)-Calafianins (5) {½aꢁ ꢀ253.2 (c 0.2, acetone)
D
2
D
2
and ½aꢁ +249.4 (c 0.2, acetone)} were synthesized by
1
6
utilizing (+)- and (ꢀ)-13 as previously reported.
Unfortunately, clear optical rotation of the natural
products was not available, but only a positive sign was
19. Rinehart mentioned that data of the X-ray crystallo-
2
c
graphic analysis was still ambiguous.