Synthetic studies toward anisatin: a formal synthesis of (+/-)-8-deoxyanisatin.

Article abstract of DOI:10.1021/ol006918c

[figure: see text] An efficient strategy to construct the congested C-7a quaternary chiral center of anisatin was developed, by way of an Eschenmoser-Claisen rearrangement. Conversion of the resultant amide to Kende's epsilon-lactone intermediate 3 in four steps completed a concise formal synthesis of (+/-)-8-deoxyanisatin (2).

Full text of DOI:10.1021/ol006918c

ORGANIC
LETTERS
2
001
Vol. 3, No. 2
79-281
Synthetic Studies toward Anisatin: A
Formal Synthesis of (±)-8-Deoxyanisatin
2
Teck-Peng Loh* and Qi-Ying Hu
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmlohtp@nus.edu.sg
Received November 23, 2000
ABSTRACT
An efficient strategy to construct the congested C-7a quaternary chiral center of anisatin was developed, by way of an Eschenmoser−Claisen
rearrangement. Conversion of the resultant amide to Kende’s E-lactone intermediate 3 in four steps completed a concise formal synthesis of
(±)-8-deoxyanisatin (2).
Anisatin (1), the convulsant principal of the seeds of Japanese
star anise (Illicium anisatum, L.), was first isolated pure by
In view of its intricate architecture and biological activity,
anisatin has attracted extensive synthetic studies. In 1982,
4
1
Lane et al. in 1952 and fully characterized by Yamada’s
the late Woodward’s group disclosed an elegant intramo-
lecular ene model study to construct the quaternary C-7a and
2
group in 1968. The sesquiterpene toxin features a highly
4
a
oxygenated indan backbone with eight contiguous chiral
centers, among which four are adjacent quaternary carbons,
the construction of which represents one of the most
vicinal C-8 chiral centers in one step. Unfortunately,
ensuing application of this strategy to the synthesis of anisatin
4
b
proved unsuccessful as far. Three years later, Kende and
3
4c
demanding tasks in multistep complex molecule synthesis.
Chen reported the total synthesis of (()-8-deoxyanisatin,
Consequently, synthetic studies toward anisatin offer numer-
ous opportunities for the development of new synthetic
strategies to this end. We hereby present an efficient approach
to forge the congested C-7a quaternary chiral center in a
labile system, leading to a formal synthesis of (()-8-
deoxyanisatin (2, Figure 1).
but it was not until 1990, nearly forty years since its isolation,
that Niwa et al. published the first total synthesis of anisatin
4
d
in 39 steps. Both routes employed Robinson annulation to
generate C-7a in an early stage of synthesis. The introduction
of C-7a at a later stage offers an alternative concise avenue
to the target, despite earlier futile attempts due to Woodward,
inspiring us to carry out studies.
(
1) Lane, J. F.; Koch, W. T.; Leeds, N. S.; Gorin, G. J. Am. Chem. Soc.
952, 74, 3211.
2) Yamada, K.; Takada, S.; Nakamura, S.; Hirata, Y. Tetrahedron 1968,
4, 199.
1
2
3
(
(
88.
3) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
(4) (a) Lindner, D. L.; Doherty, J. B.; Shoham, G.; Woodward, R. B.
Tetrahedron Lett. 1982, 23, 5111. (b) Lindner, D. L. Ph.D. Thesis, Harvard
University, Cambridge, MA, 1982. (c) Kende, A. S.; Chen, J. J. Am. Chem.
Soc. 1985, 107, 7184. (d) Niwa, H.; Nisiwaki, M.; Tsukada, I.; Ishigaki,
T.; Ito, S.; Wakamatsu, K.; Mori, T.; Ikagawa, M.; Yamada, K. J. Am.
Chem. Soc. 1990, 112, 9001. (e) Charonnat, J. A.; Nishimura, N.; Travers,
B. W.; Waas, J. R. Synlett 1996, 1162.
Figure 1.
1
0.1021/ol006918c CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/28/2000

Our retrosynthetic analysis of anisatin is outlined in
Scheme 1. The key step in our plan involves a [3,3]-Claisen
key intermediate 6 in 65% yield, amounting to 42% total
yield over four steps.
At this junction, we moved into the second phase of
synthesis entailing the introduction of quaternary chiral center
C-7a (Scheme 3). To this end, 1,4-diene 5 was obtained via
Scheme 1
Scheme 3a
rearrangement to construct the C-7a quaternary center in 4.
We envisaged that a few manipulations would convert 4 into
ꢀ
-lactone 3, which was a key intermediate in Kende’s total
synthesis of (()-8-deoxyanisatin.
Our synthesis commences from the preparation of key
intermediate carboxyindanol 6 (Scheme 2). Michael addition
(
a) Na, NH
c) LDA, THF, -78 °C, then BnOCH
CH dCHOEt, reflux; (e) Ac O, Et N, DMAP, CH
LiHMDS, THF, -78 °C, then TMSCl, to 25 °C; (g) CH
NMe (5 equiv), xylene, reflux, 48 h.
3
, reflux, 1 h, then NH
4
Cl; (b) CH
Cl, to 0 °C; (d) Hg(OAc)
Cl , 0 °C; (f)
2
C(OMe) -
2 2 2
N , Et O, 0 °C;
(
2
2
,
2
2
3
2
2
Scheme 2a
3
2
Birch reduction7d,8 of 6, followed by esterification with
CH in 60% yield. It is suspected that cyclohexa-1,4-diene
will be susceptible to re-aromatization or isomerization
2 2
N
8
,9
5
to the corresponding 1,3-diene. To prevent these, attempts
were made to alkylate C-4 which nevertheless failed due to
10
the facile re-aromatization of 5 under basic conditions. For
this reason, our attention turned to implementation of the
(
a) p-TolMgBr, CuI (5 mol %), Et
C, 48 h; (c) NaBH , CeCl ‚7H O, MeOH, -78 °C, 2 h; (d) n-BuLi
4 equiv), TMEDA (4 equiv), hexane, reflux, 3 h, then CO , 0 °C,
overnight, then 1 M HCl, 0 °C.
2
O, 0 °C, 3 h; (b) PPA, 90
[
3,3]-Claisen rearrangement protocol to construct C-7a
°
(
4
3
2
3
,11
12
instead. A vinyl ether Claisen rearrangement was first
2
(
7) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Panetta, C. A.; Dixit,
A. S. Synthesis 1981, 59. (c) Meyer, N.; Seebach, D. Chem. Ber. 1980,
1
13, 1304. (d) Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc.
1997, 119, 12031.
of p-TolMgBr to methyl crotonate (7) with a catalytic amount
of CuI in ether at 0 °C afforded the methyl ester 8 in 80%
yield, which underwent a smooth intramolecular Friedel-
(
8) (a) Hook, J. M.; Mander, L. N. Nat. Prod. Rep. 1986, 3, 35. (b)
Schultz, A. G. J. Chem. Soc., Chem. Commun. 1999, 1263. (c) Rabideau,
P. W.; Marcinow, Z. In Organic Reactions; Paquette, L. A. ed.; Wiley:
New York, 1992; Vol. 42, Chapter 1.
5
Crafts acylation to indanone 9 in 93% yield. To reach
(
9) (a) Plieninger, H.; Ege, G. Angew. Chem. 1958, 70, 505. (b) Hendry,
D. G.; Schuetzle, D. J. Am. Chem. Soc. 1975, 97, 7123.
10) Baker, A. J.; Goudie, A. C. J. Chem. Soc., Chem. Commun. 1972,
25.
11) For recent review, see: (a) Pereira, S.; Srebnik, M. Aldrichimica
6
carboxyindanol 6, 9 was reduced under Luche conditions
(
at -78 °C to provide a 10:1 ratio of the required syn vs anti
diastereomeric indanol 10 in 96% yield. Finally, carboxyl-
9
(
7
ation by means of directed ortho metalation gave the desired
Acta 1993, 26, 17. For examples, see: (b) McMurry, J. E.; Andrus, A.;
Ksander, G. M.; Musser, J. H.; Johnson, M. A. J. Am. Chem. Soc. 1979,
1
01, 1330. (c) Ireland, R. E.; Godfrey, J. D.; Thaisrivongs, S. J. Am. Chem.
(
5) Corey, E. J.; Behforouz, M.; Ishiguro, M. J. Am. Chem. Soc. 1979,
01, 1608.
6) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
Soc. 1981, 103, 2446. (d) Deng, W.; Jensen, M. S.; Overman, L. E.; Rucker,
P. V.; Vionnet, J.-P. J. Org. Chem. 1996, 61, 6760. (e) Nussbaumer, C.;
Fr a´ ter, G.; Kraft, P. HelV. Chim. Acta 1999, 82, 1016.
1
(
280
Org. Lett., Vol. 3, No. 2, 2001

explored, but only an unidentified tarry product was obtained.
product 4 was obtained predominantly in 40% yield, which
underwent selective reduction of the ester functionality to
provide 14 in 50% yield. The amide in 14 was next
hydrolyzed by heating with KOH in ethylene glycol at 200
°C under sealed tube conditions to afford carboxylic acid
15. Finally, mild lactonization to ꢀ-lactone 3 was effected
by heating with catalytic amount of p-TsOH in toluene at
70 °C in 70% yield over two steps. The structure of 3 was
proved by comprehensive 2D NMR studies (COSY, NOESY,
HMQC, and HMBC), and the proton NMR is substantially
Ensuing investigation with Ireland-Claisen rearrangement
also resulted in re-aromatized products.1
1,13
These failures
hinted at the lability of 5, which posed additional challenges
to our synthesis. Fortunately, subsequent experimentation
14
with Eschenmoser-Claisen rearrangement succeeded in the
generation of quaternary C-7a, providing amide 13 in 50%
yield. The syn relative stereochemistry at C-1 and C-7a in
13 was established by NOESY.
The successful preparation of 13 marked the entry into
the next synthetic phase, that is the synthesis of Kende’s
1
5
identical to that of Kende and Chen.
ꢀ
-lactone key intermediate 3 (Scheme 4). First, a selective
In summary, an efficient strategy for the construction of
sterically congested quaternary chiral centers in labile system
has been developed by means of an Eschenmoser-Claisen
rearrangement after a Birch reduction, in the course of
pursuing the total synthesis of anisatin. This strategy was
realized in the successful generation of the C-7a quaternary
chiral center, leading to a concise formal synthesis of
Scheme 4a
(()-8-deoxyanisatin. The synthesis of Kende’s ꢀ-lactone
intermediate 3 was accomplished in 11 steps from readily
available starting materials. Further synthetic studies toward
anisatin are currently in progress.
Acknowledgment. We are indebted to Professor Kende
of the University of Rochester for kindly forwarding to us a
copy of the data for ꢀ-lactone 3 and his helpful discussion.
We gratefully acknowledge the National University of
Singapore for generous financial support. We also wish to
thank Madam Han Yan-Hui for high-field NMR (500 MHz)
assistance.
(
a) LDA, cyclohexane/THF, -78 °C, then BnOCH
2
Cl, to 25 °C,
Supporting Information Available: Complete experi-
mental details, including characterization data for all new
compounds, and copies of COSY, NOESY, HMQC, and
HMBC NMR spectra of ꢀ-lactone 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
h; (b) LiBH , THF, 25 °C, 48 h; (c) KOH, ethylene glycol, sealed
tube, 200 °C, 12 h; (d) p-TsOH, toluene, 70 °C, 0.5 h.
4
alkylation at C-4, in the presence of several other potential
alkylation sites, was required. Under optimal conditions
OL006918C
(
LDA, cyclohexane/THF, -78 °C), the desired alkylation
(
14) (a) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chim.
Acta 1964, 47, 2425. (b) Kanematsu, K.; Nishizaki, A.; Shiro, S. M.
Tetrahedron Lett. 1992, 33, 4967.
(15) Personal communications with Professor A. S. Kende from the
University of Rochester.
(
12) Burghstahler, A. W.; Nordin, I. C. J. Am. Chem. Soc. 1961, 83,
98.
13) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897.
1
(
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