Synthesis and absolute configuration of (-)-serantrypinone

Article abstract of DOI:10.1016/j.tetlet.2007.08.013

A synthesis of (-)-serantrypinone (3) has been achieved from l-tryptophan. A key reaction involves the transformation of a selenoxide to an acetate via trapping of a presumed intermediate in a seleno-Pummerer reaction.

Full text of DOI:10.1016/j.tetlet.2007.08.013

Tetrahedron Letters 48 (2007) 7069–7071
Synthesis and absolute configuration of (ꢀ)-serantrypinone
David J. Hart* and Gabriel Oba
Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, OH 43210, USA
Received 12 July 2007; revised 1 August 2007; accepted 2 August 2007
Available online 8 August 2007
Abstract—A synthesis of (ꢀ)-serantrypinone (3) has been achieved from L-tryptophan. A key reaction involves the transformation
of a selenoxide to an acetate via trapping of a presumed intermediate in a seleno-Pummerer reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Serantrypinone is a spirooxindole alkaloid whose struc-
ture was first reported by a Danish group in 2001 after
isolation from the fungus Penicillium thymicola
(Fig. 1).1 This natural product was assigned structure
1 with the absolute configuration based on the similarity
of its CD spectrum with that of (+)-alantrypinone (2), a
structurally related alkaloid whose absolute configura-
tion was initially based on X-ray crystallographic stud-
ies (anomolous dispersion method) and later supported
by total synthesis of its enantiomer.2,3 Serantrypinone
was also isolated by Japanese scientists from the fungus
Aspergillus terreus, and shown to have insecticidal prop-
erties based on its ability to bind to GABA (c-aminobu-
tyric acid) receptors.4 Some doubt remains regarding
the absolute configurations of these materials because
the materials from P. thymicola and A. terreus were
reported to be levorotatory and dextrorotatory, respec-
tively. In addition, the reported optical rotations also
differed in magnitude.
To resolve this issue, we undertook a synthesis of seran-
trypinone, with the absolute configuration depicted by
structure 3 in Figure 1, from L-tryptophan. Our results
are reported here.
The synthesis began with compound 4, prepared from
L-tryptophan ethyl ester in six steps as previously
described.3 Treatment of 4 with phenylselenenyl chloride
(1.0 equiv) in dichloromethane (rt, 60 min) provided
bridged indole 5 in 78% yield (Scheme 1).5 We hoped
to convert the phenylselenyl group to the required
hydroxyl group by sequential oxidation to the selen-
oxide, a seleno-Pummerer rearrangement,6 hydrolysis
of the resulting Se,O-acetal to the aldehyde, and reduc-
tion to a hydroxymethyl group. Oxidation to a mixture
of diastereomeric selenoxides 6 was accomplished in
72% yield using m-CPBA. To our surprise, treatment
of this mixture with acetic anhydride (75 ꢁC, 5 h) gave
material that was clearly acetate 7, albeit in only 15%
yield. The structure of 7 was clear based on spectro-
scopic data (MS, 1H NMR, 13C NMR, and selected
COSY spectra).7 For example, the AB system due to
the acetoxymethyl group appeared as a doublet of dou-
blets (J = 11 Hz) at d 5.07 and 5.11 (DMSO-d6).
In unpublished work, we had prepared iodide 8 and
determined that it failed to undergo substitution reac-
tions with several oxygen nucleophiles. Thus, we
thought it unlikely that the acetoxy group was intro-
duced by an intermolecular displacement reaction. It
appeared more reasonable that the acetate be intro-
duced by intramolecular delivery from N2 of 7. Based
on this reasoning we converted 5 to imide 9 in 78%
yield using acetic anhydride (100 ꢁC, 21 h) (Scheme 2).
Oxidation of 9 with m-CPBA followed by immediate
reaction of the resulting mixture of selenoxides 10 with
Figure 1. Structures of serantrypinone and alantrypinone.
*
Corresponding author. Tel.: +1 614 292 1677; fax: +1 614 292
1685; e-mail: hart@chemistry.ohio-state.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.013

7070
D. J. Hart, G. Oba / Tetrahedron Letters 48 (2007) 7069–7071
Scheme 3. Possible mechanism for conversion of 10 to 7.
We suggest that the conversion of selenoxide 10 to ace-
tate 7 occurs via the mechanism outlined in Scheme 3.
Acylation of the selenoxide activates the selenium for
nucleophilic displacement. Neighboring group partici-
pation of the N-acetyl group of imide 12 affords an
intermediate of type 13, which is captured by water (or
an equivalent nucleophile) to provide 14. Breakdown
of this tetrahedral intermediate occurs with cleavage of
the imide N–C bond to afford the observed product 7.8
Scheme 1. Preparation of acetate 7 from enamide 4.
The synthesis of serantrypinone was completed by
oxidative rearrangement of 7 to spirooxindole 11
(17%) in a manner similar to that used in our syntheses
of (ꢀ)-alantrypinone and (ꢀ)-lapatin B.3,9 The rear-
rangement of 7 also provided 17-epi-11 in 4% yield.
Methanolysis of the ester (11) was accomplished in
76% yield using sodium methoxide (5.0 equiv) in DMSO
at room temperature for 72 h. Spectral data of the syn-
thetic serantrypinone (1H NMR, 13C NMR, and MS)
agreed with those reported for serantrypinone by the
Danish group.1,10 This material was also identical
(TLC, 1H NMR, and 13C NMR) to an authentic sample
of serantrypinone isolated by the Japanese group.4
Compound 3 was levorotatory.10 Chiral HPLC analysis
indicated that 3 was the enantiomer of the serantrypi-
none reported by the Japanese group.4,11,12 CD spec-
troscopy also indicated that 3 was the enantiomer of
the serantrypinone isolated by the Danish group.1 This
establishes the absolute configuration of (ꢀ)-serantrypi-
none and (+)-serantrypinone as 3 and 1, respectively,
and suggests that P. thymicola and A. terreus both pro-
duce (+)-serantrypinone.
Acknowledgments
We thank Mr. Eric King for assistance with the CD
spectra, Professor T. V. Rajanbabu and Dr. Bing Wu
for assistance developing the chiral HPLC analysis,
and Professor Yoshihisa Ozoe for helpful discussions
and kindly supplying a sample of (+)-serantrypinone
(PF1198B) from A. terreus.
Scheme 2. Synthesis of serantrypinone.
acetic anhydride (75 ꢁC, 5 h) gave 7 in 30–53% overall
yield.

D. J. Hart, G. Oba / Tetrahedron Letters 48 (2007) 7069–7071
7071
(CH), 120.7 (C), 123.0 (CH), 126.8 (CH), 127.4 (C), 127.7
(CH), 127.8 (CH), 131.4 (C), 135.2 (CH), 135.7 (C), 146.8
(C), 152.3 (C), 159.6 (CO), 169.3 (CO), 170.9 (CO); exact
mass (EI) calcd for C23H18N4O4+Na: m/z 437.1226;
found, m/z 437.1237.
References and notes
1. Ariza, M. R.; Larsen, T. O.; Petersen, B. O.; Duus, J. Ø.;
Christophersen, C.; Barrero, A. F. J. Nat. Prod. 2001, 64,
1590–1592; Also see: Larsen, T. O.; Svendsen, A.;
Smedsgaard, J. Appl. Environ. Microbiol. 2001, 67, 3630–
3635.
2. Larsen, T. O.; Frydenvang, K.; Frisvad, J. C.; Christo-
phersen, C. J. Nat. Prod. 1998, 61, 1154–1157.
3. Hart, D. J.; Magomedov, N. A. Tetrahedron Lett. 1999,
40, 5429–5432; Hart, D. J.; Magomedov, N. A. J. Am.
Chem. Soc. 2001, 123, 5892–5899.
8. To our knowledge, displacement of a selenenic acid ester
in a substitution reaction has not been reported. A
reaction that mechanistically resembles our proposal
(Scheme 3) is the cyanogen bromide mediated cleavage
of peptides at the carboxyl side of methionine residues:
Gross, E. Methods Enzymol. 1967, 11, 238–255; Hancock,
W. S.; Marshall, G. R. J. Am. Chem. Soc. 1975, 97, 7488–
7489.
4. Kuriyama, T.; Kakemoto, E.; Takahashi, N.; Imamura,
K.; Oyama, K.; Suzuki, E.; Harimaya, K.; Yaguchi, T.;
Ozoe, Y. J. Agric. Food Chem. 2004, 52, 3884–3887, This
paper also refers to (+)-serantrypinone as PF1198B; Ozoe,
Y.; Takahashi, N.; Oyama, K.; Imamura, K.; Harimaya,
T.; Yaguchi, T. Japanese Patent No. 2002-142795, 2002.
5. We first examined oxygen electrophiles including
dimethyldioxirane and m-CPBA without success. Details
will be provided in a full account of this research.
6. For examples of seleno-Pummerer rearrangements see:
Veerapen, N.; Taylor, S. A.; Walsby, C. J.; Pinto, B. M. J.
Am. Chem. Soc. 2006, 128, 227–239; Uneyama, K.;
Tokunaga, Y.; Maeda, K. Tetrahedron Lett. 1993, 34,
1311–1312; Nagao, Y.; Ochiai, M.; Kaneko, K.; Maeda,
A.; Watanabe, K.; Fujita, E. Tetrahedron Lett. 1977, 18,
1345–1348; Reich, H. J.; Shah, S. K. J. Org. Chem. 1977,
42, 1773–1776.
9. Pellegrini, C.; Stra¨ssler, C.; Weber, M.; Borschberg, H.-J.
Tetrahedron: Asymmetry 1994, 5, 1979–1992; Stahl, R.;
Borschberg, H.-J.; Acklin, P. Helv. Chim. Acta 1996, 79,
1361–1378; Hart, D. J.; Walker, S. J. Tetrahedron Lett.
2007, 48, 6214–6216.
10. Some properties of (ꢀ)-serantrypinone: mp >240 ꢁC; [a]D
ꢀ4.0 (c 0.2, EtOH); 1H NMR (DMSO-d6, 500 MHz) d
2.38 (dd, J = 13.0, 2.0 Hz, 1H, CH2), 2.42 (dd, J = 13.0,
2.0 Hz, 1H, CH2), 3.58 (dd, J = 14.0, 6.5 Hz, 1H, CH2O),
3.71 (dd, J = 14.0, 6.5 Hz, 1H, CH2O), 4.59 (t, J = 6.5 Hz,
1H, OH), 5.55 (d, J = 2 Hz, 1H, CHN), 6.89 (d, J = 8 Hz,
1H, ArH), 7.08 (t, J = 7.5 Hz, 1H, ArH), 7.22 (d,
J = 7 Hz, 1H, ArH), 7.30 (t, J = 8 Hz, 1H, ArH), 7.61
(t, J = 8 Hz, 1H, ArH), 7.75 (d, J = 7.5 Hz, 1H, ArH),
7.88 (t, J = 8 Hz, 1H, ArH), 8.23 (dd, J = 8, 1.5 Hz, 1H,
ArH), 9.78 (s, 1H, NHCO), 10.52 (s, 1H, NH oxindole);
13C NMR (CDCl3, 62.9 MHz) d 38.0 (CH2), 52.6 (CH),
53.1 (C), 58.2 (CH2), 65.5 (C), 110.3 (CH), 120.6 (C), 122.5
(CH), 124.3 (CH), 126.8 (CH), 127.8 (CH), 128.2 (CH),
129.6 (CH), 130.1 (C), 135.2 (CH), 143.0 (C), 147.1 (C),
152.7 (C), 158.8 (CO), 170.0 (CO), 177.3 (CO); exact mass
(EI) calcd for C21H16N4O4+Na: m/z 411.1069; found, m/z
411.1069.
22
7. Characterization data for 7: mp >200 ꢁC; ½aꢁD +145 (c
0.85, EtOAc); IR (NaCl plates) 3306, 3080, 2904, 1735,
1690, 1608, 1468 cmꢀ1; 1H NMR (DMSO-d6, 400 MHz) d
2.14 (s, 3H, CH3), 3.42 (dd, J = 14.0, 2.0 Hz, 1H, CH2),
3.46 (dd, J = 14.0, 2 Hz, 1H, CH2), 5.07 (d, J = 10.9 Hz,
1H, CH2Se), 5.11 (d, J = 10.9 Hz, 1H, CH2Se), 5.73
(broad s, 1H, CHN), 7.00 (t, J = 8.0 Hz, 1H, ArH), 7.13 (t,
J = 8.0 Hz, 1H, ArH), 7.38 (d, J = 8.0 Hz, 1H, ArH), 7.41
(d, J = 8.0 Hz, 1H, ArH), 7.46 (t, J = 8.0 Hz, 1H, ArH),
7.56 (d, J = 8.0 Hz, 1H, ArH), 7.72 (t, J = 8.0 Hz, 1H,
ArH), 8.07 (d, J = 8.0 Hz, 1H, ArH), 9.75 (broad s, 1H,
NHCO), 11.32 (s, 1H, NH indole); 13C NMR (DMSO-d6,
125.75 MHz) d 21.5 (CH3), 26.0 (CH2), 54.3 (CH), 56.9
(C), 62.9 (CH2), 106.8 (C), 112.3 (CH), 118.6 (CH), 119.9
11. HPLC conditions: Column = Chiracel OJ (250 · 4.6 (ID)
mm from Daicel Chemical Industries); Solvent = hexanes/
isopropyl alcohol, 4:1; flow rate = 1 mL/min; retention
times for 1 and 3 = 13.6 and 22.0 min, respectively.
12. The specific rotations reported for serantrypinone from P.
thymicola1 and A. terreus4 are ꢀ12 and +21.7, respectively
(Na D-line at room temperature).