Concise syntheses of the 1,7-dihydropyrano[2,3-g]indole ring system of the stephacidins, aspergamides and norgeamides

Article abstract of DOI:10.1016/j.tetlet.2005.10.112

Three approaches towards the synthesis of the 1,7-dihydropyrano[2,3-g] indole ring system of the stephacidins, paraherquamides and norgeamides have been investigated. The first involves a tandem nitrene insertion/aromatic Claisen rearrangement. The second

Full text of DOI:10.1016/j.tetlet.2005.10.112

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 9013–9016
Concise syntheses of the 1,7-dihydropyrano[2,3-g]indole ring
system of the stephacidins, aspergamides and norgeamides
Alan W. Grubbs, Gerald D. Artman, III and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
University of Colorado Cancer Center, Aurora, CO 80045, USA
Received 16 June 2005; revised 18 October 2005; accepted 21 October 2005
Available online 8 November 2005
Abstract—Three approaches towards the synthesis of the 1,7-dihydropyrano[2,3-g]indole ring system of the stephacidins, paraher-
quamides and norgeamides have been investigated. The first involves a tandem nitrene insertion/aromatic Claisen rearrangement.
The second consists of a more conventional approach from commercially available 6-benzyloxyindole. The third approach is a
revised synthesis of the 2-prenylated pyrano indole necessary for a biomimetic Diels–Alder approach towards the stephacidins,
aspergamides and the norgeamides.
Ó 2005 Elsevier Ltd. All rights reserved.
Fungi continue to be a rich source of complex and
unprecedented indole alkaloids with a wide range of bio-
logical activity. As is often the case, the indole ring is
oxidized to produce a variety of functionalized hetero-
cyclic ring systems. In particular, the 1,7-dihydropyr-
ano[2,3-g]indole ring system has recently been
observed in several novel alkaloids. For example,
the aspergamides A (1) and B (2) were isolated from
Aspergillus ochraceus by Zeek and co-workers, who
elucidated their structures using NMR experiments
(Fig. 1).1 Both were characterized by a bicyclo[2.2.2]di-
azaoctane bridged bicycle and a 1,7-dihydropyrano-
[2,3-g]indole ring system. Furthermore, aspergamide A
(1) exhibits a unique a-hydroxy nitrone moiety, whereas
aspergamide B (2) is the dehydrated imine congener.
Structurally related to the aspergamides, avrainvilla-
mide (CJ-17,665, 3) also contains a [2.2.2] bridged
bicycle and the pyrano indole ring system, in addition
to an unprecedented vinyl nitrone moiety, which had
previously not been observed in this family.2
fungus growing in the North Sea.3 The norgeamides
A-D (4–7) are unique, in that they do not contain the
bridged diazaoctane observed in related alkaloids.
Instead, norgeamides A (4) and B (5) are comprised of
a pyrano 2-oxindole moiety bearing a reverse prenyl
group at C3, one of the two quaternary centers present
in these compounds. An oxidized diketopiperazine
(DKP) unit harbors the remaining quaternary center
at C17. Alternatively, norgeamides C (6) and D (7) find
the reverse prenyl group at C2 of a pyrroloindole ring
system and a hydroxyl group at C3. Preliminary biologi-
cal assays of the norgeamides reveal that norgeamide A
(4) to be the most cytotoxic against several carcinoma
cell lines.3
However, the most intriguing alkaloid recently isolated
containing the pyrano indole ring system is stephacidin
B (9). Isolated by Bristol-Meyers Squibb (BMS) from
the fungus A. ochraceus WC76466,4 the stephacidins A
(8) and B (9) both displayed in vitro cytotoxicity against
a panel of carcinoma cell lines with 9 being five- to
thirty-fold more cytotoxic than 8 possessing a high affin-
ity for testosterone-dependent prostate LNCaP cancer
cells. However, the cytotoxicity of stephacidin B (9)
is eclipsed by its unprecedented structure, which was
determined using NMR experiments and X-ray crystal-
lography. Stephacidin B contains fifteen rings, nine ste-
reogenic centers and two pyrano indole rings and was
proposed to be a dimer of 3.5 The unique structure,
cytotoxicity and biosynthetic relationships between
In addition to the aspergamides and avrainvillamide, a
German institute cultivated four alkaloids containing
the aforementioned indole ring system from a marine
Keywords: Indoles; Stephacidins; Norgeamides; Aspergamides; Pyrans;
Nitrenium ion; Aromatic Claisen; Reverse prenylation.
*
Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491
3944; e-mail: rmw@chem.colostate.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.112

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A. W. Grubbs et al. / Tetrahedron Letters 46 (2005) 9013–9016
Figure 1. Recently isolated alkaloids containing a 1,7-dihydropyrano[2,3-g]indole ring system.
these alkaloids have recently resulted in intense synthetic
interest including the first total synthesis of avrainvill-
amide (3) and stephacidin B (9) by Myers,6 and more
recently, BaranÕs revised total synthesis of stephacidin
A (8) en route to stephacidin B (9).7
was envisioned that the lactim ether 10 can be accessed
from a coupling of the known diketopiperazine 11 and
previously unknown gramine 12.
Since we were endeavoring to access two alkaloids
from a common intermediate, it was necessary to devel-
op a concise, high yielding synthesis of gramine 12 for
the SN20 approach. To this end, we were drawn to the
elegant nitrene insertion/Claisen rearrangement chemis-
try developed by Moody for the synthesis of allyl substi-
tuted indoles.9,10 Thus, 4-hydroxybenzaldehyde (13) was
alkylated with 3-chloro-3-methyl-1-butyne (14) using KI
and K2CO3 in refluxing acetone affording the ether alde-
hyde 15 in excellent yield (Scheme 2).11 Condensation of
the aldehyde 15 with methyl azidoacetate9,10 (16) cleanly
afforded the conjugated azide 17 in good yield. Genera-
tion of the nitrene from 17 in refluxing toluene facili-
tated formation of the indole formation via CH
insertion and, additionally, the pyran ring was formed
Our laboratory has a rich history with respect to similar
alkaloids containing many of the structural features
highlighted in Figure 1.8 We developed the first intra-
molecular SN20 approach for the preparation of the
[2.2.2]diazaoctane ring system found in these alkaloids
that was employed in asymmetric total syntheses of brevi-
anamide B, paraherquamide B and paraherquamide
A.8 Retrosynthetically, we envisioned that stephacidin
A (8) could be oxidized7 to afford avrainvillamide (3)
and stephacidin B (9, Scheme 1). In turn, 4 would be
accessed from lactim ether 10 via displacement of the
allylic chloride in an SN20 fashion to produce the
bridged bicycle and subsequent cyclization at C2 of
the indole would produce the cyclohexyl ring of 8. It
Scheme 1. An SN20 retrosynthetic approach towards the stephacidins.
Scheme 2. Synthesis of indole 20 via a Claisen/nitrene insertion.

A. W. Grubbs et al. / Tetrahedron Letters 46 (2005) 9013–9016
9015
under these conditions through a Claisen cyclization12
to produce compound 18 in excellent yield and as a
single regioisomer. Subsequent saponification of methyl
ester 18 to acid 19 was uneventful. However, decarbox-
ylation of 19 proved to be capricious with yields of the
desired indole 20 ranging from 15% to 77%. Unfortu-
nately, an exhaustive effort with various forms of
copper, additives and solvents failed to provide consis-
tency to this key transformation.
Alternatively, a more direct approach to gramine 12 was
realized from commercially available 6-benzyloxyindole
(21, Scheme 3).13 Protection of the indole nitrogen of 21
with (Boc)2O, followed by debenzylation and alkylation
of the resulting crude phenol with the previously
employed chloride 14 afforded aryl ether 22 in 58% over
the three steps on a multigram scale.12b Finally, heating
of alkyne 22 in o-dichlorobenzene cleanly effected the
aromatic Claisen cyclization as well as Boc cleavage to
afford the desired pyrano indole 20 in 87% yield. Finally,
conversion of indole 20 to the desired gramine 12 was
accomplished using standard conditions in 83% yield.
Scheme 4. A Diels–Alder approach towards the stephacidins.
hydroxyindole18 (26) was protected as its Boc carbonate
to form indole 27 in 75% yield (Scheme 5). Indole 27 was
then chlorinated using NCS to afford the 3-chloroindole
28 in good yield. Pleasingly, compound 28 readily
reacted with prenyl-9-BBN19 to afford 2-prenylated
indole 29 in 56% yield. We believe that the electron-
withdrawing nature of the carbonate is vital for the
success of this reaction in that electron-rich protected
variants of 28 (i.e., silyl ethers and alkyl ethers) failed
to produce any of the desired prenylated indole. Finally,
removal of the Boc carbonate of 29 with TFA produced
the previously synthesized 6-hydroxy-2-prenyl indole 30
obtained by the Fisher indole approach. Indole 30 was
converted to the pyrano indole 25 according to our
previous report12b in three steps, thereby providing the
necessary indole for our biomimetic approach in a more
concise and regioselective manner.
More recently, our laboratory has reported the synthesis
of isotopically labelled putative biosynthetic intermedi-
ates in this family of alkaloids and feeding experiments
describing the biosynthetic pathway towards these
bridged bicycle alkaloids.8,14–16 A substantial body of
evidence suggests that the biosynthetic formation of
the bicyclo[2.2.2]diazaoctane core is accomplished via
a Diels–Alder reaction. To this end, we have developed
a secondary, biomimetic approach towards these alka-
loids (Scheme 4). In the case of the stephacidins, the
bridged diazaoctane of stephacidin A (8) can be discon-
nected retrosynthetically to afford 23. Further discon-
nection of the Diels–Alder precursor 23 generates the
DKP 24 and the prenylated indole 25.
In conclusion, we have described the synthesis of our
key gramine 12 by two different strategies. The first
route proved to be capricious and failed to afford the
desired indole precursor in high yield. The second route
produced the desired gramine 12 in only five steps and in
41% overall yield. Furthermore, we have revised our
synthesis of the prenylated indole 25 via a boron-medi-
ated reverse prenylation reaction, thereby providing
multigram quantities of 25, regioselectively. These
We recently reported the synthesis of prenylated indole
25 via a Fisher indole strategy.12b Unfortunately, the
key Fisher ring formation step exhibited poor regioselec-
tivity generating a ꢀ1:1 mixture of the 4- and 6-meth-
oxyindoles, thereby limiting the throughput of material
for further manipulation. In order to overcome the defi-
ciencies of the Fisher route, we were drawn to a report
by Tatsuta in which 3-chloroindoles can be reverse
prenylated at C2 of indole with prenyl 9-BBN.17 To this
end, the hydroxyl group of commercially available 6-
Scheme 3. Synthesis of gramine 12 from 6-benzyloxyindole (21).
Scheme 5. Synthesis of 2-reverse prenylated indole 25.

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A. W. Grubbs et al. / Tetrahedron Letters 46 (2005) 9013–9016
8. For reviews of our previous synthetic and biosynthetic
work concerning this class of alkaloids, see: (a) Williams,
R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127–139; (b)
Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711–740.
9. (a) Moody, C. J. J. Chem. Soc., Chem. Commun. 1983,
1129–1130; (b) Moody, C. J. J. Chem. Soc., Perkin Trans.
1 1984, 1333–1337; (c) Martin, T.; Moody, C. J. J. Chem.
Soc., Perkin Trans. 1 1988, 241–246; (d) Bentley, D. J.;
Fairhurst, J.; Gallagher, P. T.; Manteuffel, A. K.; Moody,
C. J.; Pinder, J. L. Org. Biomol. Chem. 2004, 2, 701–708.
10. For additional uses of the Hemetsberger–Knittel reaction
for the synthesis of indoles, see: (a) da Rosa, F. A. F.;
Rebelo, R. A.; Nascimento, M. G. J. Braz. Chem. Soc.
2003, 14, 11–15; (b) Zhao, S.; Liao, X.; Wang, T.; Flippen-
Anderson, J.; Cook, J. M. J. Org. Chem. 2003, 68, 6279–
6295; (c) Sadanandan, E. V.; Pillai, S. K.; Lakshmikan-
tham, M. V.; Billimoria, A. D.; Culpepper, J. S.; Cava, M.
P. J. Org. Chem. 1995, 60, 1800–1805; (d) Allen, M. S.;
Hamaker, L. K.; La Loggia, A. J.; Cook, J. M. Syn.
Commun. 1992, 22, 2077–2102.
substances should find broad utility in the preparation
of the stephacidins, aspergamides and norgeamides as
well as for the preparation of isotopically labelled bio-
synthetic intermediates for biosynthetic studies, which
are currently being pursued in our laboratories.
Acknowledgements
The authors acknowledge financial support from the
National Institutes of Health (CA70375) and the NSRA
Postdoctoral Fellowship for G.D.A. (GM72296-01).
Mass spectra were obtained on instruments supported
by the NIH Shared Instrumentation Grant GM49631.
In addition, we would like to thank Professor James
Cook and Professor Louis Hegedus for suggestions
regarding the decarboxylation of indole 20.
11. All starting materials were prepared using the known
literature procedures. All new compounds were charac-
terized by 1H and 13C NMR and high resolution mass
spectroscopy. See Supplementary data for experimental
details and copies of NMR spectra for new compounds.
12. (a) Elomri, A.; Michel, S.; Tillequin, F.; Koch, M.
Heterocycles 1992, 34, 799–806; (b) Cox, R. J.; Williams,
R. M. Tetrahedron Lett. 2002, 43, 2149–2152.
Supplementary data
The supplementary data is available with the paper
at ScienceDirect. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.10.112.
13. 6-Benzyloxyindole is commercially available in multigram
quantities from 3B Medical Systems, Inc.; Libertyville, IL
60048, USA.
References and notes
14. For representative studies on the biosynthesis of the
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Kno¨ll Institute. See: http://www.hki-jena.de/.
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