Synthesis of notoamide J: A potentially pivotal intermediate in the biosynthesis of several prenylated indole alkaloids

Article abstract of DOI:10.1021/jo100332c

An efficient total synthesis of notoamide J, a new prenylated indole alkaloid and potential biosynthetic precursor, is described herein. Starting from l-proline and a substituted tryptophan derivative, this synthesis also employs an oxidation and pinacol rearrangement for the formation of the oxindole in the final step.

Full text of DOI:10.1021/jo100332c

pubs.acs.org/joc
Synthesis of Notoamide J: A Potentially Pivotal Intermediate in the
Biosynthesis of Several Prenylated Indole Alkaloids
Jennifer M. Finefield and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
rmw@lamar.colostate.edu
Received February 22, 2010
An efficient total synthesis of notoamide J, a new prenylated indole alkaloid and potential
biosynthetic precursor, is described herein. Starting from L-proline and a substituted tryptophan
derivative, this synthesis also employs an oxidation and pinacol rearrangement for the formation of
the oxindole in the final step.
Introduction
indole alkaloids,1 specifically the paraherquamides,2 brevia-
namides,3 notoamides,4 and stephacidins,5 among others.
These families of secondary metabolites have been isolated
from various fungi of the genera Aspergillus and Penicillium
and have exhibited a wide range of biological activity,
including insecticidal, antitumor, anthelmintic, and antibac-
terial activity.6 Their desirable biological activity, as well as
the complex amino acid skeleton7 and bicyclo[2.2.2]dia-
zaoctane ring, makes these prenylated indole alkaloids
attractive targets for total synthesis.8
Over the past several years, the number of new prenylated
indole alkaloids isolated from fungi of both marine and
terrestrial origin has greatly increased. Recently, Tsukamoto
and co-workers isolated notoamide J (1),4b one of six novel
secondary metabolites, from a marine-derived Aspergillus
Over the past decade, our laboratory has extensively
studied the biosynthesis of naturally occurring prenylated
(1) (a) Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711–740.
(b) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127–139.
(c) Stocking, E. M.;Sanz-Cervera, J. F.; Williams, R. M. Angew. Chem. 2001,
113, 1336-1338; Angew. Chem., Int. Ed. 2001, 40, 1296-1298.
(2) (a) Yamazaki, M.; Okuyama, E.; Kobayashi, M.; Inoue, H. Tetra-
hedron Lett. 1981, 22, 135–136. (b) Ondeyka, J. G.; Goegelman, R. T.;
Schaeffer, J. M.; Kelemen, L.; Zitano, L. J. Antibiot. 1990, 43, 1375–1379.
(c) Liesch, J. M.; Wichmann, C. F. J. Antibiot. 1990, 43, 1380–1386.
(d) Banks, R. M.; Blanchflower, S. E.; Everett, J. R.; Manger, B. R.; Reading,
C. J. Antibiot. 1997, 50, 840–846.
(3) (a) Birch, A. J.; Wright, J. J. Tetrahedron 1970, 26, 2329. (b) Birch,
A. J.; Wright, J. J. S. J. Chem. Soc., Chem. Commun. 1969, 644–645. (c) Birch,
A. J.; Russell, R. A. Tetrahedron 1972, 28, 2999.
(4) (a) Kato, H.; Yoshida, T.; Tokue, T.; Nojiri, Y.; Hirota, H.; Ohta, T.;
Williams, R. M.; Tsukamoto, S. Angew. Chem., Int. Ed. 2007, 46, 2254–2256.
(b) Tsukamoto, S.; Kato, H.; Samizo, M.; Nojiri, Y.; Onuki, H.; Hirota, H.;
Ohta, T. J. Nat. Prod. 2008, 71, 2064–2067. (c) Greshock, T. J.; Grubbs,
A. W.; Jiao, P.; Wicklow, D. T.; Gloer, J. B.; Williams, R. M. Angew. Chem.,
Int. Ed. 2008, 47, 3573–3577. (d) Tsukamoto, S.; Kato, H.; Greshock, T. J.;
Hirota, H.; Ohta, T.; Williams, R. M. J. Am. Chem. Soc. 2009, 131, 3834–
3835. (e) Tsukamoto, S.; Kawabata, T.; Kato, H.; Greshock, T. J.; Hirota,
H.; Ohta, T.; Williams, R. M. Org. Lett. 2009, 11, 1297–1300.
(6) (a) Qian-Cutrong, J.; Krampitz, K. D.; Shu, Y.-Z.; Chang, L.-P.; Lowe,
S. E. U.S. Patent 6,291,461. (b) Blanchflower, S. E.; Banks, R. M.; Everett, J. R.;
Manger, B. R.; Reading, C. J. Antibiot. 1991, 44, 492–497. (c) Whyte, A. C.;
Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat. Prod. 1996, 59, 1093–1095.
(7) (a) Williams, R. M.; Stocking, E. M.; Sanz-Cervera, J. F. Top. Curr.
Chem. 2000, 209, 98–173. (b) Stocking, E. M.; Sanz-Cervera, J. F.; Unkefer,
C. J.; Williams, R. M. Tetrahedron 2001, 57, 5303.
(5) (a) Qian-Cutrong, J.; Huang, S.; Shu, Y.-Z.; Vyas, D.; Fairchild, C.;
Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S. E.; Gao, Q. J. Am.
Chem. Soc. 2002, 124, 14556–14557. (b) Kato, H.; Yoshida, T.; Tokue, T.;
Nojiri, Y.; Hirota, H.; Ohta, T.; Williams, R. M.; Tsukamoto, S. Angew.
Chem., Int. Ed. 2007, 46, 2254–2256.
(8) (a) Grubbs, A. W.; Artman, G. D., III.; Williams, R. M. Tetrahedron
Lett. 2005, 46, 9013–9016. (b) Grubbs, A. W.; Artman, G. D., III.; Tsukamoto,
S.; Williams, R. M. Angew. Chem., Int. Ed. 2007, 46, 2257–2261. (c) Miller,
K. A.; Welch, T. R.; Greshock, T. J.; Ding, Y.; Sherman, D. H.; Williams, R. M.
J. Org. Chem. 2008, 73, 3116–3119.
DOI: 10.1021/jo100332c
r
Published on Web 04/01/2010
J. Org. Chem. 2010, 75, 2785–2789 2785
2010 American Chemical Society

Finefield and Williams
JOCFeatured Article
SCHEME 1. Possible Biogenetic Relationships via Notoamide J
SCHEME 2. Retrosynthetic Plan
sp. that was collected in the Sea of Japan off the Noto
Peninsula. Like the rest of the notoamides, 1 contains both
tryptophan and proline, as well as an isoprene unit; however,
this natural product lacks the bridged bicyclo[2.2.2]dia-
zaoctane ring system, a distinguishing characteristic obser-
ved in many of the prenylated indole alkaloids such as the
paraherquamides and brevianamides. Notoamide J also
lacks the pyranoindole ring system often found in the
notoamides, norgeamides,9 and stephacidins. However, noto-
amide J does contain two notable structural features, both of
which may allow 1 to serve as an advanced intermediate
along the biosynthetic pathway to other notoamides. First,
notoamide J is only one of a handful of metabolites to
contain an oxindole ring system, in which one could envision
the oxindole moiety to serve as a biosynthetic precursor to
the numerous natural products containing the spiro-
oxindole ring system. Notoamide J is unique among the
alkaloids in these families of natural products as it displays
substitution only at the C-6 position of the indole. This
feature allows one to envisage that the unsubstituted hydroxy
group at this position could lead to the biosynthetic forma-
tion of the pyranoindole ring system. These two structural
characteristics provide provocative hints that notoamide J
could be a biosynthetic precursor to notoamide B and/or
versicolamide B. A possible series of biogenetic relationships
between notoamide J and the more advanced metabolites
(þ)-versicolamide B and (þ)-notoamide B are illustrated in
Scheme 1. It is reasonably assumed that notoamide J is
fashioned from the common biosynthetic precursor, deoxy-
brevianamide E by aromatic hydroxylation at the 6-position
of the indole ring. A subsequent oxidation and pinacol-type
rearrangement furnishes the oxindole notoamide J. Sub-
sequent prenylation of notoamide J at the C-7 position yields
7-prenylnotoamide J that would serve as the key precursor for
biosynthetic construction of the pyran ring system, yielding
3-epi-notoamide C, a natural metabolite identified by Tsuka-
moto and co-workers. Final oxidation of 3-epi-notoamide C to
an azadiene and intramolecular Diels-Alder cycloaddition
could, in principle, lead to (þ)-versicolamide B and/or (þ)-
notoamide B. The former conversion has recently been
experimentally verified by this laboratory.10
As part of our program aimed at the elucidation of the
entire notoamide/stephacidin biosynthetic pathway, we de-
sired a synthesis of notoamide J that was readily amenable to
the incorporation of stable isotopes from which probe sub-
strates could be interrogated. We report here the first synthe-
sis of notoamide J which also serves to corroborate the
structural assignment recently published by Tsukamoto
and co-workers.
Following established chemistry deployed in our labora-
tory,8 we planned notoamide J arising from an oxidation and
pinacol rearrangement of 2 (Scheme 2). The dioxopiperazine
2 could be obtained by coupling and cyclizing L-proline ethyl
ester with the reverse prenylated tryptophan derivative 3,
which we could easily obtain from 6-hydroxyindole 4.
(9) The structures of the norgeamides were published via the internet
€
detailing the research performed by the Hans-Knoll Institute. See: http://
www.hki-jena.de/index.php.
(10) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009, 1,
63–68.
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SCHEME 3. Leimgruber-Batcho Synthesis of Indole 4
SCHEME 4. Synthesis of the Reverse Prenylated Tryptophan Derivative 13
SCHEME 5. Assembly of Notoamide J
Formation of 4 could be achieved from 5 following the
Leimgruber-Batcho protocol.11
Following Boc protection of the 6-hydroxyindole
(Scheme 4), formation of the C-2 reverse prenylated indole
was carried out following the excellent procedure established
by Danishefsky and co-workers.12 The C-3 indole position of
8 was chlorinated using NCS in DMF to afford 9, which was
treated with prenyl-9-BBN in the presence of NEt3 to yield
the reverse prenylated indole 10. Pure 10 was obtained in
48% yield due to the complication of removing excess 9-BBN
from the reaction mixture. The gramine 11 was formed by
treatment of 10 with dimethylamine and formaldehyde,
which was coupled with the benzophenone imine of glycine
by a modified Somei-Kametani coupling protocol.13 Imine
Results and Discussion
Following a modified Leimgruber-Batcho indole synthe-
sis (Scheme 3), commercially available nitrophenol was read-
ily converted to the desired 6-hydroxyindole. 4-Methyl-
3-nitrophenol (5) was first protected as benzyl ether 6,
followed by condensation of the nitrotoluene with N,N-
dimethylformamide dimethyl acetal and pyrrolidine to
afford 7. Reductive cyclization and benzyl deprotection
using hydrogenation were achieved in one step to yield the
desired 6-hydroxyindole (4).
(12) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964.
(11) Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214.
J. Org. Chem. Vol. 75, No. 9, 2010 2787

Finefield and Williams
JOCFeatured Article
hydrolysis afforded the tryptophan derivative 12, which was
readily converted to the corresponding N-Boc carbamate 13.
Following standard saponification conditions of 13, the
N-Boc acid was achieved in good yield, which was subse-
quently coupled with L-proline ethyl ester in the presence of
HATU and DIPEA to provide the amide 14 (Scheme 5).
Treatment of 14 with TFA removed both Boc protecting
groups to afford the free amine, which was subsequently
cyclized with 2-hydroxypyridine to provide both the cis- and
trans-dioxopiperazines 2 as a 1:1 ratio, which were readily
separated by column chromatography.
Completion of the synthesis required the treatment of the cis-
dioxopiperazine 2 with excess Davis oxaziridine14 to afford a
2:1 ratio of notoamide J and 3-epi-notoamide J, which were
readily separable by chromatography. Synthetic 1 was identical
to the natural product in all respects (1H, 13C, HRMS, CD).4b
In summary, the first total synthesis of notoamide J was
completed in 15 steps and 0.78% overall yield. Research is
currently underway to establish both the biosynthesis of
notoamide J and its role in the biosynthetic pathway of
notoamide B and versicolamide B. The synthesis recorded
here allows for easy access to isotopomers of notoamide J,
which allow us to interrogate the potential role of this species
as a potential biosynthetic precursor to more complex nat-
ural congeners. Work along these lines is in progress and will
be reported on in due course.
(12.2 g): white crystalline solid (mp 141-143 °C); 1H NMR
(300 MHz, CDCl3) δ 8.16 (br s, 1H), 7.60 (d, J = 8.4 Hz, 1H),
7.21 (m, 1H), 7.18 (t, J = 5.7 Hz, 1H), 6.93 (dd, J = 8.7, 2.1 1H),
6.52 (m, 1H), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 153.0,
147.0, 135.7, 126.0, 125.2, 121.2, 114.2, 104.0, 102.7, 83.5, 28.0; IR
(neat) 3413, 2981, 1738, 1457, 1395, 883, 722 cm-1; HRMS (ESI/
APCI) calcd for C13H15NO3Na (M þ Na) 256.0944, found
256.0944.
tert-Butyl-3-((dimethylamino)methyl)-2-(2-methylbut-3-en-2-yl)-
1H-indol-6-yl carbonate (11): Aqueous formaldehyde (1.26 mL,
15.5 mmol) was diluted with glacial acetic acid (35 mL). Aqu-
eous dimethylamine (6.5 mL, 58.5 mmol) was added, followed
by addition of indole 10 (4.15 g, 13.7 mmol) diluted in glacial
acetic acid (10 mL). The reaction mixture was stirred at room
temperature for 14 h. The reaction mixture was diluted with 1 M
NaOH to a pH >10. The aqueous layer was extracted with
diethyl ether, and the combined organic layer was dried over
Na2SO4 and concentrated to afford 4.14 g (84%) of an amber oil
that was taken on to the next reaction without further purifica-
tion: 1H NMR (300 MHz, CDCl3) δ 7.99 (br s, 1H), 7.62 (d, J =
8.7 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.87 (dd, J = 8.4, 2.1 Hz,
1H), 6.12 (dd, J = 17.7, 11.1 Hz, 1H), 5.16 (dd, J = 6.0, 0.9 Hz,
1H), 5.12 (d, J = 0.3 Hz, 1H), 3.55 (s, 2H), 2.19 (s, 6H), 1.56 (s,
9H), 1.53 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.9, 146.5,
146.3, 142.0, 133.7, 128.6, 119.7, 113.4, 112.32, 109.0, 103.1,
83.3, 54.1, 45.5, 39.6, 28.0, 27.3; IR (neat) 3385, 2933, 1734,
1466, 1142, 1013, 886 cm-1; HRMS (ESI/APCI) calcd for
C21H31N2O3 (M þ H) 359.2329, found 359.2324.
Ethyl 2-amino-3-(6-((tert-butoxycarbonyl)oxy)-2-(2-methyl-
but-3-en-2-yl)-1H-indol-3-yl)propanoate (12): Gramine 11 (4.14
g, 11.5 mmol), N-(diphenylmethylene)glycine ethyl ester (2.80 g,
10.5 mmol), tributylphosphine (850 μL, 4.2 mmol), and aceto-
nitrile (53 mL) were combined and stirred for 20 h at reflux under
Ar. The reaction was concentrated and purified via flash column
chromatography in 10% ethyl acetate in hexanes to afford 2.76 g of
a yellow amorphous solid, which was dissolved in THF (36 mL).
Then, 1 M HCl (12.0 mL) was added, and the reaction mixture was
stirred for 30 min at room temperature. The solvent was removed
under reduced pressure, and the residue was rediluted with satu-
rated aqueous NaHCO3 until basic. The mixture was extracted
with CH2Cl2 (2 times), dried over Na2SO4, and concentrated. The
crude residue was purified by flash column chromatography (3:1
hexanes/ethyl acetate; 5:95 MeOH/CH2Cl2) to give 1.51 g (76%) of
12 as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.44 (br s, 1H),
7.43 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.83 (dd, J =
8.7, 2.1 Hz, 1H), 6.00 (dd, J = 17.7, 10.2 Hz, 1H), 5.07-5.01 (m,
2H), 4.12-4.00 (m, 2H), 3.75 (dd, J = 9.6, 5.1 Hz, 1H), 3.22 (dd,
J = 14.4, 4.8 Hz, 1H), 2.95 (dd, J = 14.4, 9.6 Hz, 1H), 1.53 (s, 9H),
1.42 (s, 6H), 1.12 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 175.6, 153.1, 146.5, 146.1, 141.6, 134.2, 127.9, 119.0, 113.3, 112.0,
106.8, 103.7, 83.4, 61.0, 56.1, 39.3, 31.3, 27.9, 27.8, 14.4, 14.2; IR
(neat) 3389, 2977, 1734, 1465, 1243, 1143, 885 cm-1; HRMS (ESI/
APCI) calcd for C23H33N2O5 (M þ H) 417.2384, found 417.2388.
Ethyl 2-((tert-butoxycarbonyl)amino)-3-(6-((tert-butoxycarbonyl)-
oxy)-2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl)propanoate (13):
Boc2O (824 mg, 3.78 mmol) and 1 M NaOH (3.60 mL, 3.60
mmol) were added to a solution of amine 12 (1.50 g, 3.60 mmol)
in dioxane (18 mL). The reaction mixture stirred at room
temperature for 1 h and then concentrated under reduced
pressure to remove the dioxane. The resulting slurry was taken
up in H2O, acidified to pH 2 with 1 M KHSO4, and extracted
with EtOAc (3 ꢀ 50 mL). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure to
afford 1.85 g of 13 as a yellow amorphous solid that was used
Experimental Section
1H and 13C spectra were obtained using 300 or 400 MHz
spectrometers. The chemical shifts are given in parts per million
(ppm) relative to TMS at δ 0.00 ppm or to residual CDCl3 δ 7.26
ppm for proton spectra and relative to CDCl3 at δ 77.23 ppm for
carbon spectra. IR spectra were recorded on an FT-IR spectro-
meter as thin films. Mass spectra were obtained using a high/
low-resolution magnetic sector mass spectrometer. Flash col-
umn chromatography was performed with silica gel grade 60
(230-400 mesh). Unless otherwise noted, materials were obta-
ined from commercially available sources and used without
further purification. Dichloromethane (CH2Cl2), tetrahydrof-
uran (THF), toluene (PhMe), N,N-dimethylformamide (DMF),
acetonitrile (CH3CN), triethylamine (Et3N), and methanol
(MeOH) were all degassed with argon and passed through a
solvent purification system containing alumina or molecular
sieves.
(E)-4-Benzyloxy-2-nitro-β-pyrrolidinostyrene 7 was synthe-
sized by a known method established within the literature.11
Compounds 9 and 10 were synthesized via literature methods.8a
tert-Butyl 1H-indol-6-yl carbonate (8): Enamine 7 (24.3 g, 74.9
mmol) was combined with 10% Pd/C (2.43 g) and dissolved in
THF (250 mL). The reaction mixture was stirred under H2 at
40 psi for 2 h. The reaction mixture was filtered through a pad of
silica gel, and the catalyst was washed with diethyl ether. The
filtrate was concentrated, and crude 4 was immediately taken up
in acetonitrile (150 mL) and cooled to 0 °C. Di-tert-butyl
dicarbonate (14.7 g, 67.4 mmol) and a catalytic amount of
DMAP were added, and the reaction mixture was stirred for
2 h at room temperature. The reaction was concentrated and
purified via flash column chromatography in 95:5 hexanes/ethyl
acetate. The product was collected as a white solid in 70% yield
(13) (a) Somei, M.; Karasawa, Y.; Kaneko, C. Heterocycles 1981, 16, 941.
(b) Kametani, T.; Kanaya, N.; Ihara, M. J. Chem. Soc., Perkin Trans. 1 1981,
959.
(14) (a) Davis, F. A.; Townson, J. C.; Vashi, D. B.; Thimma Reddy, R.;
McCauley, J. P.; Harakal, M. E.; Gosciniak, D. J. Org. Chem. 1990, 55,
1254–1261. (b) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545–563.
1
without further purification: H NMR (300 MHz, CDCl3) δ
8.11 (br s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J =
8.4 Hz, 1H), 6.07 (dd, J = 17.7, 10.5 Hz, 1H), 5.17-5.06 (m,
3H), 4.49 (m, 1H), 4.05-3.90 (m, 2H), 3.28-3.12 (m, 2H), 1.55
2788 J. Org. Chem. Vol. 75, No. 9, 2010

Finefield and Williams
JOCFeatured Article
(s, 9H), 1.52 (s, 9H), 1.32 (s, 6H), 1.02 (t, J = 6.9 Hz, 3H); 13
C
The organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The crude residue was purified via flash column
chromatography eluting with 5:95 MeOH/CH2Cl2 to afford 160
mg (27%) of the desired cis diastereomer as a cream foam. The
trans diastereomer was isolated in 23% yield (140 mg) as yellow
foam: 1H NMR (400 MHz, 20:1 CDCl3/CD3OD) δ 8.15 (m, 1H),
7.17 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.58 (dd, J =
8.4, 2.0 Hz, 1H), 6.04 (dd, J = 17.6, 10.4, 1H), 5.10-5.05 (m, 2H),
4.35 (dd, J = 11.2, 2.4 Hz, 1H), 4.00 (t, J = 7.6 Hz, 1H), 3.86-3.54
(m, 3H), 3.08 (dd, J = 14.8, 11.6 Hz, 1H), 2.30-1.82 (m, 6H),
1.45-1.38 (m, 6H); 13C NMR (75 MHz, 20:1 CDCl3/CD3OD) δ
169.7, 166.3, 153.0, 146.1, 140.3, 135.9, 123.0, 118.3, 112.3, 110.0,
103.9, 96.9, 59.4, 55.1, 45.6, 39.1, 28.5, 28.0, 26.1, 25.9, 22.7; IR
(neat) 3353, 2925, 1664, 1457 cm-1; HRMS (ESI/APCI) calcd for
C21H26N3O3 (M þ H) 368.1969, found 368.1969.
NMR (75 MHz, CDCl3) δ 173.1, 152.8, 146.7, 146.0, 141.4,
134.0, 128.0, 119.0, 113.5, 112.4, 106.1, 103.4, 83.3, 79.8, 61.4,
54.8, 39.4, 28.4, 28.0, 27.8, 27.6, 14.4, 14.0; IR (neat) 3388, 2979,
1755, 1464, 1369, 1143 cm-1; HRMS (ESI/APCI) calcd for
C28H40N2O7Na (M þ Na) 539.2728, found 539.2727.
(2S)-Ethyl-1-(2-((tert-butoxycarbonyl)amino)-3-(6-((tert-butoxy-
carbonyl)oxy)-2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl)propanoyl)-
pyrrolidine-2-carboxylate (14): The ethyl ester tryptophan deri-
vative 13 (1.85 g, 3.60 mmol) was dissolved in 2:1 H2O/THF
(36 mL), and LiOH (826 mg, 36.0 mmol) was added. The
reaction mixture was stirred at room temperature for 20 h.
The solvent was removed under reduced pressure, and the
resulting slurry was taken up in H2O, acidified to pH 2 with
1 M KHSO4, and extracted with CH2Cl2 (2 ꢀ 50 mL) and
EtOAc (2 ꢀ 50 mL). The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The
resulting crude residue was dissolved in acetonitrile (30 mL), and
L-proline ethyl ester (426 mg, 2.98 mmol) was added. HATU
Notoamide J (1). Davis oxaziridine (208 mg, 0.871 mmol) was
added to a solution of 2 (160 mg, 0.436 mmol) in CH2Cl2 (9 mL).
The reaction mixture was stirred 13 h at room temperature and
concentrated under reduced pressure. The residue was purified
via flash column chromatography eluting with MeOH/CH2Cl2
(5:95) to give 52 mg (31%) of 1 as a white amorphous solid and
26 mg (15%) of 15 as a white amorphous solid: 1H NMR (300
MHz, acetone-d6) δ 9.68 (br s, 1H), 8.59 (bs, 1H), 7.02 (d, J = 8.7
Hz, 1H), 6.49 (dd, J = 8.1, 5.7 Hz, 2H), 6.33 (br s, 1H), 6.12 (dd,
J = 17.4, 10.8 Hz, 1H), 5.05 (dd, J = 16.8, 10.8 Hz, 1H), 5.04
(dd, J = 16.8, 10.8 Hz, 1H), 4.00 (t, J = 6.9 Hz, 1H), 3.49-3.34
(m, 2H), 3.28 (d, J = 9.6 Hz, 1H), 3.10 (d, J = 14.7 Hz, 1H),
2.18-2.11 (m, 1H), 2.10 (d, J = 6.6 Hz, 1H), 1.98-1.80 (m, 3H),
1.11 (s, 3H), 1.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 183.2,
170.4, 165.7, 157.7, 143.3, 142.9, 126.8, 120.3, 114.5, 109.2, 98.6,
59.0, 57.8, 53.0, 45.9, 42.5, 31.7, 29.9, 28.2, 22.7, 21.8; IR (neat)
3265, 2971, 1670, 1429, 1155 cm-1; HRMS (ESI/APCI) calcd
for C21H25N3O4Na (M þ Na) 406.1737, found 406.1739.
i
(1.70 g, 4.47 mmol) and Pr2NEt (2.0 mL, 11.9 mmol) were
added, and the reaction mixture was stirred for 3 h at room
temperature. The reaction was quenched with 1 M HCl (40 mL)
and extracted with CH2Cl2 (3 ꢀ 75 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography and eluted with 3:1 hexanes/EtOAc to afford
1.08 g (59%) of 14 as a yellow amorphous solid: 1H NMR
(300 MHz, CDCl3) δ 8.35 (m, 1H), 7.48-6.74 (m, 3H), 6.04 (m,
1H), 5.52 (m, 1H), 5.15-5.06 (m, 2H), 4.62-1.98 (m, 9H),
1.51-1.12 (m, 30H); 13C NMR (75 MHz, CDCl3) δ 172.1,
171.3, 154.9, 152.7, 146.6, 145.3, 141.6, 133.6, 127.8, 119.2,
119.1, 113.4, 112.6, 106.0, 103.4, 83.2, 79.4, 61.1, 60.6, 59.3,
53.1, 46.6, 39.2, 28.5, 27.9, 27.4, 14.4, 14.3; IR (neat) 3351, 2979,
1753, 1634, 1497, 1450, 1143 cm-1; HRMS (ESI/APCI) calcd
for C33H48N3O8 (M þ H) 614.3436, found 614.3434.
Acknowledgment. This work was financially supported
by the National Institutes of Health (CA70375 to R.M.
W.). We wish to express our gratitude to Professor Sachiko
Tsukamoto of Kumamoto University for providing compa-
rison spectra of natural notoamide J. This paper is dedicated
to Professor Raymond L. Funk, of Pennsylvania State
University, on the occasion of his 60th birthday.
(3S,8aS)-3-((6-Hydroxy-2-(2-methylbut-3-en-2-yl)-1H-indol-
3-yl)methyl)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (2): TFA
(0.6 M) was added to a solution of 14 (1.08 g, 1.76 mmol) in
CH2Cl2 (0.6 M) at 0 °C. The reaction stirred for 3 h at room
temperature. The mixture was quenched with saturated NaHCO3
to pH 10 and extracted with EtOAc (3 ꢀ 20 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The residue was dissolved in toluene (0.2 M), and
2-hydroxypyridine (31 mg, 0.328 mmol) was added. The reaction
refluxed for 14 h under Ar atmosphere, cooled to room tempera-
ture, and concentrated under reduced pressure. The residue was
rediluted with CH2Cl2 (30 mL) and washed with 1 M HCl (30 mL).
Supporting Information Available: Full spectral character-
ization of notoamide J including comparison spectra to natural
material. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 9, 2010 2789