Total syntheses of (-)-fructigenine A and (-)-5-N-acetylardeemin

Article abstract of DOI:10.1021/jo9023107

(Chemical Equation Presented) The first total synthesis of (-)-fructigenine A and a novel approach to (-)-5-N-acetylardeemin through a common imine intermediate (+)-3 are described. The key steps include highly enantioselective preparation of (+)-3 via domino olefination/isomerization/Claisen rearrangement (OIC) of 5, reductive cyclization (RC), and regioselective oxidation of (-)-4 and a novel assembly of the pyrazino ring of these alkaloids via Ugi three-component reaction/cyclization of (+)-3 with the corresponding amino acid and isonitrile.

Full text of DOI:10.1021/jo9023107

pubs.acs.org/joc
Total Syntheses of (-)-Fructigenine A and (-)-5-N-Acetylardeemin
Satoshi Takiguchi, Toshimasa Iizuka, Yuh-suke Kumakura, Kohta Murasaki, Naoko Ban,
Kazuhiro Higuchi, and Tomomi Kawasaki*
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
kawasaki@my-pharm.ac.jp
Received October 29, 2009
The first total synthesis of (-)-fructigenine A and a novel approach to (-)-5-N-acetylardeemin
through a common imine intermediate (þ)-3 are described. The key steps include highly enantio-
selective preparation of (þ)-3 via domino olefination/isomerization/Claisen rearrangement (OIC)
of 5, reductive cyclization (RC), and regioselective oxidation of (-)-4 and a novel assembly of the
pyrazino ring of these alkaloids via Ugi three-component reaction/cyclization of (þ)-3 with the
corresponding amino acid and isonitrile.
Introduction
fructigenium has growth-inhibitory activity against Avena
coleoptile and leukemia L-5178Y cells,1 and the metabolite 2
of the fungus Aspergillus fischerii (var. brasiliensis) is one of
the most potent known inhibitors of multidrug resistance
(MDR) to antitumor agents such vinblastine, taxol, and
doxorubicin.7a,8
The unique structural array and interesting biological acti-
vities displayed by this class of compounds make them attractive
synthetic targets. Known approaches to these alkaloids started
from L-tryptophan derivatives on the basis of proposed bio-
synthetic pathways. Thus, the total synthesis of amauromine
via tryptophan anhydride (1,4-diketopiperazine) including
reverse-prenylation/cyclization was performed.9 Reverse-pre-
nylated cyclic-tryptophan (pyrroloindoline-2-carboxylate)
derivatives constructed by selenide-mediated cyclization/
prenylation of L-tryptophan was applied to synthesize 2,10
The hexahydropyrazino[20,10-5,1]pyrrolo[2,3-b]indole ring
system bearing a 1,1-dimethylallyl (“reverse-prenyl”) group at
C10b is a widely distributed structural framework present in a
number of biologically active alkaloids such as fructigenine
A (1),1 okaramine M,2 roquefortine D,3 verrucofortine,4
brevicompanine B,5 amauromine,6 and 5-N-acetylardeemin
(2)7 (Figure 1). For example, 1 isolated from Penicillium
*To whom correspondence should be addressed. Phone and fax: 81-42-
495-8763.
(1) Arai, K.; Kimura, K.; Mushiroda, T.; Yamamoto, Y. Chem. Pharm.
Bull. 1989, 37, 2937.
(2) Shiono, Y.; Akiyama, K.; Hayashi, H. Biosci. Biotechnol. Biochem.
1999, 63, 1910.
(3) Ohmomo, S.; Oguma, K.; Ohashi, T.; Abe, M. Agric. Biol. Chem.
1978, 42, 2387.
(4) Hodge, R. P.; Harris, C. M.; Harris, T. M. J. Nat. Prod. 1988, 51, 66.
(5) Kusano, M.; Sotoma, G.; Koshino, H.; Uzawa, J.; Chijimatsu, M.;
Fujioka, S.; Kawano, T.; Kimura, Y. J. Chem. Soc., Perkin Trans. 1 1998,
2823.
(6) (a) Takase, S.; Iwami, M.; Ando, T.; Okamoto, M.; Yoshida, K.;
Horiai, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1984, 37, 1320.
(b) Takase, S.; Kawai, Y.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron
1985, 41, 3037.
(8) Chou, T. C.; Depew, K. M.; Zheng, Y.-H.; Safer, M. L.; Chan, D.;
Helfrich, B.; Zatorska, D.; Zatorski, A.; Bornmann, W.; Danishefsky, S. J.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8369.
(9) (a) Takase, S.; Itoh, Y.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron
Lett. 1985, 26, 847. (b) Takase, S.; Itoh, Y.; Uchida, I.; Tanaka, H.; Aoki, H.
Tetrahedron 1986, 42, 5887.
(7) (a) Karwowski, J. P.; Jackson, M.; Rasmussen, R. R.; Humphrey,
P. E.; Poddig, J. B.; Kohl, W. L.; Scherr, M. H.; Kadam, S.; McAlpine, J. B.
J. Antibiot. 1993, 46, 374. (b) Hochlowski, J. E.; Mullally, M. M.; Spanton,
S. G.; Whittern, D. N.; Hill, P.; McAlpine, J. B. J. Antibiot. 1993, 46, 380.
(10) (a) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem.
Soc. 1994, 116, 11143. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.;
Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 11953.
1126 J. Org. Chem. 2010, 75, 1126–1131
Published on Web 01/14/2010
DOI: 10.1021/jo9023107
r
2010 American Chemical Society

Takiguchi et al.
JOCArticle
SCHEME 1. Retrosynthesis of Fructigenine A (1) and (-)-5-N-
Acetylardeemin (2)
FIGURE 1. Structures of representative pyrazino-pyrroloindole
alkaloids: Ind=3-indolyl, Im=4-imidazoyl.
amauromine,10 roquefortines,11 and brevicompanine B.12
Recently, a route to 2 via cyclic-tryptophan involving
Cu-mediated cyclopropanation of L-tryptophanol has been
reported.13 Some analogues of 2 were also prepared for
studies of the anti-MDR activity.10b,14 In view of the potential
of these natural products as lead compounds for new and more
biologically active agents, a more effective and a diverse
approach to pyrazino-pyrroloindoles is highly desirable.
On our program directed toward the synthesis of these
alkaloids and related compounds, we sought an efficient and
versatile strategy for the enantioselective assembly of the
pyrazino-pyrroloindole skeleton. During the course of our
total syntheses of pseudophrynaminol and flustramines,
we demonstrated an efficient strategy for construction of
the 3a-allylpyrrolo[2,3-b]indole architecture by domino
olefination/isomerization/Claisen rearrangement (OIC) and
reductive cyclization (RC).15 In a subsequent synthetic in-
vestigation, we developed a novel methodology for approach
to these pyrazino-pyrroloindole alkaloids (Figure 1), and we
describe herein a first total synthesis of (-)-fructigenine A (1)
together with a new concise total synthesis of (-)-5-N-
acetylardeemin (2).15e
cyclization toassemble the pyrazinoring. The imine3 could be
predicted to serve as an effectively common intermediate to
the related alkaloids and obtained by regioselective oxidation
of pyrroloindoline 4. The enantiomerically enriched com-
pound 4 could be readily prepared from 5 by our modified
protocol including asymmetric OIC and RC.15
To synthesize alkaloids 1 and 2, we began by preparing
the key imine intermediate 3 (Scheme 2). Bromination of
1-acetylindolin-3-one (6)17 at the C2 site followed by sub-
stitution with (S)-2-methyl-2-decen-4-ol (7) (99% ee)15c af-
forded ether 5 in 88% yield. Horner-Wadsworth-Emmons
reaction of 5 with diethyl cyanomethylphosphonate in the
presence of t-BuOK at -78 to 0 °C proceeded smoothly with
domino olefination/isomerization/Claisen rearrangement
(OIC) to produce an enantiomerically enriched oxindole
(-)-8 in 89% yield and 99% ee.18,19 For conversion of the
alkenyl moiety in 8 to a reverse-prenyl group, a sequence of
ozonolysis of (-)-8 and Wittig olefination with methylidene-
phosphorane was carried out to provide 3-prenylindolin-
2-one (-)-9 in 65% yield for two steps. The reductive
cyclization (RC) of (-)-9 with LiAlH4 furnished pyrroloin-
dole (-)-4 in 80% yield. Each procedure in transformation of
6 to (-)-4 was readily performed on multigram scale in good
yield. Successive N1-Boc-protection of (-)-4 with Boc2O and
DMAP (90%), acetylation with acetyl chloride in the pre-
sence of NaOH and Bu4NHSO4 (90%), and removal of the
Boc group with TFA (90%) afforded N8-acetylpyrroloindole
(þ)-10. Oxidation20 of (þ)-10 with catalytic tetrapropylam-
monium perruthenate (TPAP) and NMO as a co-oxidant
proceeded regioselectively to give imine (þ)-3 with highly
enantiomeric purity (99% ee)17 in 89% yield. The desired key
common intermediate (þ)-3 was obtained from 6 in ten steps
and 26.5% overall yield.
Results and Discussion
Our retrosynthetic analysis of 1 and 2 is shown in
Scheme 1. A powerful disconnection that has heretofore been
unexplored in the synthesis of these alkaloids would involve
the Ugi three-component reaction16 of pyrroloindoline imine
3 withthe corresponding amino acidandisonitrile followed by
ꢀ
(11) (a) Chen, W.-C.; Joullie, M. M. Tetrahedron Lett. 1998, 39, 8401.
(b) Schiavi, B. M.; Richard, D. J.; Joullie, M. M. J. Org. Chem. 2002, 67, 620.
ꢀ
ꢀ
(c) Richard, D. J.; Schiavi, B. M.; Joullie, M. M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 11971.
(12) Matsumura, K.; Kitahara, T. Heterocycles 2001, 54, 727.
(13) He, B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298.
With easily available key intermediate (þ)-3 in hand,
we progressed toward the total synthesis of fructigenine A
~
ꢀ
€
(14) (a) Caballero, E.; Avendano, C.; Menendez, J. C. Tetrahedron 1999,
ꢀ
~
55, 14185. (b) Hernandez, F.; Avendano, C.; Sollhuber, M. Tetrahedron Lett.
2003, 44, 3367.
(17) The starting 6 was readily obtained from commercially available
1-acetylindole in 2 steps: Chien, C.-S.; Hasegawa, A.; Kawasaki, T.;
Sakamoto, M. Chem. Pharm. Bull. 1986, 34, 1493.
(18) The enantiomeric excess was determined by HPLC analysis using
stationary phase.
(19) The stereochemistry at the C3 of 8 was tentatively assigned based on
comparison with the specific rotation of the 6-bromo derivative of 815c and
ultimately confirmed by NOE experiments following transformation to 12 as
shown in Scheme 3.
(15) (a) Kawasaki, T.; Ogawa, A.; Takashima, Y.; Sakamoto, M. Tetra-
hedron Lett. 2003, 44, 1591. (b) Kawasaki, T.; Ogawa, A.; Terashima, R.;
Saheki, T.; Ban, N.; Sekiguchi, H.; Sakaguchi, K.; Sakamoto, M. J. Org.
Chem. 2005, 70, 2957. (c) Kawasaki, T.; Shinada, M.; Kamimura, D.;
Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420. (d) Kawasaki, T.;
Shinada, M.; Ohzono, M.; Ogawa, A.; Terashima, R.; Sakamoto, M.
J. Org. Chem. 2008, 73, 5959. (e) Kawasaki, T. Yuki Gosei Kagaku Kyokaishi
(J. Synth. Org. Chem. Jpn.) 2009, 67, 1012.
€
(16) Review: (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
(20) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
€
3168. (b) Domling, A. Chem. Rev. 2006, 106, 17.
J. Org. Chem. Vol. 75, No. 4, 2010 1127

Takiguchi et al.
SCHEME 3. Synthesis of (-)-Fructigenine A (1)
JOCArticle
SCHEME 2. Synthesis of Pyrroloindoline Imine (þ)-3
SCHEME 4. Synthesis of (-)-5-N-Acetylardeemin (2)
(1, Scheme 3). When (þ)-3 was treated with N-Boc-L-phe-
nylalanine and p-methoxyphenyl (PMP)-isonitrile at room
temperature, the stereoselective Ugi three-component reac-
tion21 proceeded smoothly to afford dipeptide (þ)-11 in 78%
yield.22 On removal of the Boc group from (þ)-11 with TFA
and smooth cyclization in heating toluene, diketopiperazine
(þ)-12 was obtained in quantitative yield. The stereochem-
istry of (þ)-12 was confirmed by NOE experiments as shown
in Scheme 3. This indicates that the isonitrile attacks pre-
dominantly on the side opposite the bulky reverse-prenyl
group of imine (þ)-3 in the Ugi reaction. Since (þ)-12 is a
C11a-epimer of the natural product 1, epimerization of (þ)-
12 was carried out with NaOH at low temperature to provide
(-)-123 in 58% yield together with a C11a-epimer of 1 (23%).
The first total synthesis of fructigenine A (1) was achieved in
four steps and 45% overall yield from imine 3.
alanine and isonitrile 1324,25 provided stereoselectively a
71% yield of tripeptide (þ)-14.26 Boc-deprotection of (þ)-
14 followed by heating in toluene easily liberated the anthra-
nilic ester to form diketopiperazine (þ)-15, of which the
stereochemistry was determined by NOE experiments on
(þ)-15. For assembling the pyrazino[2,1-b]quinazolinone
structure27 of 2, double-condensation among amino, amide,
and ester groups of (þ)-14 was required. In our preliminary
exploration of suitable condensing agents, we found the use
of phosphorus oxychloride to achieve the desired ring clo-
sure. After removal of the Boc group of (þ)-14, successive
heating with phosphorus oxychloride directly constructed
the pyrazine and pyrimidine rings together with epimerizion
at C15b to give (-)-2 in 53% yield.23 The physical and
spectral data of the synthetic product (-)-2 are identical
with those of the natural product. The total synthesis of 5-N-
acetylardeemin (2) was accomplished in a 37.6% three-step
yield from the common intermediate 3.
Next, we performed the synthesis of 5-N-acetylardeemin
(2, Scheme 4). The Ugi reaction of (þ)-3 with N-Boc-D-
(21) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T. J. Am. Chem. Soc. 2002, 124, 6552.
(22) The stereochemistry of 11 was confirmed by NOE experiments on 12
as shown in Scheme 3.
(23) The physical and spectral data of the synthetic product are identical
with those of the natural product.
(24) Isonitrile 13 was obtained in quantitative yield from methyl anthra-
nilate via formylation (HCO2H, toluene, reflux) and dehydration (POCl3,
Et3N, THF, rt): Kobayashi, K.; Nakashima, T.; Mano, M.; Morikawa, O.;
Konishi, H. Chem. Lett. 2001, 30, 602.
Conclusion
(25) Only a few reactions of isonitrile 13 are known for the preparation of
¨
quinolines24 and pyrazolo[5,1-b]quinazoline: Atlan, V.; Buron, C.; Kaım, L.
Synlett 2000, 489.
In summary, we have completed the asymmetric total
syntheses of two pyrazino-pyrroloindole alkaloids, fructi-
genine A (1) and 5-N-acetylardeemin (2), via Ugi reaction/
cyclization of the common imine intermediate (þ)-3, which
was easily prepared in highly enantiomeric purity, and we
demonstrated a novel and concise synthetic methodology
for a variety of pyrazino-pyrroloindole compounds. In
addition, this first use of isonitrile 13 in Ugi reaction/
cyclization inspires a new route to a series of pyrazino[2,1-b]-
quinazolinone compounds. Further synthetic studies of this
(26) The stereochemistry of 14 was determined by NOE experiments on
15 as shown in Scheme 4.
(27) This scaffold is contained in a number of bioactive fungal metabo-
lites other than 2, such as fumiquinazolines, alanttrypinone, and so on: (a)
Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.; Kumeda,
Y.; Numata, A. J. Chem. Soc., Perkin Trans. 1 1995, 2345. (b) Cledera, P.;
~
ꢀ
Avendano, C.; Menendez, J. C. J. Org. Chem. 2000, 65, 1743. (c) Hart, D. J.;
Magomedov, N. A. J. Am. Chem. Soc. 2001, 123, 5892. (d) Snider, B. B.;
Zeng, H. J. Org. Chem. 2003, 68, 545. (e) Liu, J.; Ye, P.; Zhang, B.; Bi, G.;
Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70,
6339.
1128 J. Org. Chem. Vol. 75, No. 4, 2010

Takiguchi et al.
JOCArticle
class of alkaloids as well as SAR studies of the anti-MDR
properties of 2 are now in progress.
was removed under reduced pressure and the residue was roughly
purified by silica gel column chromatography (AcOEt/n-hexane =
1/2) to give an aldehyde (1.5 g). Under N2 atmosphere, to a
suspension of Ph3PCH3I (8.5 g, 21 mmol) in THF (30 mL) was
added n-BuLi (10.2 mL, 2.6 M in n-hexane, 26.5 mmol) at -78 °C.
After being stirred for 10 min, the mixture was added to a solution
of the above aldehyde (1.5 g, 6.0 mmol) in THF (30 mL) at the
same temperature. After consumption of the aldehyde, the result-
ing mixture was warmed to 0 °C, quenched with water, and
extracted with AcOEt. The organic layer was washed with brine,
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chromato-
graphy (AcOEt/n-hexane = 3/7) to give (-)-9(1.19g, 65%from8,
99% ee CHIRALCEL AD flow 0.5 mL/min EtOH/n-hexane =
13.0/87.0) as colorless crystals. Mp 154-155 °C (AcOEt/n-hexane)
[lit.15b (()-9 mp 154-155 °C]; [R]27D -133.8 (c 0.05, EtOH); IR
(CHCl3) 3434, 2255, 1716 cm-1; 1H NMR (CDCl3, 300 MHz) δ
1.08 (3H, s), 1.16 (3H, s), 2.86 (1H, d, J = 16.2 Hz), 3.00 (1H, d,
J=16.5 Hz), 5.10 (1H, dd, J = 17.7, 0.9 Hz), 5.22 (1H, dd, J = 0.6,
10.8Hz), 6.09(1H, dd,J= 17.8, 10.8 Hz), 6.93 (1H, br s), 7.07 (1H,
ddd, J=0.9, 0.9, 0.9Hz), 7.29(2H, brs), 8.43(1H, brs);13CNMR
(CDCl3, 75 MHz) δ 21.5, 21.9, 21.9, 41.6, 55.4, 110.1, 115.3, 116.8,
122.3, 125.7, 128.2, 129.3, 141.5, 141.8, 178.4; MS (EI) m/z (%)
240 (Mþ, 6), 170 (100), 145 (59), 69 (92), 41 (50); HRMS (EI) m/z
calcd for C15H16N2O 240.1263, found 240.1263. Anal. Calcd for
C15H16N2O: C 74.97; H 6.71; N 11.66. Found: C 74.62; H 6.61;
N 11.31.
Experimental Section
1-Acetyl-2-[(S)-2-methyldec-2-en-4-yloxy]indolin-3-one (5). A
CH2Cl2 solution of Br2 (1 M, 14.5 mL, 14.5 mmol) was added to
a solution of 6 (2.1 g, 12.1 mmol) in CH2Cl2 (24 mL) at 0 °C.
After being stirred at the same temperature for 1 h, the mixture
was concentrated and dissolved in MeCN-DMF (10:1, 25 mL).
To the mixture was added MS 4A (powder, 12 g) and (S)-2-
methyl-2-decen-4-ol (7) (4.1 g, 24.3 mmol, 99% ee) at 0 °C. After
the mixture was stirred at room temperature for 3 days, excess 7
was acetylated with Ac2O (2.3 mL, 24.3 mmol), pyridine (30 mL,
36.5 mmol), and DMAP (0.29 g, 2.4 mmol) in CH2Cl2 (240 mL)
at room temperature for 1 h with stirring. The mixture was
washed with water and brine. The organic layer was dried over
MgSO4 and concentrated. The residue was purified by silica gel
column chromatography with AcOEt/n-hexane (1/6) as an
eluent to give 5 (3.60 g) in 88% yield as a viscous oil. IR
(CHCl3) 2930, 1728, 1682, 1464, 1385 cm-1 1H NMR (300
;
MHz CDCl3, 1:2 diastereomer mixture) δ 0.85 (3H, m), 1.09 (1/
3H, s), 1.24 (8H, m), 1.39 (1/3H, s), 1.50 (2/3H, d, J = 0.9 Hz),
1.64 (2/3H, d, J = 0.6 Hz), 2.36 (2/3H, s), 2.44 (1/3H, s), 4.27 (1/
3H, br s), 4.76 (2/3H, ddd, J = 6.6, 3.3, 6.6 Hz), 4.99-5.05 (1H,
m), 5.12 (2/3H, s), 5.35 (1/3H, s), 7.18 (1H, m), 7.66 (2H, m), 8.46
(1H, br s); 13C NMR (CDCl3, 75 MHz) δ 14.0, 17.5, 18.0, 22.5,
23.7, 24.1, 24.8, 25.1, 25.46, 25.47, 25.61, 25.64, 29.8, 31.7, 35.6,
36.0, 72.1, 74.1, 82.75, 82.79, 85.77, 85.80, 118.1, 118.2, 122.7,
122.8, 123.5, 123.6, 123.9, 124.2, 124.9, 125.4, 135.5, 137.3,
137.8, 139.0, 152.6, 153.1, 169.66, 169.75, 195.2, 196.4; MS
(EI) m/z (%) 343 (Mþ, 2), 190 (20),175 (11), 153 (26), 149 (17),
148 (100), 132 (19), 97 (18), 83 (13), 69 (45), 43 (13); HRMS (EI)
m/z calcd for C21H29NO3 343.2148, found 343.2148.
(R,E)-2-[3-(2-Methyldec-3-en-2-yl)-2-oxoindolin-3-yl]aceto-
nitrile [(-)-8]. Under N2 atmosphere, to a solution of t-BuOK
(3.7 g, 33 mmol) in DMF (110 mL) was added (EtO)2P(O)-
CH2CN (6.0 mL, d 1.13, 37 mmol) at 0 °C and the mixture was
stirred at the same temperature for 2 h. After cooling at -78 °C,
to the mixture was added slowly a solution of 5 (3.8 g, 11 mmol)
at the same temperature. After consumption of 5 (0.5 h), the
stirred reaction mixture was warmed gradually to 0 °C for 7 h,
quenched with satd aqueous NH4Cl, and extracted with
Et2O. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (AcOEt/
n-hexane=1/7) to give (-)-8 (3.2 g, 89%, 99% ee CHIRALCEL
AD flow 0.5 mL/min EtOH/n-hexane=4.0/96.0) as a viscous oil.
[R]26D -118 (c 0.11, EtOH); IR (CHCl3) 3431, 2928, 1722, 1620,
1472 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.89 (3H, t, J=6.6
Hz), 1.03 (3H, s), 1.16 (3H, s), 1.25-1.43 (8H, m), 2.06 (2H, dd,
J = 6.9, 12.9 Hz), 2.84 (1H, d, J=16.5 Hz), 2.98 (1H, d, J = 16.5
Hz), 5.45 (1H, dt, J=15.6, 6.6 Hz), 5.62 (1H, d, J=15.6 Hz), 6.89
(1H, t, J = 7.5 Hz), 7.06 (1H, t, J =7.5 Hz), 7.25-7.32 (2H, m),
7.56 (1H, br s); 13C NMR (CDCl3, 75 MHz) δ 14.2, 21.7, 22.5,
22.8, 23.0, 29.0, 29.5, 31.8, 32.9, 41.1, 55.7, 109.8, 116.8, 122.1,
125.6, 128.4, 129.0, 131.3, 133.3, 141.2, 178.0; MS (EI) m/z (%)
324 (Mþ, 1), 172 (65), 153 (100), 97 (68), 69 (93); HRMS (EI) m/z
calcd for C21H28N2O 324.2202, found 324.2205. Anal. Calcd for
C21H28N2O: C, 77.74; H, 8.70; N, 8.63. Found: C, 77.70; H, 8.85;
N, 8.58.
(3aR,8aR)-3a-(2-Methylbut-3-en-2-yl)-1,2,3,3a,8,8a-hexahydro-
pyrrolo[2,3-b]indole [(-)-4]. To a solution of (-)-9 (2.5 g, 11 mmol)
in 1,4-dioxane (104 mL) was added LiAlH4 (4.2 g, 110 mmol).
After heating under reflux for 3 h, the mixture was cooled to 0 °C
and quenched with THF/H2O (5/1). The resulting mixture was
filtered through a Celite pad and the filtrate was concentrated
under reduced pressure. The residue was diluted with AcOEt and
then the solution was washed with satd aqueous NaHCO3 and
brine. The concentrated residue was purified by silica gel column
chromatography (CH2Cl2/MeOH = 5/1) to give (-)-4 (1.9 g,
80%) as colorless crystals. Mp 57-60 °C (n-pentane), [lit.15b (()-4
mp 57-60 °C]; [R]25D -115° (c 0.88, MeOH); IR (CHCl3) 3425,
1
1608, 1485, 1472 cm-1; H NMR (300 MHz, CDCl3) δ 1.01 (s,
3H), 1.13 (3H, s), 1.89 (1H, ddd, J = 11.7, 5.1, 1.2 Hz), 2.10 (1H,
dt, J= 11.1, 6.6 Hz), 2.61 (1H, td, J = 11.4, 5.4 Hz), 2.99 (1H, ddd,
J = 10.8, 6.3, 1.2 Hz), 4.91 (1H, s), 5.03 (1H, dd, J = 17.1, 1.5 Hz),
5.08 (1H, dd, J = 10.5, 1.5 Hz), 6.03 (1H, dd, J = 17.4, 10.8 Hz),
6.54 (1H, dd, J = 7.5, 0.6 Hz), 6.68 (1H, td, J = 7.5, 1.2 Hz), 7.03
(1H, td, J = 7.8, 1.2 Hz), 7.11-7.14 (1H, m); 13C NMR (75 MHz,
CDCl3) δ 23.0, 23.3, 37.4, 41.1, 46.5, 65.4, 80.3, 108.3, 113.1, 118.0,
125.4, 127.8, 132.0, 145.0, 151.3; MS (EI) m/z (%) 228 (Mþ, 25),
159 (100), 130 (31), 77 (3), 69 (3), 41 (4); HRMS (EI) m/z calcd for
C15H20N2 228.1626, found 228.1629. Anal. Calcd for C15H20N2:
C, 78.90; H, 8.83; N, 12.27. Found: C, 78.52; H, 9.18; N, 12.15.
(3aR,8aR)-8-Acetyl-3a-(2-methylbut-3-en-2-yl)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole [(þ)-10]. Boc2O (1.7 mL, 7.4
mmol) was added to a solution of (-)-4 (1.4 g, 6.1 mmol)
in CH2Cl2 (61 mL) at room temperature. After being stirred
for 4.5 h, 28% aqueous NH3 (0.7 mL) was added to the mixture
in order to quench excess Boc2O. The mixture was washed with
H2O and the combined water layer was extracted with CH2Cl2.
The combined organic layer was washed with brine and dried
over anhydrous MgSO4. The concentrated residue was purified
by silica gel column chromatography (AcOEt/n-hexane = 1/10)
to give a N-Boc compound (1.8 g, 90%, 99% ee CHIRALCEL
AD flow 0.5 mL/min EtOH/n-hexane = 5.0/95.0) as a white
solid. Mp 115-118 °C (AcOEt); [R]21D -361 (c 0.13, MeOH); IR
(CHCl3) 3422, 1678, 1606, 1481, 1466, 1408 cm-1; 1H NMR (400
MHz, DMSO-d6, 80 °C) δ 0.86 (3H, s), 0.96 (3H, s), 1.36 (9H, s),
1.85 (1H, dd, J = 12.2, 5.9 Hz), 2.14 (1H, td, J = 12.2, 8.3 Hz),
2.64 (1H, td, J = 10.4, 5.9 Hz), 3.47 (1H, dd, J = 10.4, 8.3 Hz),
2-[3-(2-Methylbut-3-en-2-yl)-2-oxoindolin-3-yl]acetonitrile [(-)-
9]. A solution of (-)-8 (2.3 g, 7.1 mmol) in CH2Cl2/MeOH (14 mL,
10/1) was cooled to -78 °C, and O3 gas was bubbled into the
stirred mixture at -78 °C for 1.5 h. Excess O3 was purged with N2
gas at the same temperature for 5 min and PPh3 (5.6 g, 21.3 mmol)
was added to the mixture. The reaction mixture was allowed
to warm to room temperature, then stirred for 6 h. The solvent
J. Org. Chem. Vol. 75, No. 4, 2010 1129

Takiguchi et al.
JOCArticle
4.93 (1H, dd, J = 17.6, 1.5 Hz), 4.97 (1H, dd, J = 11.0, 1.5 Hz),
5.60 (1H, s), 5.82 (1H, br s), 5.93 (1H, dd, J = 17.6, 11.0 Hz),
6.47 (1H, d, J = 7.6 Hz), 6.51 (1H, td, J = 7.6, 1.2 Hz), 6.89 (1H,
td, J = 7.6, 1.2 Hz), 7.00 (1H, d, J = 7.6 Hz); 13C NMR (100
MHz, DMSO-d6, 80 °C) δ 22.1, 22.4, 23.4, 26.6, 27.8, 30.9, 31.8,
40.4, 76.6, 78.4, 107.7, 112.5, 116.4, 123.8, 127.3, 144.0, 150.2;
MS (EI) m/z (%) 328 (Mþ, 17), 272 (4), 203 (100), 159 (21), 130
(16), 77 (1), 69 (3); HRMS (EI) m/z calcd for C20H28N2O2
328.2151, found 328.2150. Anal. Calcd for C20H28N2O2: C,
73.14; H, 8.59; N, 8.53. Found: C, 73.23; H, 8.82; N, 8.50.
To a solution of the N-Boc compound (65 mg, 0.20 mmol),
NaOH (47 mg, 1.2 mmol), and n-Bu4NHSO4 (1 mg, 2 μmol) in
CH2Cl2 (2.0 mL) was added AcCl (28 μL, 0.60 mmol). After
stirring at room temperature for 10 min, the precipitate was
filtered off in the mixture, and the filtrate was washed with brine
and dried over anhydrous MgSO4. The concentrated residue
was purified by silica gel column chromatography (AcOEt/
n-hexane=1/4) to give a N-Boc-N0-Ac compound (66 mg, 90%)
as a viscous oil. [R]20D -128 (c 0.31, MeOH); IR (CHCl3) 1689,
MHz, CDCl3) δ 0.96 (3H, s), 1.10 (3H, s), 2.56 (3H, s), 2.86 (1H,
dt, J = 18.3, 1.5 Hz), 3.13 (1H, d, J = 18.3 Hz), 5.09 (1H, dd,
J = 17.7, 0.9 Hz), 5.13 (1H, dd, J = 10.8, 0.9 Hz), 5.83 (1H, dd,
J = 17.1, 10.8 Hz), 5.96 (1H, d, J = 1.8 Hz), 7.05 (1H, td, J =
7.5, 0.9 Hz), 7.21 (1H, br s), 7.26 (1H, br s), 7.60 (1H, s), 8.20 (1H,
d, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 23.0, 23.5, 24.2,
40.7, 47.3, 58.9, 94.3, 114.2, 117.3, 123.5, 125.0, 128.7, 134.1,
141.6, 143.6, 168.4, 169.0; MS (EI) m/z (%) 268 (Mþ, 26), 226
(11), 199 (8), 157 (100), 130 (39), 69 (7), 41 (4); HRMS (EI) calcd
for C17H20N2O 268.1576, found 268.1574.
(2R,3aR,8aR)-8-Acetyl-1-[(S)-2-tert-butoxycarbonylamino-3-
phenylpropanoyl]-2-(4-methoxyphenylcarbamoyl)-3a-(2-methyl-
but-3-en-2-yl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole [(þ)-
11]. A solution of (þ)-3 (24 mg, 89 μmol), 4-methoxyphenyl-
isonitrile (18 mg, 0.13 mmol), and N-Boc-L-phenylalanine
(36 mg, 0.13 mmol) in toluene (0.18 mL) was stirred at
room temperature for 1.5 h. The mixture was concentrated
under reduced pressure and the residue was purified by silica
gel column chromatography (AcOEt/n-hexane = 1/5) to give
(þ)-11 (60 mg, 78%) as a white solid. Mp 225-227 °C (CHCl3);
1
1662, 1477, 1458, 1404 cm-1; H NMR (400 MHz, CDCl3) δ
[R]21 þ159 (c 1.08, CHCl3); IR (CHCl3) 3445, 3348, 1699,
0.99 (3H, s), 1.12 (3H, s), 1.46 (9H, s), 1.95 (1H, dd, J = 11.8, 5.0
Hz), 2.17 (1H, td, J = 11.8, 7.6 Hz), 2.54 (3H, br s), 2.72 (1H, td,
J = 11.8, 5.0 Hz), 3.75 (1H, br s), 5.07 (1H, d, J = 17.1 Hz), 5.08
(1H, d, J = 11.0 Hz), 5.84 (1H, dd, J = 17.1, 11.0 Hz), 5.98 (1H,
br s), 7.08 (1H, t, J = 7.6 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.26 (1H,
t, J = 7.6 Hz), 8.06 (1H, br s); 13C NMR (100 MHz, CDCl3) δ
22.4, 23.6, 24.1 28.4, 32.6, 40.7, 46.5, 63.3, 79.6, 80.4, 113.7,
118.2, 123.6, 124.3, 128.2, 133.0, 143.4, 143.6, 153.8, 170.2; MS
(EI) m/z (%) 370 (Mþ, 39), 328 (7), 272 (16), 203 (100), 159 (71),
130 (33), 69 (7), 57 (14), 41 (7); HRMS (EI) m/z calcd for
C22H30N2O3 370.2256, found 370.2255. Anal. Calcd for
C22H30N2: C, 71.32; H, 8.16; N, 7.56. Found: C, 71.59; H,
8.44; N, 7.33.
D
1
1662, 1601, 1537, 1512 cm-1; H NMR (400 MHz, CDCl3) δ
0.74 (3H, s), 0.84 (3H, s), 1.35 (9H, s), 2.10 (1H, dd, J = 12.4, 9.6
Hz), 2.31 (3H, s), 2.70 (1H, d, J = 12.4 Hz), 2.94 (1H, dd, J =
12.4, 6.8 Hz), 3.06 (1H, dd, J = 12.4, 8.8 Hz), 3.73 (3H, s), 4.72
(1H, d, J = 8.8 Hz), 4.85 (1H, br s), 4.88 (1H, d, J = 17.2 Hz),
4.95 (1H, d, J = 10.8 Hz), 5.43 (1H, dd, J = 16.8, 10.4 Hz), 5.51
(1H, br s), 5.98 (1H, s), 6.61 (2H, d, J = 9.2 Hz), 6.92-7.44
(11H, m), 7.73 (1H, br s); 13C NMR (100 MHz, CDCl3) δ 22.2,
23.2, 23.6, 28.4, 32.9, 38.6, 40.2, 52.0, 55.4, 61.5, 62.3, 78.5, 79.8,
112.8, 114.1, 117.6, 121.7, 124.7, 127.2, 128.6, 128.8, 129.6,
130.9, 134.6, 135.3, 142.2, 142.8, 155.4, 155.6, 167.9, 170.4,
173.2; MS (EI) m/z (%) 666 (Mþ, 65), 566 (31), 548 (4), 497 (12),
475 (11), 447 (20), 419 (10), 378 (11), 334 (37), 332 (34), 308 (27),
269 (100), 201 (31), 159 (40), 120 (84), 69 (28); HRMS (EI) m/z
calcd for C39H46N4O6 666.3417, found 666.3412.
TFA (1.8 mL, 24.3 mmol) was added to a suspension of the
N-Boc N-Ac compound (180 mg, 0.49 mmol) in CH2Cl2
(9.7 mL) at room temperature. After being stirred for 30 min,
the mixture was neutralized with satd aqueous NaHCO3 and
extracted with CH2Cl2. The extract was dried over anhydrous
MgSO4 and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (AcOEt) to
give (þ)-10 (117 mg, 90%) as a viscous oil. [R]22D þ21 (c 7.26,
(3S,5aR,10bR,11aR)-6-Acetyl-10b-(2-methylbut-3-en-2-yl)-3-
benzyl-1,2,3,4,5a,10b,11,11a-octahydro-6H-pyrazino[10,20:1,2]py-
rrolo[4,5-b]indole-1,4-dione [(þ)-12]. To a solution of (þ)-11
(33 mg, 50 μmol) in CH2Cl2 (1.0 mL) was added TFA (180 μL,
2.5 mmol) at room temperature. After being stirred for 1 h, the
mixture was neutralized with satd aqueous NaHCO3 and ex-
tracted with CH2Cl2. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was diluted
with toluene (1.0 mL) and heated at 100 °C for 23 h. The mixture
was concentrated under reduced pressure and the residue was
purified by silica gel column chromatography (AcOEt/n-hexane =
1/4) to give (þ)-12 (22 mg, quant) as a white solid. Mp
MeOH); IR (CHCl3) 3362, 1651, 1595, 1481, 1460, 1399 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.97 (2.4H, s), 1.01 (0.6H, s), 1.07
(0.6H, s), 1.12 (2.4H, s), 2.20 (1H, td, J=12.0, 6.8 Hz), 2.16-2.23
(2H, m), 2.33 (2.4H, s), 2.43 (0.6H, s), 2.57 (1H, td, J = 11.0, 5.1
Hz), 3.00 (1H, dd, J = 11.0, 6.8 Hz), 5.06 (1H, d, J = 17.3 Hz),
5.11 (1H, d, J =10.7 Hz), 5.25 (0.8H, s), 5.62 (0.2H, s), 5.95
(1H, dd, J=17.3, 10.7 Hz), 7.04 (1H, t, J=7.4 Hz), 7.21-7.32
(2H, m), 8.18 (1H, d, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3)
δ 22.7, 23.0, 23.5, 23.6, 24.1, 25.0, 31.6, 35.9, 36.5, 41.1, 45.2,
46.3, 63.5, 81.1, 82.5, 113.3, 113.6, 116.3, 122.9, 123.2, 124.7,
126.2, 127.7, 128.0, 133.8, 143.5, 144.1, 168.8; MS (EI) m/z (%)
270 (Mþ, 23), 201 (35), 159 (100), 130 (24), 77 (2), 69 (2), 41 (2);
HRMS (EI) m/z calcd for C17H22N2O 270.1732, found
270.1732.
125-128 °C (CHCl3); [R]22 þ56 (c 0.52, MeOH); IR (CHCl3)
D
3397, 1680, 1599 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.85 (3H,
s), 1.01 (3H, s), 2.29 (1H, dd, J = 13.4, 9.6 Hz), 2.48 (1H, dd, J =
13.6, 9.2 Hz), 2.57 (3H, br s), 2.69 (1H, br s), 2.96 (1H, dd, J =
13.2, 3.6 Hz), 3.23 (1H, dd, J = 13.2, 6.0 Hz), 4.09 (1H, br s), 5.06
(1H, d, J = 17.2 Hz), 5.09 (1H, d, J = 10.4 Hz), 5.43 (1H, br s),
5.61 (1H, dd, J = 15.6, 10.4 Hz), 6.02 (1H, s), 7.06 (1H, t, J = 7.6
Hz), 7.15 (1H, d, J = 7.6 Hz), 7.19-7.26 (3H, m), 7.30-7.39 (3H,
m), 7.96(1H, brs); 13C NMR (68 MHz, CDCl3) δ 21.9, 22.4, 24.4,
34.3, 40.4, 41.1, 55.4, 58.9, 114.7, 118.7, 124.3, 125.5, 125.7, 127.7,
128.4, 128.9, 129.9, 135.4, 141.4, 142.9, 168.6; MS (EI) m/z (%)
443 (Mþ, 12), 401 (13), 332 (100), 304 (4), 241 (4), 157 (15), 130
(17), 69 (3), 41 (2); HRMS (EI) m/z calcd for C27H29N3O3
443.2209, found 443.2212.
(3aR,8aR)-8-Acetyl-3a-(2-methylbut-3-en-2-yl)-3,3a,8,8a-tetra-
hydropyrrolo[2,3-b]indole [(þ)-3]. Under N2 atmosphere, to a
solution of (þ)-10 (880 mg, 3.3 mmol) in MeCN (65 mL)
was added MS4A (2.5 g), NMO (1.1 g, 9.9 mmol), and TPAP
(114 mg, 0.33 mmol) at room temperature. After 15 min of
stirring, activated charcoal (4.0 g) was added to the mixture,
which was then stirred for 5 min. Then the mixture was filtered
through Celite and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column chromato-
graphy (AcOEt/n-hexane = 1/1) to give (þ)-3 (779 mg, 89%
99% ee CHIRALCEL OD flow 0.5 mL/min EtOH/n-hexane =
(-)-Fructigenine A [(-)-1]. To a solution of (þ)-12 (13 mg,
29 μmol) in MeOH (0.59 mL) was added NaOH (35 mg,
0.88 mmol) at 0 °C. After being stirred at the same temperature
for 30 min, the mixture was neutralized with satd aqueous
NH4Cl and extracted with AcOEt. The extract was dried over
anhydrous MgSO4 and concentrated under reduced pressure.
25.0/75.0) as a colorless oil. [R]22 þ88 (c 0.26, MeOH); IR
D
(CHCl3) 1663, 1628, 1595, 1479, 1462, 1400 cm-1; 1H NMR (300
1130 J. Org. Chem. Vol. 75, No. 4, 2010

Takiguchi et al.
JOCArticle
The residue was purified by silica gel column chromatography
(AcOEt/n-hexane = 3/1) to give (-)-fructigenine A [(-)-1, 7.5
mg, 58%] as a white solid. Mp 83-85 °C (CH2Cl2); [R]27D -170
(c 0.14, CHCl3) [lit.1 [R]D -178 (c 0.24, CHCl3)]; IR (KBr) 3347,
1674, 1595 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.98 (3H, s),
1.13 (3H, s), 2.27 (1H, dd, J = 12.0, 11.7 Hz), 2.57 (1H, dd, J =
12.3, 5.7 Hz), 2.66 (3H, s), 2.80 (1H, dd, J = 14.4, 10.5 Hz), 3.55
(1H, dd, J = 14.4, 3.3 Hz), 3.80 (1H, dd, J = 10.5, 5.5 Hz), 4.23
(1H, dd, J = 10.5, 2.4 Hz), 5.11 (1H, d, J = 17.4 Hz), 5.13 (1H,
d, J = 10.5 Hz), 5.62 (1H, s), 5.78 (1H, dd, J = 17.1, 10.8 Hz),
6.06 (1H, s), 7.13 (1H, td, J = 7.5, 0.9 Hz), 7.16-7.21 (2H, m),
7.24-7.38 (5H, m), 8.00 (1H, br s); 13C NMR (75 MHz, CDCl3)
δ 22.4, 23.2, 23.6, 36.0, 37.0, 40.4, 56.0, 59.2, 60.9, 79.4, 114.6,
119.2, 124.5, 127.7, 129.1, 129.4, 132.0, 135.3, 143.1, 143.3,
164.9, 168.1, 170.1; MS (EI) m/z (%) 443 (Mþ, 25), 401 (17),
374 (10), 332 (100), 304 (6), 241 (3), 157 (21), 130 (20), 69 (3), 41
(2); HRMS (EI) m/z calcd for C27H29N3O3 443.2209, found
443.2215.
238-240 °C (CH2Cl2); [R]17D þ52 (c 0.22, MeOH); IR (CHCl3)
3408, 1688 cm-1; 1H NMR(500 MHz, CDCl3) δ 0.91 (3H, s), 1.14
(3H, s), 1.31 (3H, d, J = 6.7Hz), 2.52 (3H, brs), 2.65 (1H, dd, J =
14.1, 10.4 Hz), 2.92 (1H, br s), 3.94 (1H, dd, J = 13.4, 6.7 Hz),
4.16 (1H, dd, J = 10.4, 4.6 Hz), 5.11 (1H, d, J = 18.0 Hz), 5.14
(1H, d, J = 11.0 Hz), 5.63 (1H, br d, J = 11.3 Hz), 5.77 (1H, br s),
5.82 (1H, dd, J = 17.4, 10.7 Hz), 7.09 (1H, t, J = 7.6 Hz), 7.25
(1H, t, J = 8.0, Hz), 7.29 (1H, d, J = 8.2 Hz), 7.92 (1H, br s); 13
C
NMR (125 MHz, CDCl3) δ 14.1, 15.4, 22.2, 22.7, 24.0, 30.4, 31.6,
40.9, 51.7, 58.1, 61.1, 80.9, 114.6, 118.8, 124.2, 125.8, 128.8, 133.2,
141.3, 143.2, 169.3; MS (EI) m/z (%) 367 (Mþ, 18), 325 (14), 257
(17), 256 (100), 157 (13), 130 (11); HRMS (EI) m/z calcd for
C21H25N3O3 367.1896, found 367.1895.
(-)-5-N-Acetylardeemin [(-)-2]. TFA (1.0 mL, 13.7 mmol)
was added to a solution of (þ)-14 (170 mg, 0.27 mmol) in
CH2Cl2 (1.5 mL) at room temperature. The reaction mixture
was stirred at the same temperature for 1 h, neutralized with
aqueous NaHCO3, and extracted with CH2Cl2. The organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. Then a solution mixture of the
residue and phosphorus(V) oxychloride (50 μL, 0.54 mmol) in
dichloroethane (6.0 mL) was heated under reflux for 5 h,
neutralized with satd aqueous NaHCO3, and extracted with
CH2Cl2. The residue was purified by silica gel column with
AcOEt/n-hexane (1/3) as an eluent to afford (-)-N-acetylardee-
min (2) (106 mg, 53%) as white crystals. Mp 211-215 °C
(2R,3aR,8aR)-8-Acetyl-1-[(R)-2-tert-butyloxycarbonylamino-
3-propanoyl]-2-(2-methoxycarbonyl-phenyl)-3a-(2-methylbut-3-en-
2-yl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b] indole [(þ)-14]. A so-
lution of imine (þ)-3(8.0mg, 30μmol), o-methoxycarbonylphenyl
isonitrile 13 (7.0 mg, 45 μmol), and N-Boc-D-Ala (11.0 mg,
60 μmol) in toluene (0.6 mL) was stirred at room temperature
for 45 min. The resulted mixture was concentrated under reduced
pressure to give a residue, which was purified by silica gel column
with AcOEt/n-hexane (1/2) as an eluent to afford (þ)-14 (13.0 mg,
(MeOH) [lit.10b mp 229-231 °C]; [R]25 -34 (c 0.10, MeOH),
D
[R]18 -48 (c 0.25, CHCl3) [lit. [R]26 -33 (c 0.78, MeOH),7
D
71%) as a viscous oil. [R]18 þ52 (c 0.62, MeOH); IR (CHCl3)
D
D
D
[R]20 -43 (c 0.45, CHCl3)10b]; IR (CHCl3) 2982, 1684, 1605,
1
3433, 3267, 1701, 1670 cm-1; H NMR (400 MHz, DMSO-d6,
1476, 1460, 1433, 1402, 1389, 1335, 1306, 1287, 1246, 1159 cm-1
;
80 °C) δ 0.95 (3H, s), 1.06 (3H, s), 1.10-1.38 (12H, m), 2.42 (3H,
br s), 2.53-2.64 (1H, m), 2.71 (1H, d, J =12.8 Hz), 3.85 (3H, s),
4.76 (1H, d, J = 8.8 Hz), 5.01 (1H, d, J = 17.6 Hz), 5.03 (1H, d,
J = 10.4 Hz), 5.88 (1H, dd, J = 17.2, 10.8 Hz), 6.25-6.82 (1H,
br m), 6.68 (1H, t, J = 7.6 Hz), 6.78 (1H, t, J = 7.6 Hz), 7.04 (1H,
dt, J = 8.4, 1.2 Hz), 6.97-7.27 (1H, br m), 7.21 (1H, d, J = 7.2
Hz), 7.38 (1H, dt, J = 8.4, 1.2 Hz), 7.85 (1H, dd, J = 8.0, 1.6 Hz),
8.15 (1H, d, J = 8.4, Hz), 10.69 (1H, br s); 13C NMR (100 MHz,
DMSO-d6, 80 °C) δ 16.9, 21.7, 22.7, 23.1, 27.6, 27.8, 40.0, 46.7,
51.7, 61.2, 62.1, 77.7, 78.6, 113.1, 114.4, 116.5, 118.4, 121.7, 123.0,
125.5, 127.3, 129.5, 133.1, 139.3, 142.3, 142.3, 142.9, 154.0, 166.5,
168.1, 168.8, 173.5; MS (FAB) m/z (%) 619 (Mþ þ 1, 23), 201 (13),
190 (10), 185 (80), 159 (10), 134 (22), 130 (10), 93 (100), 75 (24), 57
(16); HRMS (FAB, MþH) m/z calcd for C34H43N4O7 619.3132,
found 619.3128.
1H NMR (300 MHz, CDCl3) δ 1.03 (3H, s), 1.22 (3H, s), 1.44
(3H, d, J = 7.2 Hz), 2.62-2.73 (1H, m), 2.67 (3H, br s), 3.02 (1H,
dd, J = 12.9, 5.7 Hz), 4.41 (1H, dd, J = 10.8, 5.7 Hz), 5.08-5.12
(1H, m), 5.13-5.20 (1H, m), 5.41 (1H, q, J = 7.2 Hz), 5.85 (1H,
dd, J = 17.4, 10.5 Hz), 6.06 (1H, br s), 7.18 (1H, dt, J = 7.5, 1.2
Hz), 7.30-7.42 (2H, m), 7.50 (1H, ddd, J = 8.1, 7.2, 1.2 Hz),
7.66 (1H, br d, J = 7.5 Hz), 7.78 (1H, ddd, J = 8.4, 7.2, 1.5 Hz),
8.02 (1H, br s), 8.26 (1H, dd, J = 7.8, 1.2 Hz); 13C NMR (75
MHz, CDCl3) δ 17.0, 22.4, 23.1, 23.4, 37.3, 40.4, 53.4, 58.2, 60.9,
79.4, 114.5, 119.5, 120.4, 124.4, 124.5, 126.8, 127.1, 127.2, 129.1,
132.2, 134.6, 142.9, 143.0, 147.0, 150.3, 159.7, 165.9, 170.0; MS
(EI) m/z (%) 468 (Mþ, 21), 426 (17), 358 (24), 357 (100), 355 (12),
130 (13); HRMS (EI) m/z calcd for C28H28N4O3 468.2161,
found 468.2160.
(3R,5aR,10bR,11aR)-6-Acetyl-10b-(2-methyl-but-3-en-2-yl)-3-
methyl-1,2,3,4,5a,10b,11,11a-octahydro-6H-pyrazino[10,20:1,2]py-
rrolo[4,5-b]indole-1,4-dione [(þ)-15]. TFA (170 μL, 2.32 mmol)
was added to a solution of (þ)-14 (29 mg, 46 μmol) in CH2Cl2
(0.9 mL) atroom temperature. The reactionmixturewas stirredat
the same temperature for 30 min, neutralized with satd aqueous
NaHCO3, and extracted with CH2Cl2. The organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Then a solution of the residue (22.6 mg) in
toluene (870 μL) was heated at 100 °C for 30 h. The reaction
mixture was concentrated under reduced pressure and the residue
was purified by silica gel column with AcOEt as an eluent
to afford (þ)-15 (15.9 mg, 55%) as a colorless solid. Mp
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (C) (No. 19590020) and for the
High-Tech Research Center Project (S0801043) from the
Ministry of Education, Culture, Sports, Science and Techno-
logy (MEXT), Japan. We are grateful to N. Eguchi, T. Koseki,
and S. Kubota at the Analytical Center of MPU for performing
microanalysis, mass spectrometry, and NOE experiments.
1
Supporting Information Available: H and 13C NMR spectra
of compounds 1-5, 8-12, 14, and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 4, 2010 1131