Synthetic routes to pyrroloiminoquinone alkaloids. A direct synthesis of makaluvamine C

Article abstract of DOI:10.1021/jo981547n

Makaluvamine C is a pyrroloiminoquinone which has been isolated from marine sponges. This molecule has been synthesized in 13 steps from p- anisidine. The key steps in this synthesis include an intramolecular nucleophilic aromatic substitution mediated by

Full text of DOI:10.1021/jo981547n

9
846
J . Org. Chem. 1998, 63, 9846-9849
Syn th etic Rou tes to P yr r oloim in oqu in on e Alk a loid s. A Dir ect
Syn th esis of Ma k a lu va m in e C
George A. Kraus* and Natesan Selvakumar
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received August 3, 1998
Makaluvamine C is a pyrroloiminoquinone which has been isolated from marine sponges. This
molecule has been synthesized in 13 steps from p-anisidine. The key steps in this synthesis include
an intramolecular nucleophilic aromatic substitution mediated by potassium tert-butoxide, the
selective reduction of a dinitro ester using catalytic hydrogenation, and the novel use of Fremy’s
salt to synthesize an iminoquinone from an amino phenol. The synthesis of makaluvamine C has
been achieved from p-anisidine in 13.1% overall yield.
A number of biologically active alkaloids possessing the
been reported, our synthetic plan is strategically quite
distinct from that of existing syntheses. We now report
that a modification of our previous approach has led to a
direct total synthesis of makaluvamine C (1).
8
pyrroloiminoquinone nucleus have been isolated in recent
1
years. Recently, the makaluvamines, a group of potent
antineoplastic agents, have been isolated from marine
sponges. This novel class of metabolites has been shown
Initial efforts to prepare A from picric acid proved to
be cumbersome. Both O-alkylation of the phenol and
selective reduction of the nitro group in the 4-position
were difficult to achieve on a large scale. We eventually
converted p-anisidine and succinic anhydride in boiling
toluene into imide 49 in 91% yield. Imide 4 is cleanly
nitrated to produce a dinitro imide in 86% yield which
reacts rapidly with sodium methoxide in methanol to
generate ester 5 in 96% yield. The imide moiety was
important for efficient nitration. Nitration of the mono
amide of succinic acid was not as selective.
2
to be topoisomerase II inhibitors. Several pyrroloimino-
quinones are cytotoxic against human colon tumor cell
line HCT-116.3 Representative members of this class
include makaluvamine C (1), veiutamine (2),4 and
makaluvamine A (3).2
2
Several syntheses and synthetic approaches have been
5
reported. In most cases the tricyclic skeleton was gener-
ated from an indole. There are also reports which start
from a quinoline or tetrahydroquinoline precursor. Re-
cently, we reported a synthetic route to a tricyclic
6
precursor to makaluvamine A (3) or veiutamine (2). Our
synthetic plan was based on the intramolecular nucleo-
7
philic aromatic substitution of a dinitroanisole. Although
an approach using an intermolecular substitution has
(
1) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(2) Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.;
Kramer, R. A.; Ireland, C. M. J . Am. Chem. Soc. 1993, 115, 1632.
3) Venables, D. A.; Barrows, L. R.; Lassota, P.; Ireland, C. M.
(
Tetrahedron Lett. 1997, 38, 721. Radisky, D. C.; Radisky, E. S.;
Barrows, L. R.; Copp, B. R.; Kramer, R. A.; Ireland, C. M. J . Am. Chem.
Soc. 1993, 115, 1632.
The key intramolecular nucleophilic aromatic substitu-
tion was attempted with various bases (LDA, NaOMe,
KOtBu) at different temperatures. The resulting dark red
σ complex was oxidized in situ with ceric ammonium
nitrate (CAN). The best conditions involved deprotona-
tion of the amide ester 5 with potassium tert-butoxide
from -78 to -30 °C followed by CAN oxidation at -30
(
4) Venables, D. A.; Barrows, L. R.; Lassota, P.; Ireland, C. M.
Tetrahedron Lett. 1997, 38, 721.
5) White, J . D.; Yager, K. M.; Yakura, T. J . Am. Chem. Soc. 1994,
16, 1831. Roberts, D.; J oule, J . A.; Bros, M. A.; Alvarez, M. J . Org.
(
1
Chem, 1997, 62, 568. Yamada, F.; Hamabuchi, S.; Shimizu, A.; Somei,
M. Heterocycles 1995, 41, 1905. Peat, A. J .; Buchwald, S. L. J . Am.
Chem. Soc. 1996, 118, 1028. Sadanandan, E. V.; Pillai, S. K.; Laksh-
mikantham, M. V.; Billimoria, A. D.; Culpepper, J . S.; Cava, M. P. J .
Org. Chem. 1995, 60, 1800. Zhao, R.; Lown, J . W. Synth. Commun.
°
C. This provided lactam ester 6 in 53% yield. We felt
1
997, 27, 2103. Makoza, M.; Stalewski, J .; Maslennikova, O. S.
Synthesis 1997, 1131. Izawa, T.; Nishiyama, S.; Yamamura, S.
Tetrahedron 1994, 50, 13593. Kita, Y.; Watanabe, H.; Egi, M.; Saiki,
T.; Fukuoka, Y.; Tohma, H. J . Chem. Soc., Perkin Trans. 1 1998, 635
and references therein.
that this cyclization would proceed via a dianion, favoring
six-membered ring formation. Confirmation of this ex-
(6) Kraus, G. A.; Selvakumar, N. Synlett 1998, 845.
(8) Makoza, M.; Stalewski, J .; Maslennikova, O. S. Synthesis 1997,
(
7) Nucleophilic aromatic substitution: Terrier, F. Chem. Rev. 1982,
1131.
8
2, 77.
(9) Piutti, A. Chem. Ber. 1896, 29, 84.
1
0.1021/jo981547n CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/26/1998

Synthetic Routes to Pyrroloiminoquinone Alkaloids
J . Org. Chem., Vol. 63, No. 26, 1998 9847
makaluvamine C in 73% yield.14 This represents a novel
Sch em e 1
1
5
use of Fremy’s salt to synthesize iminoquinones. The
1
3
NMR and C NMR spectra in DMSO were identical to
those reported.16 Additionally, our compound was identi-
cal to an authentic sample provided by Professor Ireland
1
7
by TLC analysis in two different solvent systems.
A synthesis of makaluvamine C has been achieved in
1
3 steps from p-anisidine in 13.1% overall yield. The key
steps include an intramolecular nucleophilic aromatic
substitution reaction, the selective reduction of a dinitro
ester, and an oxidation using Fremy’s salt. This synthesis
of makaluvamine C is a flexible one which should make
possible the synthesis of quantities of 1 plus other
members of the makaluvamine family.
Exp er im en ta l Section
pectation came from the 2D-COSY experiment on com-
pound 7 which confirmed the tetrahydroquinoline struc-
ture. Lactam ester 6, the product of the intramolecular
Proton NMR spectra were measured at 300 MHz unless
otherwise mentioned. 13C NMR spectra were recorded at 75
MHz. High-resolution mass spectra (HRMS) were EI spectra.
Sgc refers to silica gel flash chromatography. Organic extracts
were dried over sodium sulfate.
nucleophilic substitution reaction, was treated with BH
3
in THF to afford the amine 7 in 84% yield. To achieve
the substitution pattern for makaluvamine C, the amine
was methylated by formylation with formic acetic anhy-
dride followed by borane reduction to 9 in 88% overall
yield (Scheme 1).10
In our previous approach, both nitro groups were
reduced simultaneously by catalytic hydrogenation. For-
tunately, hyrdogenation for a short time afforded selec-
tive reduction of the less hindered nitro group in 90%
yield. This furnished the opportunity to protect the amine
as its BOC derivative 11 in 92% yield. The ability to
protect the amine before the indole was introduced
proved to be a key factor in the synthesis of 1. The
reduction of the ester 11 with DIBAL produced the
aldehyde 12 and the alcohol 13 in a 2.35:1 ratio in a
combined yield of 97%. Alcohol 13 could be oxidized to
2
-(4-Meth oxyp h en yl)su ccin im id e (4). A mixture of p-
anisidine (31.31 g, 0.254 mol) and succinic anhydride (24.19
g, 0.242 mol) in dry toluene (150 mL) was boiled for 36 h.
Toluene (100 mL) was then added, and 200 mL was distilled
out to effect azeotropic removal of water. The residue was
cooled and filtered to give the product as a blue-colored solid
which is sufficiently pure for the next step (45.15 g, 91%). An
analytical sample was prepared by recrystallization from hot
ethanol and Norit to afford 4 as a colorless solid: mp 163-
9
1
1
4
64 °C (lit. mp 162-163 °C); H NMR (CD
3
COCD
3
) δ 2.82 (s,
3
COCD )
13
H), 3.82 (s, 3 H), 6.95-7.22 (m, 4 H); C NMR (CD
3
δ 29.2, 55.8, 114.8, 126.8, 129.1, 160.2, 177.5. Anal. Calcd for
11 3
C H11NO
.44; N, 6.86.
: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.35; H,
5
Meth yl N-(4-Meth oxy-3,5-d in itr op h en yl)su ccin im id a te
5). To a three-necked round-bottomed flask, fitted with a
(
mechanical stirrer, an internal thermometer, and an addition
funnel, were added the imide 4 (10.31 g, 50 mmol) and
concentrated sulfuric acid (41 mL). The resultant vigorously
stirred solution was cooled in an ice-salt bath. After the
temperature drops below -5 °C, an ice cold mixture of fuming
1
2 using the Dess-Martin periodinane reagent.
Hydrogenation of aldehyde 12 required 21 h to go to
completion and afforded indole 14 in 76% yield. This
compound could be purified by chromatography and was
stable to storage in the refrigerator. The corresponding
amino indole was much less stable. Indole 14 was treated
with CAN, a reagent previously employed to generate the
pyrroloiminoquinone framework.11 Unfortunately, this
oxidation produced only decomposition. Attempted de-
methylation of 14 with butanethiolate in HMPA led to
recovered starting material.12 Treatment of 14 with
aqueous trifluoroacetic acid resulted in decomposition.
3 2 4
HNO (19 mL) and concentrated H SO (30 mL) was added
dropwise through the addition funnel at such a rate that the
internal temperature will not rise above 0 °C. The reaction
mixture was vigorously stirred for 10 min after the end of the
addition and was loaded into a separatory funnel. This was
added dropwise into a mechanically stirred ice-water mixture.
The resultant mixture was extracted into EtOAc (4 × 400 mL),
and the combined organic extracts were washed with water
(2 × 200 mL) and brine (200 mL) and dried. The solvent was
evaporated to yield the dinitro imide (12.69 g, 86%) as a yellow
powder which was sufficiently pure for the next step. A sample
However, treatment of 14 with chlorotrimethylsilane and
sodium iodide in acetonitrile13 followed by in situ oxida-
tion of the resulting amine with Fremy’s salt afforded
(14) Teuber, H.-J .; Hasselbach, M. Chem. Ber. 1959, 92, 674. Teuber,
H.-J . Org. Synth. 1972, 52, 88.
(
10) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315.
(15) Yamada, F.; Hamabuchi, S.; Shimizu, A.; Somei, M. Heterocycles
1995, 41, 1905. Teuber, H.-J .; Glosauer, O. Chem. Ber. 1965, 98, 2939.
(16) Izawa, T.; Nishiyama, S.; Yamamura, S. Tetrahedron 1994, 50,
13593. Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.;
Kramer, R. A.; Ireland, C. M. J . Am. Chem. Soc. 1993, 115, 1632.
(11) Nishiyama, S.; Cheng, J .-F.; Tao, X. L.; Yamamura, S. Tetra-
hedron Lett. 1991, 32, 4151.
(
12) Bartlett, P. A.; J ohnson, W. S. Tetrahedron Lett. 1970, 4459.
(13) Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra,
R. J . Org. Chem. 1979, 44, 1247. Olah, G. A.; Narang, S. C. Tetrahedron
982, 38, 2225.
(17) TLC data: R
HOAc.
f 3 f
0.43 in 1:3 MeOH:CHCl ; R 0.46 in 1:1 MeOH:
1

9
848 J . Org. Chem., Vol. 63, No. 26, 1998
Kraus and Selvakumar
for analytical purposes was obtained by recrystallization from
cooled to room temperature. To this stirred reagent of acetic
formic anhydride was added dry THF (2 mL) followed by a
solution of amine ester 7 (0.23 g, 0.74 mmol) in dry THF (4
mL). A TLC control revealed the reaction to be complete at
the end of 4 h. The solvent was removed, and the residue was
left on a high vacuum pump for 10 min.
1
ethyl acetate: mp 174 °C; H NMR (CD
3
COCD
H), 4.11 (s, 3 H), 8.30 (s, 2 H); C NMR (CD COCD
2C), 65.3, 128.3 (2C), 129.7, 145.9, 147.2 (2C), 176.7 (2C); IR
3
) δ 2.94 (s, 4
1
3
3
3
) δ 29.3
(
(
-1
Nujol) cm 1707, 1531. Anal. Calcd for C11
9 3 7
H N O : C, 44.76;
H, 3.07; N, 14.23. Found: C, 44.78; H, 3.02; N, 13.98.
To a stirred solution of dinitro imide (2.00 g, 6.8 mmol) in
dry THF (75 mL) and MeOH (15 mL) in a room-temperature
water bath was added NaOMe (0.44 g, 8.15 mmol) in one
portion. After 15 min at the same temperature, a saturated
The residue obtained above was dissolved in dry THF (6
mL) and cooled in an ice bath. To this stirred mixture was
added 1 M BH ‚THF (2.96 mL, 2.96 mmol) dropwise, and at
3
the end of addition, TLC showed complete consumption of
starting material. The reaction mixture was quenched by
careful dropwise addition of moist ether, followed by water and
extracted with ether (4 × 20 mL). The combined organic
extract were washed with water and brine and dried. The
residue obtained after evaporation of solvent was chromato-
4
aqueous NH Cl solution (50 mL) was added and the resultant
mixture was concentrated in vacuo to remove THF and MeOH.
The aqueous layer was extracted with EtOAc (4 × 100 mL),
and the combined organic extracts were washed with water
(70 mL) and brine (70 mL) and dried. The residue obtained
after evaporation of solvent was filtered through a short
column of silica gel with hexane-ethyl acetate (1:1) to yield
the amide ester 5 (2.13 g, 96% yield) as a yellow powder. An
graphed on silica gel to afford the product 9 (0.212 g, 88% yield)
1
as reddish orange solid: mp 99-100 °C; H NMR (CDCl
3
) δ
1.94-2.07 (m, 1 H), 2.30-2.38 (m, 1 H), 3.01 (s, 3 H), 3.23-
analytical sample was obtained by recrystallization from ethyl
3.31 (m, 1 H), 3.37-3.47 (m, 1 H), 3.71 (s, 3 H), 3.82-3.85 (m,
1
13
acetate: mp 128-129 °C; H NMR (CDCl
3
) δ 2.68-2.72 (m, 2
3
1 H), 3.90 (s, 3 H), 7.18 (s, 1 H); C NMR (CDCl ) δ 23.5, 38.7,
H), 2.78-2.82 (m, 2 H), 3.76 (s, 3 H), 4.03 (s, 3 H), 8.28 (s, 2
H), 8.35 (brs, 1 H); C NMR (CDCl
2C), 31.4, 51.8, 64.7, 119.3 (2C), 135.0, 142.3, 145.1, 170.8,
73.0; IR (neat film) cm
39.4, 46.6, 53.0, 65.0, 107.7, 116.0, 135.3, 142.6, 143.6, 148.0,
1
3
-1
3
and CD
3
COCD
3
) δ 28.5
171.9; IR (neat) cm 1735, 1540; MS m/z 325, 308, 291, 266,
(
1
249, 219, 189, 160, 132; HRMS m/z 325.09090, calcd for
C H N O 325.09100. Anal. Calcd for C13H N O : C, 48.00;
13 15 3 7 15 3 7
-
1
3351, 1732. Anal. Calcd for
C
12
H
13
N
3
O
8
: C, 44.04; H, 4.00; N, 12.84. Found: C, 44.03; H,
H, 4.65; N, 12.92. Found: C, 48.34; H, 4.67; N, 12.73.
Meth yl N-Meth yl-7-a m in o-1,2,3,4-tetr a h yd r o-6-m eth -
oxy-5-n itr oqu in olin e-4-ca r boxyla te (10). A suspension of
amino ester 9 (0.1046 g, 0.32 mmol) and 10% Pd-C (10 mg)
in ethanol (9 mL) was stirred under an atmosphere of
3
.96; N, 12.66.
Met h yl 1,2,3,4-Tet r a h yd r o-6-m et h oxy-2-oxo-5,7-d in i-
tr oqu in olin e-4-ca r boxyla te (6). To a suspension of t-BuOK
0.214 g, 1.9 mmol) in dry THF (7 mL) at -78 °C was added
(
a cooled (-78 °C) solution of dinitro ester 5 (0.208 g, 0.64
mmol) in dry THF (8 mL) via a cannula under a positive
pressure of argon over 20 min. The resultant dark brown
reaction mixture was stirred and warmed to -35 °C over 4 h
under argon, at which temperature the reaction was stirred
for a further 2 h. The reaction mixture was recooled to -78
hydrogen. The progress of the reaction was followed by TLC,
1
and the reaction was complete after about 2 /
2
h. The reaction
was then filtered on a Celite pad and washed with with ethyl
acetate. The filtrate was evaporated, and the residue was
purified by sgc to afford the monoreduction product 10 (0.0852
g, 90% yield): 1H NMR (CDCl
) δ 1.92-2.06 (m, 1 H), 2.16-
3
°
C, and ceric ammonium nitrate (0.348 g, 0.64 mmol) was
2.24 (m, 1 H), 2.88 (s, 3 H), 3.05-3.15 (m, 1 H), 3.25-3.35 (m,
added in three lots over 2 min. The resultant mixture was
stirred for 3 h while warming to -40 °C slowly. The mixture
was diluted with ethyl acetate (100 mL) and filtered through
a pad of Celite and silica gel. The filtrate was evaporated, and
the residue was chromatographed on silica gel. Elution with
1 H), 3.67 (s, 3 H), 3.71-3.74 (m, 1 H), 3.76 (s, 3 H), 3.88 (brs,
2 H), 6.08 (s, 1 H); 13C NMR (CDCl
) δ 24.6, 37.9, 39.6, 47.0,
3
52.4, 61.8, 99.8, 100.4, 129.6, 141.1, 143.4, 146.5, 173.9; IR
-
1
(neat) cm 3374, 1736, 1530; MS m/z 295, 280, 236, 189, 161;
HRMS m/z 295.11750, calcd for C13 295.11682.
17 3 5
H N O
1
:1 hexane-ethyl acetate afforded the cyclized dinitro ester 6
Met h yl N-Met h yl-7-BOC-a m in o-1,2,3,4-t et r a h yd r o-6-
m eth oxy-5-n itr oqu in olin e-4-ca r boxyla te (11). A solution
of the amine 10 (0.0303 g, 0.1 mmol) and (BOC) O (0.0448 g,
2
0.21 mmol) in dry dioxane (3 mL) was boiled under an argon
atmosphere. After 24 h, TLC showed a small amount starting
2
material, and more BOC O (0.0448 g, 0.21 mmol) was added.
The reaction mixture was refluxed for a further 24 h at which
time the TLC showed a clean conversion. Evaporation of
solvent followed by chromatography of the residue on silica
1
(
1
4
3
0.111 g, 53% yield): H NMR (CDCl ) δ 2.82 (dd, J ) 6.9,
6.8 Hz, 1 H), 3.13 (dd, J ) 1.8, 16.8 Hz, 1 H), 3.73 (s, 3 H),
.01 (s, 3 H), 4.16 (dd, J ) 1.8, 6.9 Hz, 1 H), 7.55 (s, 1 H), 9.06
1
3
(s, 1 H); C NMR (CDCl ) δ 31.7, 38.5, 53.7, 65.5, 114.4, 119.3,
3
-
1
1
1
1
34.6, 142.2, 144.0, 147.2, 169.1, 169.3; IR (neat) cm 3321,
736, 1698. Anal. Calcd for C12 : C, 44.32; H, 3.41; N,
H
11
N
3
O
8
2.92. Found: C, 44.35; H, 3.28; N, 12.62.
Meth yl 1,2,3,4-Tetr a h yd r o-6-m eth oxy-5,7-d in itr oqu in -
olin e-4-ca r boxyla te (7). To a solution of dinitroamide ester
gel afforded 11 (0.0373 g, 92% yield) as reddish orange solid:
1
6
1
(51.6 mg, 0.16 mmol) in dry THF (4 mL) at 0 °C was added
M BH ‚THF (0.8 mL, 0.8 mmol) dropwise under argon. The
3
H NMR (CDCl ) δ 1.52 (s, 9 H), 1.92-2.60 (m, 1 H), 2.20-
3
2.28 (m, 1 H), 2.97 (s, 3 H), 3.12-3.20 (m, 1 H), 3.28-3.39 (m,
1 H), 3.67 (s, 3 H), 3.76 (s, 3 H), 3.74-3.78 (m, 1 H), 6.88 (s, 1
resultant mixture was warmed to 20 °C while being stirred
over 12 h at which point TLC showed the disappearance of
the starting material. The reaction mixture was cooled to 0
H), 7.58 (s, 1 H); 13C NMR (CDCl
) δ 24.3, 28.5 (3 C), 38.1,
3
39.7, 47.0, 52.5, 63.1, 81.4, 103.2, 104.0, 130.5, 133.1, 143.3,
-
1
°
C, and wet ether was added to quench excess BH
3
. The
145.8, 152.6, 173.4; IR (neat) cm 1737, 1537. MS m/z 395,
product was extracted into ether (4 × 15 mL), and the
combined extracts were washed with water and brine and
dried. The residue obtained after evaporation of solvents was
chromatographed on a short silica gel column. The amine ester
25 3 7
339, 280, 234, 57; HRMS m/z 395.16975, calcd for C18H N O
395.16925.
N-Meth yl-7-BOC-a m in o-1,2,3,4-tetr a h yd r o-6-m eth oxy-
5-n itr oqu in olin e-4-ca r boxa ld eh yd e (12). To a stirred solu-
tion of ester 11 (0.0358 g, 0.091 mmol) in dry toluene (3 mL)
was added a precooled (-78 °C) solution of 1 M DIBAL in
CH Cl (0.54 mL, 0.54 mmol) in dry toluene (3 mL) via a
2 2
cannula over 30 min. The resultant mixture was stirred at
the same temperature for 3 h, and another batch of 1 M DIBAL
7
(41.5 mg, 84% yield) was obtained by elution with 2:1
hexanes-ethyl acetate. A yellow oil solidified upon standing:
1
H NMR 400 MHz (CDCl
m, 1 H), 3.28-3.43 (m, 2 H), 3.72 (s, 3 H), 3.85-3.87 (m, 1
3
) δ 1.85-1.98 (m, 1 H), 2.28-2.38
(
1
3
H), 3.90 (s, 3 H), 4.5 (br s, 1 H), 7.16 (s, 1 H); C NMR (CDCl
3
)
δ 23.0, 37.7, 38.3, 53.0, 65.1, 111.4, 114.5, 136.1, 141.3, 143.5,
2 2
in CH Cl (0.27 mL, 0.27 mmol) was added over 10 min. After
1
2
3
48.1, 172.1; IR (neat) cm-1 3415, 1734, 1539; MS m/z 311,
a further 30 min at -78 °C, the reaction mixture was quenched
by careful addition of a -78 °C solution of MeOH (0.5 mL) in
toluene (3 mL) over 30 min. A saturated aqueous solution of
potassium sodium tartrate (15 mL) was added at -78 °C, and
the resultant mixture was extracted with ether (4 × 15 mL).
The combined organic extracts were washed with water and
brine and dried. The residue after evaporation of solvent was
chromatographed on silica gel and eluted with 1:3 ethyl
94, 252, 235, HRMS m/z 311.07490, calcd for C12
11.07535.
13 3 7
H N O
Met h yl N-Met h yl-1,2,3,4-t et r a h yd r o-6-m et h oxy-5,7-
d in itr oqu in olin e-4-ca r boxyla te (9). A solution of 96%
formic acid (1.23 mL, 32.5 mmol) was added dropwise to acetic
anhydride (2.51 mL, 26.6 mmol) at 0 °C under argon. After
the addition, the mixture was heated to 60 °C for 2 h and

Synthetic Routes to Pyrroloiminoquinone Alkaloids
J . Org. Chem., Vol. 63, No. 26, 1998 9849
+
acetate-hexane to afford the aldehyde 12 (22.5 mg, 68%
m/z (EI) 317.2 (M ), 261, 202; HRMS m/z 317.17346, calcd for
1
yield): H NMR (CDCl
3
) δ 1.53 (s, 9 H), 1.86-2.0 (m, 1 H),
C
17
H
23
N
3
O
3
317.17394.
Ma k a lu va m in e C (1). To a mixture of 14 (6 mg, 0.0189
mmol), NaI (11.3 mg, 0.0756 mmol), and dry CH CN (0.35 mL)
under argon was added TMSCl (9.59 µL, 0.0756 mmol). The
reaction mixture was stirred for 45 min resulting in a cloudy
appearance. Monobasic phosphate buffer (0.5 mL, pH 7) was
added at which time the reaction mixture turned to a clear
yellow solution. To this solution was added Fremy’s salt (11.1
mg, 0.0413 mmol) in one portion, and the resultant reddish
orange mixture was stirred for 2 h. The reaction mixture was
2
3
.39-2.47 (m, 1 H), 2.94 (s, 3 H), 3.13-3.18 (m, 2 H), 3.52-
.55 (m, 1 H), 3.79 (s, 3 H), 6.90 (s, 1 H), 7.60 (s, 1 H), 9.64 (d,
3
1
3
J ) 0.6 Hz, 1 H); C NMR (CDCl
3
) δ 21.4, 28.5, 39.6, 45.3,
7.2, 63.2, 81.5, 102.4, 103.2, 130.5, 133.4, 143.9, 146.1, 152.6,
00.2; IR (neat) cm-1 1731. MS m/z 365, 336, 309, 280, 236,
7; HRMS m/z 365.15876, calcd for C17 365.15864.
Further elution with 1:2 ethyl acetate-hexane afforded the
alcohol 13 (9.7 mg, 29.2% yield). The combined yield is 97%.
4
2
5
23 3 6
H N O
1
1
2
1
3
3: H NMR (CDCl ) δ 1.52 (s, 9 H), 1.7-1.9 (m, 1 H), 2.1-
.23 (m, 1 H), 2.90-2.95 (m, 1 H), 2.95 (s, 3 H), 3.13-3.21 (m,
H), 3.37-3.43 (m, 1 H), 3.55-3.62 (m, 1 H), 3.71-3.78 (m, 1
extracted with CHCl
dried to yield makaluvamine C (2.8 mg, 73%): H NMR
3
(4 × 2 mL), and the organic layer was
1
1
3
H), 3.75 (s, 3 H), 6.83 (s, 1 H), 7.47 (s, 1 H); C NMR (CDCl
3
)
3 3
(CD SOCD ) δ 2.93 (t, J ) 7.5 Hz, 2 H), 3.32 (s, 3 H), 3.91 (t,
δ 22.2, 28.4 (3 C), 34.7, 39.2, 46.0, 63.1, 64.5, 81.2, 102.3, 106.9,
J ) 7.5 Hz, 2 H), 5.64 (s, 1 H), 7.30 (d, J ) 2.7 Hz, 1 H), 8.68
29.6, 132.2, 143.1, 146.0, 152.6; IR (neat) cm-1 3431, 1728,
532; MS m/z 367, 311, 280, 57; HRMS m/z 367.174566, calcd
(br s, 1 H), 9.29 (br s, 1 H), 13.03 (br s, 1 H); C NMR
13
1
1
3 3
(CD SOCD ) δ 18.9, 39.0, 52.7, 85.4, 118.1, 123.3, 123.4, 126.7,
155.8, 156.5, 167.5.
for C17
H
25
N
3
O
6
367.17430.
7
-BOC-a m in o-8-m eth oxy-5-m eth yl-1,3,4,5-tetr a h yd r o-
p yr r olo[4,3,2-d e]qu in olin e (14). A mixture of 10% Pd-C (3
Ack n ow led gm en t. We thank Iowa State University
for financial support through a postdoctoral fellowship
to N.S. We thank Professor Chris Ireland from the
University of Utah for providing an authentic sample.
mg) and the aldehyde 12 (22.5 mg, 0.06 mmol) in ethanol (3
2
mL) was stirred under an atmosphere of H for 21 h. The
mixture was filtered on a Celite mat and washed with ethyl
acetate. The filtrate was evaporated, and the residue was
purified by sgc to afford compound 14 (14.8 mg, 76% yield) as
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
a slightly decomposing colorless oil, which was used for the
data for compounds which lack elemental analyses (14 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
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1
next step as soon as possible: H NMR (CD
9
3
COCD
3
) δ 1.50 (s,
H), 2.88 (s, 3 H), 2.97 (dt, J ) 0.9, 6 Hz, 2 H), 3.20 (t, J ) 6
Hz, 2 H), 3.83 (s, 3 H), 6.73 (t, J ) 0.9 Hz, 1 H), 6.90 (s, 1 H),
7
3
1
.27 (s, 1 H), 9.80 (s, 1 H); 13C NMR (CD
COCD ) δ 24.1, 28.7,
3 3
8.5, 53.6, 60.7, 79.6, 93.8, 111.5, 116.1, 117.6, 127.1, 127.2,
29.0, 140.1 154.1; IR (neat) cm-1 3421, 3356, 1700, 1539; MS
J O981547N