Total synthesis of the slime mold alkaloids arcyroxocin A and B

Article abstract of DOI:10.1055/s-0030-1258340

The synthesis of the slime mold pigments arcyroxocin A and B is described. The key step in the synthesis is the oxidative ring closure of an N-protected 3-(4-hydroxyindol-3-yl)-4-indol-3-ylmaleimide with DDQ/PPTS, which affords exclusively the desired arc

Full text of DOI:10.1055/s-0030-1258340

330
PAPER
Total Synthesis of the Slime Mold Alkaloids Arcyroxocin A and B
Total
S
ynthesis of
u
A
rcyroxocin
i
A
a
nd
d
B
o Mayer, Gregor Wille, Michael Brenner, Kirsten Zeitler,1 Wolfgang Steglich*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5–13, 81377 München, Germany
Fax +49(89)218077756 ; E-mail: wos@cup.uni-muenchen.de
Received 7 October 2010
Dedicated to Professor Gerhard Höfle on the occasion of his 70th birthday
As starting compound for arcyroxocin A (4a) we chose
the arcyriarubin derivative 8a, in which the imide nitrogen
is protected by a methyl group and one of the indole nitro-
gens by the tert-butoxycarbonyl residue (Scheme 1).
Abstract: The synthesis of the slime mold pigments arcyroxocin A
and B is described. The key step in the synthesis is the oxidative ring
closure of an N-protected 3-(4-hydroxyindol-3-yl)-4-indol-3-ylma-
leimide with DDQ/PPTS, which affords exclusively the desired ar-
cyroxocin derivative. Attempts to obtain the arcyroxocin system Compound 8a has already been used for the total synthe-
sis of arcyriacyanin A.4 The corresponding 6-benzyloxy
from a 3-(4-hydroxyindolyl)-4-(2-oxoindolinyl)maleimide precur-
sor were less successful and led to oxidative formation of a spiroin-
doline compound.
derivative 8b, needed for the synthesis of arcyroxocin B,
was prepared by reaction of the N-Boc-protected bromo-
maleimide 5b9 with 4-(tetrahydro-2H-pyran-2-yloxy)-
Key words: alkaloids from myxomycetes, oxidative cyclization,
1H-indole (6)4 to yield the bisindolylmaleimide 7b,10 fol-
oxocin ring formation, arcyroxocins
lowed by selective acid-catalyzed cleavage of the THP
group with Amberlyst 15.
Myxomycetes (plasmodial slime molds) produce a great
For the crucial cyclization reaction, the combination of
variety of metabolites, often with unusual structures.2
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) with
Thus, the tiny red sporangia of Arcyria species contain
pyridinium p-toluenesulfonate (PPTS) in an inert solvent
condensed alkaloids of the arcyriaflavin (2),3 arcyriacya-
(e.g. toluene or benzene) gave the best results. This re-
nin (3),4 and arcyroxocin types 4 (Figure 1),2a,b,5,6 which
agent combination has been developed by Bergman and
are biogenetically related to the more simple arcyriarubins
Pelcman11 for the efficient conversion of arcyriarubins
(1).3 Several of these compounds are inhibitors of protein
(e.g., 1) into arcyriaflavins (e.g., 2). Fortunately, in the
kinases,7 and the arcyroxocins A (4a) and B (4b) exhibit
case of the 4-hydroxyarcyriarubin derivatives 8a and 8b
cytotoxicity against Jurkat cells.6 Since these alkaloids
the expected 2,2¢-coupling to give the corresponding 4-
can only be obtained in small amounts from the natural
hydroxyarcyriaflavin derivatives 13 did not occur, as was
sources, their synthesis is of importance for pharmacolog-
evident from an HPLC analysis of the crude reaction mix-
ical studies. Having reported the total synthesis of arcy-
ture, which revealed that apart from small amounts of im-
roxocin A (4a) in a preliminary communication,8 we now
purities only the oxocins 9a and 9b were formed. The best
provide the experimental details for the synthesis of both
yields were obtained with an equimolar mixture of DDQ
of the known arcyroxocin alkaloids.
and PPTS (9a: 78%, 9b: 81%). Catalytic amounts of
PPTS afforded 9a in only 56% yield, which dropped to
H
H
34% yield when the acidic catalyst was omitted. Again,
none of the corresponding arcyriaflavin 13a could be de-
tected. A plausible mechanism for the formation of the
oxocin ring is given in Scheme 2.11 The structures of 9a
and 9b were confirmed by X-ray structure analyses. The
non-planar arrangement of the oxocin ring is clearly visi-
ble in the ORTEP plot for 9a (Figure 2).
N
N
O
O
O
O
N
N
N
N
H
H
H
H
arcyriarubin A (1)
arcyriaflavin A (2)
H
H
N
N
O
First attempts to cleave the Boc group in 9a under stan-
dard conditions (e.g., PPTS in refluxing toluene) gave N-
methylarcyroxocin A (10a) in less than 10% yield. In con-
trast, heating of the neat compounds in substance for 10
minutes at 180 °C resulted in smooth removal of the Boc
residue from the nitrogen and afforded the free indoles
10a and 10b each in 87% yield. The progress of the reac-
tion was indicated by a color change from orange-red to
dark red. Similar yields for the deprotection were obtained
by adsorbing the N-Boc indoles on silica gel and heating
the mixture to 50 °C for 24 hours under reduced pres-
sure.12
O
O
O
R
NH
NH
N
N
H
O
H
arcyriacyanin A (3)
R = H: arcyroxocin A (4a)
R = OH: arcyroxocin B (4b)
Figure 1 Selected bisindolylmaleimides from slime molds
SYNTHESIS 2011, No. 2, pp 0330–0336
Advanced online publication: 08.12.2010
DOI: 10.1055/s-0030-1258340; Art ID: Z25010SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

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Total Synthesis of Arcyroxocin A and B
331
Me
N
Me
Me
N
N
O
O
O
O
O
+
O
OTHP
OTHP
OH
4
b
a
Br
4'
2
2'
6'
N
N
N
H
N
N
N
BnO
BnO
R
H
Boc
Boc
7
Boc
H
7'
5b
6
7b
8a R = H
8b R = OBn
Me
Me
N
N
O
O
O
O
O
O
O
R
R
R
c
d
e
NH
NH
NH
N
N
N
O
O
O
Boc
H
H
9a R = H
9b R = OBn
10a R = H
10b R = OBn
11a R = H
11b R = OBn
H
N
O
O
2
3
13
14
1
12
14c
3a
3b
8b
4
R
14a
f
14b
9a
5 NH
4b R = OH,
arcyroxocin B
11
10
10a
(12b)
8a
8
5a
N
O
H
9
6
7
4a R = H, arcyroxocin A
12b R = OBn
Scheme 1 Reagents and conditions: (a) 6, EtMgCl (each 2.3 equiv), THF, then 5b, 50 °C, 56%; (b) Amberlyst 15, MeOH, reflux, 8b: 89%;
(c) DDQ (1 equiv), PPTS (1 equiv), benzene, 60 °C, 9a: 78%, 9b: 81%; (d) 180 °C, 10a: 87%, 10b: 87%; (e) KOH, H2O–EtOH, reflux (anhy-
dride 11a: 87%), then HMDS, DMF, MeOH, r.t., 4a: 78%, 12b: 57% (2 steps); (f) cyclohexa-1,4-diene, Pd/C, EtOH, r.t., 67%.
Me
N
O
O
OH
H+
8a,b
DDQ
N
N
R
H+
H
Boc
13a,b
Me
Me
N
N
O
OH
O
O
R
R
H
H
O
NH
NH
N
N
HO
Boc
Boc
DDQ
9a,b
Scheme 2 Plausible mechanism for the oxidative cyclization of 3-
(4-hydroxyindolyl)-4-indolylmaleimides 8 to arcyroxocins 9
anolic potassium hydroxide in order to hydrolyze the N-
methylmaleimide moiety. The anhydride 11a was isolated
in 87% yield and characterized before further use, where-
as the crude anhydride 11b was employed for the synthe-
sis of O-benzylarcyroxocin B (12b) without further
purification. Best results for the amination were achieved
with hexamethyldisilazane (HMDS) in N,N-dimethylform-
amide containing a small volume of methanol.13 By this
method, arcyroxocin A (4a) was obtained in 78% yield
Figure 2 ORTEP-plot of the X-ray crystal structure of 9a (crystal-
lographic numbering)
The removal of the remaining N-methyl group was carried
out by our standard solvolysis-reamination protocol.4
Each of the compounds 10a and 10b was treated with eth-
Synthesis 2011, No. 2, 330–336 © Thieme Stuttgart · New York

332
G. Mayer et al.
PAPER
from 11a, whereas the corresponding O-benzylarcyroxo-
cin B (12b) was formed in 57% yield starting from 10b
(two steps). The last remaining protecting group was re-
moved under hydrogen transfer conditions (cyclohexa-
1,4-diene, Pd/C) to provide arcyroxocin B (4b) in 67%
yield. Utilization of hydrogen with palladium on carbon
resulted in partial reduction of the chromophore that was
reversible upon exposing the material to air. The synthetic
arcyroxocins 4a and 4b were identical with the natural
products by comparison of the IR, NMR, and mass spec-
tra.
In a second approach to the arcyroxocins, we tried to form
the intramolecular oxygen bridge from a bisindolylmale-
imide 19, containing both a 4-hydroxyindole and an indo-
lin-2-one unit (Scheme 3). The synthesis of the required
compound commenced from 3,4-dibromo-N-methylmale-
imide (14), which was reacted with 4-(tetrahydro-2H-py-
ran-2-yloxy)indole (6) under standard conditions14 to
yield bromo(indolyl)maleimide 15. After protection of the
indole nitrogen with the Boc residue, the resulting com-
pound 16 was condensed with the lithium enolate of 1-(di-
ethoxymethyl)indolin-2-one (17)15 to yield the fully
protected bisindolylmaleimide 18. Cleavage of the acid-
labile protecting groups with titanium(IV) chloride gave
the desired starting material 19, which on treatment with
4-toluenesulfonic acid in refluxing toluene afforded N-
methylarcyroxocin A (10a), albeit in only 8% yield. In an
Figure 3 ORTEP plot of the X-ray crystal structure of spiroether 20
(crystallographic numbering)
attempt to form the arcyroxocin by alkali-catalyzed elim-
ination of water from 19, spiroether 20 was obtained in
quantitative yield. Its structure follows from the mass and
NMR spectra and was confirmed by an X-ray structure
analysis (Figure 3). The same ether was also formed di-
rectly from the protected bisindolylmaleimide 18 by treat-
ment with DDQ in the presence of catalytic amounts of 4-
toluenesulfonic acid.
Me
N
O
Me
N
O
O
O
N
O
OTHP
Br
Br
DEM
17
In conclusion, we have developed a convenient strategy
for the synthesis of arcyroxocin alkaloids, which is based
on the building blocks 3,4-dibromo-N-methylmaleimide
(14), 4-(tetrahydro-2H-pyran-2-yloxy)-1H-indole (6) and
either indole or 6-(benzyloxy)indole. In this manner, the
arcyroxocins A and B could be synthesized in overall
yields of 15 and 9%, respectively, from indole and 6-ben-
zyloxyindole, respectively.
OTHP
14
Br
c
a
N
H
N
R
6
15 R = H
16 R = Boc
b
Me
Me
N
N
O
O
O
O
OTHP
OH
d
Melting points (uncorrected): Reichard Kofler micro hot-stage ap-
paratus. UV/Vis spectra: Perkin-Elmer Lambda 16 spectrophotom-
eter. IR spectra: Perkin-Elmer FT 1000 and 1420 Ratio Recording
spectrophotometer. NMR spectra: Bruker WH 90, ARX 300, ARX
600, and Varian VXR 400S instruments. Spectra were recorded in
DMSO-d6 or acetone-d6, using the residual solvent peak as internal
standard (DMSO-d6, dH = 2.49 and dC = 39.5, acetone-d6, dH = 2.04
and dC = 29.8). Mass spectra (EI, 70 eV): Finnigan MAT 90 and
MAT 95 Q. HRMS (EI, 70 eV): Finnigan MAT 95Q. FAB spectra
were taken using a 3-nitrobenzyl alcohol matrix.
O
O
N
N
H
N
N
Boc
18
DEM
H
19
f
e
g
Me
N
Me
N
10'
8'
O
O
O
O
O
9'
7a'
10a'
1'
2
3
3a
1NH
7a
10b'
2'
HN
6'
HN
10c'
O
Flash chromatography: Merck silica gel 60 (0.043–0.063 mm) un-
less otherwise stated. TLC: Aluminum-backed silica gel 60 F254
(Merck). Solvents for flash chromatography were distilled before
use. All water sensitive reactions were carried out under an argon
atmosphere in dried vessels. THF was distilled under argon from
Na/benzophenone. Anhyd DMF was purchased from Sigma-Aldrich,
and anhyd EtOH was purchased as dry solvent and stored over mo-
lecular sieves. Petroleum ether (PE) refers to the fraction bp 40–60
°C. All reactions were monitored by TLC on Merck silica gel.
7
N
5a'
4
O
2a'
H
5'
6
3'
5
4'
20
10a
Scheme 3 Reagents and conditions: (a) 6, EtMgBr (1.1 equiv),
THF, r.t., then 14, 70%; (b) Boc2O, DMAP, THF, 0 °C, 98%; (c) 17,
LDA, THF, –78 °C, then 16, r.t., 52%; (d) TiCl4, CH2Cl2, 0 °C, 43%;
(e) DDQ, p-TsOH, toluene, reflux, 86%; (f) NaH, toluene, r.t., quant.;
(g) p-TsOH, toluene, reflux, 8%. DEM = diethoxymethyl.
Synthesis 2011, No. 2, 330–336 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Arcyroxocin A and B
333
3-[6-(Benzyloxy)-1-(tert-butoxycarbonyl)-1H-indol-3-yl]-1-
methyl-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1H-indol-3-yl]-
1H-pyrrole-2,5-dione (7b)
10-(tert-Butoxycarbonyl)-2-methyl-5,10-dihydro-1H-pyrro-
lo[3¢,4¢:4,5]oxocino[2,3-b:6,7,8-c¢,d¢]diindole-1,3(2H)-dione (9a)
To a soln of bisindolylmaleimide 8a4 (0.10 g, 0.22 mmol) and DDQ
(50 mg, 0.22 mmol) in anhyd benzene (25 mL) was added PPTS (55
mg, 0.22 mmol), and the mixture was refluxed for 3 h. The mixture
was then cooled to r.t., filtered, and concentrated under reduced
pressure. Flash chromatography (silica gel, PE–EtOAc, 4:1) yielded
oxocin 9a (78 mg, 78%) as a red solid; mp 185 °C; TLC: Rf = 0.37
(PE–EtOAc, 2:1).
To a soln of indole 64 (0.91 g, 4.2 mmol) in anhyd THF (30 mL) was
added 2.8 M EtMgCl in THF (1.55 mL, 4.34 mmol) at r.t. After
heating the mixture for 45 min at 50 °C, a soln of bromomaleimide
5b14 (1.00 g, 1.91 mmol) in anhyd THF (15 mL) was added drop-
wise, and the mixture was heated at 50 °C for a further 6 h. The re-
action was quenched by careful addition of ice water and the
resulting soln adjusted to pH 5 with 5% aq KHSO4. The aqueous
layer was extracted with EtOAc (3 × 50 mL), and the combined or-
ganic layers were dried (MgSO4) and concentrated. Flash chroma-
tography (silica gel, PE–EtOAc, gradient 5:1 to 4:1) furnished 7b
(705 mg, 56%) as an orange solid; mp 124 °C; TLC: Rf = 0.13 (PE–
EtOAc, 3:1).
IR (KBr): 3340, 2982, 1750, 1700, 1691, 1639, 1514, 1366, 1355,
1211, 748 cm–1.
1H NMR (600 MHz, acetone-d6): d = 1.79 (s, 9 H, t-Bu), 3.15 (s, 3
H, NCH3), 7.18 (pseudo-t, 1 H), 7.24 (pseudo-t, 1 H), 7.28 (pseudo-
t, 1 H), 7.47 (pseudo-d, J = 7.0 Hz, 1 H), 7.57 (pseudo-d, J = 7.9 Hz,
1 H), 7.62 (pseudo-d, J = 7.9 Hz, 1 H), 7.93 (pseudo-d, J = 8.4 Hz,
1 H), 8.19 (d, J = 2.4 Hz, 1 H), 11.41 (br s, 1 H, NH).
13C NMR (150.9 MHz, acetone-d6): d = 24.3 (NCH3), 28.3 (3 CH3),
85.8, 101.1, 105.8 (CH), 111.2 (CH), 115.2 (CH), 115.5, 120.1
(CH), 122.2 (CH), 122.8 (CH), 123.6 (CH), 124.1, 125.3, 126.2,
131.3, 132.0, 133.3, 140.3, 149.2, 152.0, 152.5, 171.3, 171.6.
IR (KBr): 3428, 2905, 2783, 1737, 1704, 1617, 1547, 1384, 1370,
1245, 1154, 766, 736, 697 cm–1.
1H NMR (300 MHz, acetone-d6): d = 1.60–1.90 (m, 6 H, THP), 1.73
(s, 9 H, t-Bu), 3.18 (s, 3 H, NCH3), 3.62 (m, 1 H, THP), 3.98 (m, 1
H, THP), 5.03 (s, 2 H, Bn), 5.62 (m, 1 H, THP), 6.75 (pseudo-t,
J = 8 Hz, 1 H), 6.83 (pseudo-d, J = 8 Hz, 1 H), 6.91 (d, J = 3.6 Hz,
1 H), 7.04 (d, J = 2.4 Hz, 1 H), 7.35–7.50 (m, 8 H), 8.12 (s, 1 H),
10.9 (s, 1 H, NH).
MS (FAB): m/z (%) = 456 (2) [M+ + H], 455 (3) [M+], 400 (1), 399
(3), 356 (7), 355 (10).
13C NMR (75 MHz, acetone-d6): d = 24.6 (NCH3), 26.2 (CH2), 26.7
(CH2), 28.3 (3 CH3), 31.3 (CH2), 61.7 (OCH2, THP), 70.8 (OCH2,
Bn), 85.0 [OC(CH3)3], 96.7, 97.4, 101.3, 104.4, 105.0, 106.4, 112.0,
112.9, 118.7, 122.1, 123.6, 124.4, 126.7, 128.5 (2 C), 128.7, 129.0,
129.3 (2 C), 131.2, 138.1, 138.5, 139.2, 149.8, 152.0, 156.9, 171.7,
176.0.
12-(Benzyloxy)-10-(tert-butoxycarbonyl)-2-methyl-5,10-dihy-
dro-1H-pyrrolo[3¢,4¢:4,5]oxocino[2,3-b:6,7,8-c¢,d¢]diindole-
1,3(2H)-dione (9b)
To a soln of bisindolylmaleimide 8b (0.50 g, 0.87 mmol) and DDQ
(207 mg, 0.91 mmol) in anhyd benzene (100 mL) was added PPTS
(173 mg, 0.91 mmol), and the mixture was heated to 60 °C for 45
min (color turns to yellow). The mixture was then cooled to r.t., fil-
tered, and concentrated under reduced pressure. Flash chromatog-
raphy (silica gel, PE–EtOAc, 4:1) yielded oxocin 9b (404 mg, 81%)
as a dark red solid; mp 172 °C; TLC: Rf = 0.72 (PE–EtOAc, 1:1).
MS (ESI): m/z (%) = 547 (4) [M+ – CO2 – C4H8], 463 (100), 372
(91), 344 (12), 287 (12), 91 (20), 84 (16).
UV/Vis (MeOH): lmax (log e) = 220 (4.75), 255 (sh, 4.31), 283 (sh,
4.11), 448 nm (3.94).
IR (KBr): 3340, 2929, 2908, 1760, 1703, 1610, 1522, 1364, 1337,
1221, 1170, 777, 750 cm–1.
3-[6-(Benzyloxy)-1-(tert-butoxycarbonyl)-1H-indol-3-yl]-4-(4-
hydroxy-1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione (8b)
To a soln of THP ether 7b (0.70 g, 1.08 mmol) in MeOH (30 mL)
was added Amberlyst 15 (0.16 g), and the mixture was refluxed for
1 h. The ion exchanger was then removed by filtration and the fil-
trate concentrated under reduced pressure. Flash chromatography
(silica gel, PE–EtOAc, gradient 4:1 to 1:1) furnished phenol 8b
(0.54 g, 89%) as a dark red solid; mp 136 °C; TLC: Rf = 0.46 (PE–
EtOAc, 2:1).
1H NMR (300 MHz, acetone-d6): d = 1.77 (s, 9 H, t-Bu), 3.15 (s, 3
H, NCH3), 5.16 (s, 2 H, Bn), 6.93 (dd, J = 8.8, 2.3 Hz, 1 H), 7.24 (t,
J = 8.0 Hz, 1 H), 7.32 (m, 1 H, Bn), 7.37 (pseudo-t, J = 7.5 Hz, 2 H,
Bn), 7.46 (pseudo-d, J = 7.5 Hz, 2 H, Bn), 7.53 (d, J = 8.8 Hz, 1 H),
7.57 (dd, J = 8.0, 1.0 Hz, 1 H), 7.59 (d, J = 2.3 Hz, 1 H), 8.19 (d,
J = 3.0 Hz, 1 H, H4), 11.34 (br s, 1 H, NH).
13C NMR (75 MHz, acetone-d6): d = 24.3 (NCH3), 28.3 (3 CH3),
70.9 (CH2), 85.7 (OC(CH3)3), 101.0, 101.3 (CH), 105.9, 111.1
(CH), 113.2 (CH), 115.1 (CH), 120.0, 120.1, 122.3, 123.5 (CH),
124.0 (CH), 128.3 (2 CH, Bn), 128.5 (CH, Bn), 129.2 (2 CH, Bn),
131.2 (CH), 132.7, 133.0, 138.3, 140.3, 149.2, 151.8, 152.1, 157.8,
171.4, 171.6.
IR (KBr): 3421, 2929, 1737, 1689, 1617, 1534, 1386, 1371, 1320,
1257, 1154, 767, 736, 697 cm–1.
1H NMR (300 MHz, acetone-d6): d = 1.77 (s, 9 H, t-Bu), 3.14 (s, 3
H, NCH3), 5.09 (s, 2 H, Bn), 6.53 (m, 1 H), 6.55 (m, 1 H), 6.68 (d,
J = 8.8 Hz, 1 H), 7.10 (m, 2 H), 7.30 (pseudo-d, J = 3.0 Hz, 1 H),
7.33 (m, 1 H, Bn), 7.38 (m, 2 H, Bn), 7.47 (m, 2 H, Bn), 7.81 (d,
J = 2.2 Hz, 1 H), 8.04 (br s, 1 H, OH), 8.18 (s, 1 H), 10.68 (br s, 1
H, NH).
13C NMR (75 MHz, acetone-d6): d = 24.4 (NCH3), 28.2 (3 CH3),
70.7 (CH2), 85.1 [OC(CH3)3], 95.4, 101.2, 104.9, 105.2, 107.6,
112.0, 112.7, 117.2, 121.8, 123.4, 124.5, 128.4 (2 C), 128.6, 128.8,
129.1, 129.2 (2 C), 133.0, 137.4, 138.3, 139.9, 150.0, 152.1, 157.8,
171.7, 174.4.
UV/Vis (CH3CN): lmax (log e) = 209 (4.73), 250 (sh, 4.39), 451 nm
(3.73).
2-Methyl-5,10-dihydro-1H-pyrrolo[3¢,4¢:4,5]oxocino[2,3-
b:6,7,8-c¢,d¢]diindole-1,3(2H)-dione (10a)
Neat urethane 9a (45 mg, 0.10 mmol) was heated for 5 min at 180
°C. The crude thermolysate was dissolved in acetone and purified
by flash chromatography (silica gel, PE–EtOAc, gradient 3:1 to 2:1)
to yield free indole 10a (31 mg, 87%) as a red solid; mp 188 °C;
TLC: Rf = 0.30 (PE–EtOAc, 1:1).
MS (EI): m/z (%) = 563 (4) [M+], 463 (64), 372 (100), 287 (11), 91
(20).
IR (KBr): 3387, 2930, 1757, 1694, 1510, 1216, 741 cm–1.
HRMS (EI): m/z [M+ – CO2 – C4H8] calcd for C28H21N3O4:
463.1532; found: 463.1527.
1H NMR (300 MHz, acetone-d6–DMSO-d6): d = 3.12 (s, 3 H,
NCH3), 7.02 (m, 1 H), 7.11 (m, 1 H), 7.20 (m, 1 H), 7.30 (m, 1 H),
7.32 (m, 1 H), 7.44 (m, 1 H), 7.67 (m, 1 H), 8.08 (s, 1 H), 12.72 (br
s, 2 H, 2 NH).
UV/Vis (MeOH): lmax (log e) = 203 (3.86), 217 (3.85), 258 (3.46),
465 nm (2.79).
Synthesis 2011, No. 2, 330–336 © Thieme Stuttgart · New York

334
G. Mayer et al.
PAPER
13C NMR (75 MHz, DMSO-d6): d = 24.1 (CH3), 92.7, 104.5, 110.4
(CH), 111.3 (CH), 112.5 (CH), 119.0, 120.1 (CH), 121.6 (CH),
122.2 (CH), 122.9 (CH), 123.5, 125.1, 128.5, 129.8 (CH), 130.5,
139.0, 149.9, 152.5, 171.0, 171.3.
MS (FAB): m/z (%) = 356 (3), 355 (4) [M+].
HRMS (EI): m/z [M+] calcd for C21H13N3O3: 355.0957; found:
IR (KBr): 3350 (s, br), 2950 (m), 1670 (m),1630 (w), 1515 (s), 1460
(s), 1345 (s), 1210 (s), 753 cm–1 (m).
1H NMR (600 MHz, DMSO-d6): d = 7.02 (ddd, J = 8.1, 7.6, 1.0 Hz,
1 H, H13), 7.11 (ddd, J = 8.0, 7.6, 1.3 Hz, 1 H, H12), 7.21 (m, 1 H,
H7), 7.24 (m, 1 H, H8), 7.29 (br d, J = 7.5 Hz, 1 H, H11), 7.42 (dd,
J = 7.0, 2.0 Hz, 1 H, H6), 7.73 (br d, J = 8.1 Hz, 1 H, H14), 8.13 (d,
J = 2.8 Hz, 1 H, H4), 9.84 (br s, 1 H, NH-2), 11.26 (br s, 1 H, NH-
10), 11.28 (br s, 1 H, NH-5).
355.0957.
12-(Benzyloxy)-2-methyl-5,10-dihydro-1H-pyrrolo[3¢,4¢:4,5]-
oxocino[2,3-b:6,7,8-c¢,d¢]diindole-1,3(2H)-dione (10b)
Neat urethane 9b (0.48 g, 0.85 mmol) was heated for 10 min at 180
°C. Flash chromatography of the crude thermolysate (silica gel, PE–
EtOAc, gradient 3:1 to 2:1) furnished 10b (0.34 g, 87%) as a red sol-
id; mp 175 °C; TLC: Rf = 0.56 (PE–EtOAc, 1:1).
13C NMR (100.6 MHz, DMSO-d6): d = 92.7 (C14b), 104.3 (C3b),
110.4 (CH-6), 111.2 (CH-11), 112.4 (CH-8), 119.1 (C8b), 120.1
(CH-13), 121.5 (CH-14), 122.1 (CH-12), 122.8 (CH-7), 124.2
(C3a), 125.1 (C14a), 129.1 (C14c), 129.8 (CH-4), 130.5 (C10a),
138.9 (C5a), 149.8 (C8a), 152.5 (C9a), 172.2 (C1 or C3), 172.5 (C1
or C3). The signals were assigned by H,H-COSY, NOESY, HET-
COR, and COLOC experiments.
IR (KBr): 3395, 3067, 2934, 1756, 1694, 1623, 1555, 1219, 1155,
772, 738, 698 cm–1.
MS (EI): m/z (%) = 342 (32) [M+ + H], 341 (100) [M+], 312 (13),
271 (20), 270 (91), 242 (31), 214 (15).
HRMS (EI): m/z [M+] calcd for C20H11N3O3: 341.0800; found:
341.0798.
1H NMR (300 MHz, acetone-d6): d = 3.05 (s, 3 H, NCH3), 5.13 (s,
2 H, Bn), 6.91 (dd, J = 8.8, 2.2 Hz, 1 H), 7.12 (d, J = 2.2 Hz, 1 H),
7.28 (t, J = 7.7 Hz, 1 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.31 (m, 1 H, Bn),
7.38 (pseudo-t, J = 7.5 Hz, 2 H, Bn), 7.44 (d, J = 7.7 Hz, 1 H), 7.45
pseudo-d, J = 7.5 Hz, 2 H, Bn), 7.64 (d, J = 8.8 Hz, 1 H), 8.13 (d,
J = 2.8 Hz, 1 H), 11.03 (br s, 1 H, NH), 11.20 (br s, 1 H, NH).
13C NMR (150 MHz, acetone-d6): d = 24.2 (NCH3), 70.9 (CH2),
94.3, 96.9 (CH), 106.2, 109.3, 110.8 (CH), 111.3 (CH), 113.2 (CH),
120.2, 121.7, 123.68 (CH), 123.73 (CH), 125.1, 128.3 (2 CH), 128.5
(CH), 129.2 (2 CH), 130.4 (CH), 132.3, 138.8, 140.1, 151.4, 152.8,
156.7, 172.0, 172.3.
UV/Vis (MeOH): lmax (log e) = 276 (4.15), 285 (sh, 4.12), 364
(3.76), 465 nm (3.91).
The synthetic compound was identical with the natural product by
comparison of the IR, NMR and mass spectra and HPLC co-injec-
tion.
Anhydride 11b and O-Benzylarcyroxocin B (12b)
To a 10% aq soln of KOH (30 mL) was added a soln of 10b (0.13
g, 0.27 mmol) in EtOH (5 mL), and the mixture was refluxed for 2
h. The mixture was adjusted to pH 5 with 2 M HCl and extracted
with EtOAc (3 × 30 mL). The combined organic layers were washed
with H2O and brine, dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography (silica gel, PE–EtOAc, gradient 3:1
to 1:1) furnished anhydride 11b as a red solid (TLC: Rf = 0.38, PE–
EtOAc, 1:1), which was dissolved in a mixture of anhyd DMF (22
mL) and MeOH (0.1 mL) and treated with HMDS (0.8 mL, 3.9
mmol). The mixture was stirred for 60 h at r.t., H2O (30 mL) was
added, the pH was adjusted to 5 with 2 M HCl and the soln was ex-
tracted with EtOAc (3 × 50 mL). The combined organic layers were
washed with H2O and brine, dried (MgSO4), and concentrated under
reduced pressure. Flash chromatography (silica gel, PE–EtOAc,
1:1) yielded 12b (71 mg, 57%) as a red solid; mp 312 °C (dec);
TLC: Rf = 0.18 (PE–EtOAc, 1:1).
MS (EI): m/z (%) = 461 (42) [M+], 370 (100), 91 (3).
HRMS (EI): m/z [M+] calcd for C28H19N3O4: 461.1376; found:
461.1385.
UV/Vis (MeOH): lmax (log e) = 211 (4.75), 245 (sh, 4.44), 385
(3.54), 482 nm (3.72).
5,10-Dihydrofuro[3¢,4¢:4,5]oxocino[2,3-b:6,7,8-c¢,d¢]diindole-
1,3-dione (11a)
To degassed 10% aq KOH (25 mL) was added 10a (50 mg, 0.14
mmol) in EtOH (2.5 mL), and the mixture was refluxed for 30 min.
The aqueous layer was acidified with dil HCl and then extracted
with EtOAc. The combined organic layers were washed with H2O
and brine and dried (MgSO4). Flash chromatography (silica gel,
CH2Cl2–acetone, gradient 30:1 to 20:1) furnished anhydride 11a
(42 mg, 87%) as a red solid; mp 155 °C (dec); TLC: Rf = 0.57
(CH2Cl2–acetone, 20:1).
IR (KBr): 3402, 2975, 2928, 1749, 1693, 1619, 1513, 1213, 1160,
760, 736 cm–1.
IR (CH2Cl2): 3300, 2970, 1755, 1700, 1618, 1496, 1245, 742 cm–1.
1H NMR (300 MHz, acetone-d6): d = 5.10 (s, 2 H, Bn), 6.81 (dd,
J = 8.5, 2 Hz, 1 H), 6.92 (d, J = 2 Hz, 1 H), 7.19 (t, J = 7 Hz, 1 H),
7.22 (d, J = 7 Hz, 1 H), 7.28 (m, 1 H), 7.36 (pseudo-t, J = 7.5, 2 H,
Bn), 7.44 (m, 3 H, Bn), 7.62 (d, J = 8.5 Hz, 1 H), 8.12 (d, J = 2.5
Hz, 1 H), 9.77 (s, 1 H, NH), 11.06 (br s, 1 H, NH), 11.24 (br s, 1 H,
NH).
1H NMR (300 MHz, acetone-d6): d = 7.11 (m, 1 H), 7.18 (m, 1 H),
7.26 (m, 1 H), 7.30–7.38 (m, 2 H), 7.52 (m, 1 H), 7.75 (m, 1 H), 8.27
(d, J = 3 Hz, 1 H), 11.49 (br s, 2 H, 2 NH).
13C NMR (75 MHz, acetone-d6): d = 92.5, 104.6, 110.5, 111.1,
113.0, 118.9, 120.7, 121.6, 122.7, 123.5, 124.9, 125.1, 129.7, 130.7,
130.9, 139.3, 149.7, 153.1, 165.4, 166.2.
MS (EI): m/z (%) = 448 (18), 447 (61) [M+], 357 (30), 356 (100), 91
(13).
MS (FAB): m/z (%) = 343 (1), 342 (2) [M+].
UV/Vis (MeOH): lmax (log e) = 213 (4.61), 245 (4.22), 471 nm
(3.57).
5,10-Dihydro-1H-pyrrolo[3¢,4¢:4,5]oxocino[2,3-b:6,7,8-c¢,d¢]di-
indole-1,3(2H)-dione (Arcyroxocin A, 4a)
Anhydride 11a (40 mg, 0.12 mmol) was dissolved in anhyd DMF
(10 mL) and treated with HMDS (0.37 mL, 1.8 mmol) and MeOH
(0.04 mL). The mixture was stirred for 36 h at r.t. It was acidified
with dil HCl and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with H2O and brine and dried
(MgSO4). The resulting residue was chromatographed (Sephadex
LH-20, acetone–MeOH, 4:1) to yield 4a (31 mg, 78%) as a red sol-
id; mp >300 °C; TLC: Rf = 0.30 (CHCl3–MeOH, 10:1).
12-Hydroxy-5,10-dihydro-1H-pyrrolo[3¢,4¢:4,5]oxocino[2,3-
b:6,7,8-c¢,d¢]diindole-1,3(2H)-dione (Arcyroxocin B, 4b)
To a stirred soln of benzyl ether 12b (18 mg, 0.04 mmol) in anhyd
EtOH (8 mL) were added Pd/C (cat.) and cyclohexa-1,4-diene (0.04
mL, 0.42 mmol). The mixture was maintained under an argon atmo-
sphere and the stirring continued for 3 h. Then, the soln was filtered
through Celite and concentrated under reduced pressure. The resi-
due was purified over an HPLC cartridge (RP-18, MeCN–H2O, 1:1)
Synthesis 2011, No. 2, 330–336 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Arcyroxocin A and B
335
to yield the free phenol 4b (10 mg, 67%) as a red solid; mp >300 °C;
TLC: Rf = 0.13 (PE–EtOAc, 1:1).
MS (EI): m/z (%) = 506 (0.5), 504 (0.3) [M+], 422 (16), 420 (16),
366 (89), 364 (89), 322 (35), 320 (35), 241 (32), 184 (38), 156 (12),
85 (80), 67 (16), 57 (100).
HRMS (EI): m/z [M+] calcd for C23H25N2O679Br: 504.0896; found:
504.0877.
IR (KBr): 3388 (s, br), 2938 (s), 2854 (m), 1756 (sh, m), 1702 (s),
1640 (m), 1630 (m), 1521 (w), 1466 (m), 1390 (w), 1357 (m), 1321
(m), 1250 cm–1 (w).
1H NMR (300 MHz, acetone-d6): d = 6.64 (dd, J = 8.5, 2.0 Hz, 1 H,
H13), 6.74 (d, J = 2.0 Hz, 1 H, H11), 7.19 (m, 1 H, H7), 7.21 (m, 1
H, H8), 7.44 (dd, J = 7.5, 1.0 Hz, 1 H, H6), 7.53 (d, J = 8.5 Hz, 1 H,
H14), 7.96 (s, 1 H, OH), 8.11 (d, J = 2.5 Hz, 1 H, H4), 9.72 (s, 1 H,
NH-2), 10.86 (s, 1 H, NH-5), 11.18 (s, 1 H, NH-10).
UV/Vis (MeOH): lmax (log e) = 228 (4.45), 248 (sh, 4.30), 294
(3.93), 396 nm (3.38).
Anal. Calcd for C23H25N2O6Br (505.4): C, 54.66; H, 4.99; N, 5.54.
Found: C, 54.47; H, 4.95; N, 5.67.
13C NMR (75 MHz, acetone-d6): d = 97.2 (C14b), 97.3 (CH-11),
108.6 (C3b), 110.7 (CH-13), 111.0 (CH-6), 113.1 (CH-8), 118.7
(C8b), 121.6 (C3a), 123.6 (CH-14), 123.7 (CH-7), 126.1 (C14a),
129.7 (C14c), 130.4 (CH-4), 132.7 (C10a), 140.1 (C5a), 151.3
(C8a), 152.4 (C9a), 154.8 (C12), 172.5 (C1 or C3), 172.6 (C1 or
C3).
MS (EI): m/z (%) = 357 (100) [M+], 328 (10), 314 (3), 286 (66) [M+
– CONHCO], 258 (22) [C17H10N2O], 229 (6) [C16H9N2], 228 (6)
[C16H8N2], 114 (17) [C8H4N], 57 (23).
3-[1-(tert-Butoxycarbonyl)-4-(tetrahydro-2H-pyran-2-yloxy)-
1H-indol-3-yl]-3-[1-(diethoxymethyl)-2-oxo-2,3-dihydro-1H-in-
dol-3-yl]-1-methyl-1H-pyrrole-2,5-dione (18)
To a freshly prepared soln of LDA (0.78 g, 7.26 mmol) in anhyd
THF (100 mL) was added dropwise at –78 °C a soln of 1-(di-
ethoxymethyl)indolin-2-one15 (17, 1.50 g, 6.40 mmol) in anhyd
THF (50 mL). After 1 h, the soln was allowed to warm to 20 °C.
Then, the mixture was treated dropwise with a soln of bromide 16
(3.3 g, 6.5 mmol) in anhyd THF (50 mL). After concentration under
reduced pressure, the residue was dissolved in EtOAc and immedi-
ately washed with brine. The organic phase was dried (MgSO4),
concentrated under reduced pressure, and purified by column chro-
matography (PE–EtOAc, 5:1 to 3:1) to yield 18 (2.07 g, 48%) as an
orange oil; TLC: Rf = 0.26 (PE–EtOAc, 5:1).
HRMS (EI): m/z [M+] calcd for C20H11N3O4: 357.0749; found:
357.0762.
UV/Vis (MeOH): lmax = 206, 290 (sh), 390, 483 nm.
The synthetic compound was identical with the natural product by
comparison of the IR, NMR and mass spectra.
1H NMR (300 MHz, CDCl3): d = 1.05–1.20 (m, 6 H), 1.05–1.95 (m,
15 H), 3.02 (br s, 3 H), 3.57–4.00 (m, 6 H), 4.80 (br s, 1 H), 5.59 (br
s, 1 H), 6.20 (br s, 1 H), 6.82–7.09 (m, 4 H), 7.23–7.30 (m, 2 H),
7.43–7.46 (m, 1 H), 7.60–7.80 (m, 1 H).
3-Bromo-1-methyl-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1H-in-
dol-3-yl]-1H-pyrrole-2,5-dione (15)
To a soln of 4-(tetrahydro-2H-pyran-2-yloxy)-1H-indole (6, 1.14 g,
5.23 mmol) in anhyd THF (20 mL) was added dropwise 1 M EtMg-
Br in THF (6 mL, 6 mmol). The mixture was stirred for 1 h at r.t., a
soln of 3,4-dibromo-1-methylmaleimide (14, 0.64 g, 2.38 mmol) in
anhyd THF (20 mL) was added dropwise. The mixture was stirred
at r.t. for a further 2 h, hydrolyzed with ice, and carefully neutralized
with 20% aq citric acid. The volatiles were removed under reduced
pressure and the aqueous residue was extracted with EtOAc (3 ×
100 mL). The combined organic phases were dried (MgSO4), con-
centrated under reduced pressure, and purified by chromatography
(silica gel, CH2Cl2) to yield indolylmaleimide 15 as orange crystals
(0.65 g, 70%). Recrystallization (MeOH) gave an analytically pure
sample; mp 136 °C; TLC: Rf = 0.18 (CH2Cl2).
4-(4-Hydroxy-1H-indol-3-yl)-1-methyl-3-(2-oxo-2,3-dihydro-
1H-indol-3-yl)-1H-pyrrole-2,5-dione (19)
To a soln of bisindolylmaleimide 18 (165 mg, 0.25 mmol) in anhyd
CH2Cl2 (25 mL) was added at 0 °C TiCl4 (0.05 mL, 1 mmol), and
the temperature was maintained for 3 h at 0 °C. The resulting dark
red-brown soln was hydrolyzed with H2O and diluted with CHCl3.
The organic phase was washed with H2O and brine and dried
(MgSO4). After concentration of the soln under reduced pressure at
0 °C, the resulting residue was purified by column chromatography
(CHCl3–MeOH, gradient 15:1 to 10:1) to yield the deprotected
compound 19 (40 mg, 43%) as orange-red crystals; mp 134 °C;
TLC: Rf = 0.26 (CHCl3–MeOH, 10:1).
1H NMR (90 MHz, acetone-d6): d = 1.33–1.76 (m, 6 H), 3.04 (s, 3
H), 3.31–3.93 (m, 2 H), 5.47 (‘s’, 1 H), 6.78 (dd, J = 8, 7 Hz, 1 H),
7.08 (d, J = 8 Hz, 1 H), 7.10 (d, J = 7 Hz, 1 H), 7.56 (m, 1 H), 10.44
(br s, 1 H, NH).
IR (KBr): 3370, 2950, 1699, 1620, 1592, 1510, 1472, 1455, 1388,
1320, 1265, 751, 674, 598 cm–1.
1H NMR (300 MHz, acetone-d6): d = 2.93 (s, 3 H), 5.03 (s, 1 H),
6.59 (m, 1 H), 6.89 (m, 1 H), 6.92 (m, 1 H), 7.03 (m, 2 H), 7.11 (m,
1 H), 7.18 (m, 1 H), 7.68 (br s, 1 H, OH), 8.43 (s, 1 H), 9.61 (br s, 1
H, NH), 10.82 (br s, 1 H, NH).
UV/Vis (MeOH): lmax (log e) = 222 (4.52), 238 (sh, 4.12), 286 (sh,
3.46), 440 nm (3.60).
13C NMR (75 MHz, acetone-d6): d = 23.9, 44.7, 103.7, 105.0, 107.1,
110.3, 116.9, 122.5, 124.5, 125.1, 128.2, 129.0, 129.6, 132.5, 140.3,
140.9, 143.7, 151.7, 170.7, 172.9, 176.5.
Anal. Calcd for C18H17N2O4Br (405.3): C, 53.35; H, 4.23; N, 6.91.
Found: C, 53.12; H, 4.33; N, 7.04.
MS (FAB): m/z (%) = 413 (5) [M+ + 1 + K], 374 (10) [M+ + 1], 373
3-Bromo-4-[1-(tert-butoxycarbonyl)-4-(tetrahydro-2H-pyran-
2-yloxy)-1H-indol-3-yl]-1-methyl-1H-pyrrole-2,5-dione (16)
To an ice-cooled soln of indole 15 (1.24 g, 3.07 mmol) in THF (50
mL) were added Boc2O (0.8 g, 3.7 mmol) and DMAP (cat.), and the
mixture was stirred for 30 min at 0 °C. After concentration under re-
duced pressure, the residue was dissolved in CH2Cl2 and filtered
over a short silica gel column. Recrystallization of the product
(MeOH) yielded urethane 16 (1.52 g, 98%) as yellow crystals; mp
131 °C.
(13) [M+].
HRMS (FAB): m/z [M+] calcd for C21H15N3O4: 373.1063; found:
373.1058.
UV/Vis (MeOH): lmax = 210, 220 (sh), 250, 280 (sh), 440 nm.
9¢-Methylspiro[indole-3,7¢-pyrrolo[3¢,4¢:5,6]oxepino[4,3,2-
cd]indole]-2,8¢,10¢(1H,2¢H,9¢H)-trione (20)
From THP ether 18: To ether 18 (165 mg, 0.25 mmol) in anhyd tol-
uene (25 mL) was added DDQ (60 mg, 0.26 mmol) and a catalytic
amount of p-TsOH. The mixture was refluxed for 6 h and then
cooled to r.t. The precipitate was removed by filtration and the soln
concentrated under reduced pressure. The residue was heated for 5
1H NMR (90 MHz, CCl4): d = 1.60 (br s, 15 H), 2.97 (s, 3 H), 3.30–
3.86 (m, 2 H), 5.35 (br pseudo-s, 1 H), 6.86 (br d, J = 8 Hz, 1 H),
7.12 (t, J = 8 Hz, 1 H), 7.53 (s, 1 H), 7.67 (d, J = 8 Hz, 1 H).
Synthesis 2011, No. 2, 330–336 © Thieme Stuttgart · New York

336
G. Mayer et al.
PAPER
min at 180 °C, then dissolved in acetone and purified by column
chromatography (acetone) to yield 20 (80 mg, 86%) as orange crys-
tals; mp 315 °C; TLC: Rf = 0.36 (PE–EtOAc, 2:1).
squares, R1 = 0.0846, wR2 = 0.1921, for observed 2098 reflections
[I > 2s(I)].
From free phenol 19: To compound 19 (1.5 mg, 0.04 mmol) in an-
hyd toluene (15 mL) was added excess NaH. After the reaction was
complete (TLC control!), the mixture was hydrolyzed by careful ad-
dition of H2O and the product taken up in EtOAc. The soln was sub-
sequently washed with H2O and brine, dried (MgSO4), and
concentrated under reduced pressure. Column chromatography of
the resulting residue afforded spiro compound 20 (1.5 mg, quant.).
1H NMR (600 MHz, acetone-d6): d = 2.92 (s, 3 H, NCH3), 6.34 (dd,
J = 8, 1 Hz, 1 H, H4), 6.62 (td, J = 8, 1 Hz, 1 H, H5), 6.63 (dd, J = 8,
1 Hz, 1 H, H5¢), 6.98 (d, J = 8 Hz, 1 H, H7), 7.17 (t, J = 8 Hz, 1 H,
H6¢), 7.20 (td, J = 8, 1 Hz, 1 H, H6), 7.37 (d, J = 8 Hz, 1 H, H3¢),
8.34 (m, 1 H, H1¢), 9.78 (br s, NH-2¢), 11.44 (br s, NH-1).
1H-coupled 13C NMR (150 MHz, acetone-d6): d = 22.9 (Q, J = 144
Hz, NCH3), 81.6 (m, C3), 106.0 (dd, J = 7, 2 Hz, C10b¢), 108.1
(Ddd, J = 166, 8, 4 Hz, C3¢), 110.8 (Ddt, J = 163, 8, 2 Hz, C7),
112.7 (Ddd, J = 160, 9, 2 Hz, C5¢), 118.9 (q, J = 5 Hz, C10c¢), 121.6
(Dd, J = 160, 8 Hz, C5), 124.1 (Dddd, J = 160, 9, 3, 2 Hz, C4),
124.7 (Dm, J = 160 Hz, C4¢), 126.2 (hidden), 128.5 (D, J = 190 Hz,
C1¢), 129.1 (ddd, J = 7, 6, 1 Hz, C3a), 130.6 (Dd, J = 160, 8 Hz,
C6), 136.2 (d, J = 1 Hz, C10a¢), 138.1 (dd, J = 11, 8 Hz, C2a¢),
143.3 (tm, J = 9 Hz, C7a), 149.9 (ddd, J = 11, 4, 2 Hz, C5a¢), 168.7
(q, J = 3 Hz, C10¢), 169.3 (q, J = 3 Hz, C8¢), 170.9 (s, C2).
Acknowledgment
Financial support of this work by the Fonds der Chemischen Indu-
strie is gratefully acknowledged. We thank Dr. Kay Greenfield,
Brisbane, for her help in improving the manuscript.
References
(1) Responsible for X-ray crystal structure determinations.
(2) For reviews, see: (a) Gill, M.; Steglich, W. Prog. Chem.
Org. Nat. Prod. 1987, 51, 216. (b) Steglich, W. Pure Appl.
Chem. 1989, 61, 281. (c) Dembitsky, V. M.; Rezanka, T.;
Spizek, J.; Hanus, L. O. Phytochemistry 2005, 66, 747.
(d) Ishibashi, M. Yakugaku Zasshi 2007, 127, 1369.
(3) Steglich, W.; Steffan, B.; Kopanski, L.; Eckhardt, G. Angew.
Chem., Int. Ed. Engl. 1980, 19, 459; Angew. Chem. 1980, 92,
463.
(4) Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur.
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(5) Casser, I. Dissertation; Friedrich-Wilhelms-Universität
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(6) (a) Kamata, K.; Suetsugu, T.; Yamamoto, Y.; Hayashi, M.;
Komiyama, K.; Ishibashi, M. J. Nat. Prod. 2006, 69, 1252.
(b) The claim that arcyroxocin B (4b) was not characterized
is unjustified: the UV, 1H, and 13C NMR data of 4b are given
in ref. 2a, pp 218 and 223–226.
MS (FAB): m/z (%) = 372 (3) [M+ + 1], 371 (1) [M+].
HRMS (EI): m/z [M+] calcd for C21H13N3O4: 371.0906; found:
371.0910.
(7) See for example: Murase, M.; Watanabe, K.; Yoshida, T.;
Tobinaga, S. Chem. Pharm. Bull. 2000, 48, 81.
(8) Mayer, G.; Wille, G.; Steglich, W. Tetrahedron Lett. 1996,
37, 4483.
(9) (a) Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.;
Morishima, H. Tetrahedron 1996, 52, 8099. (b) Routier, S.;
Ayerbe, N.; Mérour, J.-Y.; Coudert, G.; Bailly, C.; Pierré,
A.; Pfeiffer, B.; Caignard, D.-H.; Renard, P. Tetrahedron
2002, 58, 6621.
(10) The exchange of EtMgCl for LiHMDS did not improve the
yield (compare, however, ref. 9a).
(11) (a) Bergman, J.; Pelcman, B. Tetrahedron Lett. 1987, 28,
4441. (b) Bergman, J.; Koch, E.; Pelcman, B. J. Chem. Soc.,
Perkin Trans. 1 2000, 2609.
(12) Apelqvist, T.; Wensbo, D. Tetrahedron Lett. 1996, 37, 1471.
(13) Davis, P. D.; Bit, R. A. Tetrahedron Lett. 1990, 31, 5201.
(14) Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W.
Tetrahedron 1988, 44, 2887.
(15) Gmeiner, P.; Bollinger, B. Synthesis 1995, 168.
(16) Sheldrick, G. M. SHELXS-86. Program for the Solution of
Crystal Structures; University of Göttingen: Germany,
1985.
(17) Sheldrick, G. M. SHELXL-93. Program for the Refinement
of Crystal Structures; University of Göttingen: Germany,
1993.
(18) Crystallographic data for the structures reported in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publications no. CCDC
267603 (9a), CCDC 783129 (9b), and CCDC 228174 (20).
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1
EZ, UK [fax: +44 (1223)336033 or e-mail:
UV/Vis (MeOH): lmax = 212, 254, 446 nm.
Crystal Structure Determinations
The X-ray diffraction analyses were carried out on an Enraf-Nonius
CAD4 diffractometer at 296(2) K using MoKa (l = 0.71069 Å) ra-
diation. The structures were solved by direct methods16 and refined
with the SHELXL-93 program.17
Arcyroxocin 9a18
C26H21N3O5, M = 455.46 g/mol, monoclinic, P21/n, 2.43 < q <
23.97, a = 10.6113(13) Å, b = 13.786 (2) Å, c = 15.347 (3) Å,
a = 90.00(14)°, b = 96.682(12)°, g = 90.00(11)°, V = 2230(6) Å3,
Z = 4, Dcalcd = 1.357 mg/m3, absorption coefficient m = 0.096 mm–1,
l = 0.71069 Å, crystal size 0.27 × 0.43 × 0.27 mm, full matrix least
squares, R1 = 0.0583, wR2 = 0.1367, for observed 2763 reflections
[I > 2s(I)].
Arcyroxocin 9b18
C33H27N3O6, M = 561.58 g/mol, triclinic, P1, 2.44 < q < 23.97,
a = 8.9372(10) Å, b = 10.526(3) Å, c = 16.3139(11) Å,
a = 104.872(11)°, b = 98.790(11)°, g = 105.99(2)°, V = 1384(4) Å3,
Z = 2, Dcalcd = 1.347 mg/m3, absorption coefficient m = 0.094 mm–1,
l = 0.71069 Å, crystal size 0.13 × 0.26 × 0.40 mm, full matrix least
squares, R1 = 0.1058, wR2 = 0.1732, for observed 2772 reflections
[I > 2s(I)].
Spiroether 2018
C21H13N3O4, M = 371.35 g/mol, monoclinic, P21/c, 2.88 < q <
22.98, a = 14.209(3) Å, b = 15.165(2) Å, c = 8.617(3) Å,
a = 90.00(14)°, b = 95.43(3)°, g = 90.00(2)°, V = 1848(8) Å3, Z = 4,
Dcalcd = 1.399 mg/m3, absorption coefficient m = 0.105 mm–1,
l = 0.71069 Å, crystal size 0.17 × 0.33 × 0.16 mm, full matrix least
deposit@ccdc.cam.ac.uk].
Synthesis 2011, No. 2, 330–336 © Thieme Stuttgart · New York