Biomimetic syntheses of lamellarin and lukianol-type alkaloids

Article abstract of DOI:10.1055/s-2006-950191

The formation of 3,4-diarylpyrrole-2,5-dicarboxylic acids from arylpyruvic acids and 2-arylethylamines was used as a key step for the synthesis of several marine pyrrole alkaloids. The utility of this method is illustrated through the development of synth

Full text of DOI:10.1055/s-2006-950191

3048
PAPER
Biomimetic Syntheses of Lamellarin and Lukianol-Type Alkaloids
B
iomimetic Synthese
s
of La
m
r
ellarin a
i
nd Luk
s
ianol Typ
t
e
Alkal
i
oids an Peschko, Christian Winklhofer, Andreas Terpin, Wolfgang Steglich*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13 (F), 81377 München, Germany
Fax +49(89)218077756; E-mail: wolfgang.steglich@cup.uni-muenchen.de
Received 22 May 2006
Dedicated to Professor Siegfried Hünig on the occasion of his 85th birthday
MeO MeO OMe OMe
Abstract: The formation of 3,4-diarylpyrrole-2,5-dicarboxylic ac-
MeO
OMe
ids from arylpyruvic acids and 2-arylethylamines was used as a key
step for the synthesis of several marine pyrrole alkaloids. The utility
of this method is illustrated through the development of syntheses
of ningalin B (5), lamellarins G (11a) and K (11b), lukianol A (32),
and a lukianol–lamellarin hybrid (24).
a
b
HO2C
CO2H
N
HO2C
66%
96%
O
Key words: biomimetic synthesis, marine alkaloids, pyrroles,
lamellarins, lukianol A
1
2
OMe
Marine-derived 3,4-diarylpyrrole alkaloids exhibit a great
structural variety and interesting biological properties.1
Based on the assumption that these compounds arise from
tyrosine (dopa), we considered 3,4-diarylpyrrole-2,5-di-
carboxylic acids as plausible intermediates in their bio-
synthesis, from which all other structural types may be
formed. This led us to develop a simple synthesis of 3,4-
diarylpyrrole-2,5-dicarboxylic acids, in which 3-aryl-
pyruvic acids and 2-arylethylamines are condensed under
oxidative conditions. Further transformations then al-
lowed syntheses of lamellarin,2 purpurone,3 polycitrin,4
polycitone,5 and storniamide6 type alkaloids. In this pub-
lication we report the synthesis of some additional marine
3,4-diarylpyrrole alkaloids using this strategy.
OMe
HO
HO
MeO MeO
HO
MeO
OH
OMe
d
O
O
R
N
N
89%
O
O
OH
OMe
OH
OMe
3, R = CO2H
4, R = H
5
Ningalin B (5) was isolated by Kang and Fenical7 from an
Australian Didemnum species. Our synthesis of this alka-
loid starts with the oxidative coupling of two equivalents
of 3-(3,4-dimethoxyphenyl)pyruvic acid (1) and in situ re-
action of the resulting 1,4-diketone with one equivalent of
2-(3,4-dimethoxyphenyl)ethylamine (Scheme 1). This
one-pot procedure afforded the pyrrole dicarboxylic acid
2 in 66% yield. Treatment of the latter with lead(IV) ace-
tate in refluxing EtOAc gave monolactone acid 3,8a which,
after decarboxylation with copper chromite and demeth-
ylation of the resulting lactone 4 with BBr3, furnished nin-
galin B (5). The alkaloid was thus obtained from
commercially available starting materials in four steps
and 52% overall yield. This compares favorably with syn-
theses of ningalin B described in the literature.8 Interest-
ingly, Boger et al.9 have recently demonstrated that
lactone 4 and several amides derived from carboxylic acid
3 exhibit potent multidrug resistance (MDR) reversal ac-
tivities.
c
93%
Scheme 1 Reagents and conditions: (a) 1. 1, n-BuLi (2 equiv), 2. I2
(0.5 equiv), 3. 3,4-(MeO)2C6H3CH2CH2NH2; (b) Pb(OAc)4; (c) cop-
per chromite, quinoline; (d) BBr3.
In our earlier synthesis of lamellarin G trimethyl ether an
effective three step procedure was applied.2a Using the
isopropyl method for O-protection10 we have now been
able to synthesize lamellarin G itself in 57% overall yield
by the same reaction sequence (Scheme 2). In the first
step pyrrole-2,5-dicarboxylic acid 8a was obtained from
3-(3-isopropoxy-4-methoxyphenyl)pyruvic acid (6a)2b
and 2-(6-bromo-3-isopropoxy-4-methoxyphenyl)ethyl-
amine (7a)2b in high yield. Treatment of 8a with lead(IV)
acetate in EtOAc afforded monolactone 9a, which was cy-
clized under Heck conditions to the pentacyclic lamellarin
derivative 10a. Selective deprotection of 10a with AlCl3
yielded lamellarin G (11a)11 thus constituting the first
synthesis of this marine alkaloid.
The same reaction sequence could be applied to the syn-
thesis of lamellarin K (11b).12 In this case, however, pyr-
role formation from 3-(4-isopropoxy-3-methoxy-
SYNTHESIS 2006, No. 18, pp 3048–3057
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950191; Art ID: Z10406SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

PAPER
Biomimetic Syntheses of Lamellarin and Lukianol-Type Alkaloids
3049
R1O
OR2
R2O
OR1
R1O R2O OR2 OR1
R1O R2O OR2 OR1
R1O
R2O OR2 OR1
6a,b
O
HO2C
CO2H
HO2C
CO2H
R3
HO2C
N
NH2
N
a
b
c
O
O
O
O
O
MeO
R4O
a: 84%
b: 43%
a: 87%
b:91%
a: 80%
b: 98%
N
Br
R3
Br
Br
R3
R3
OR4
8a,b
OR4
OR4
7a,b
9a,b
10a,b
OMe
OMe
OMe
d
11a, R1 = Me, R2 = R3 = R4 = H
11b, R1 = H, R2 = R4 = Me, R3 = OH
97%
a: R1 = Me, R2 = R4 = i-Pr, R3 = H
b: R2 = R4 = Me, R1 = i-Pr, R3 = Oi-Pr
Scheme 2 Reagents and conditions: (a) 1. 6, n-BuLi (2 equiv), THF, –78 °C, 2. I2 (0.5 equiv), –70 °C to r.t., then 7, 4 Å MS, r.t., 12 h (8a)
or reflux, 80 min (8b); (b) Pb(OAc)4, EtOAc, r.t., 20 min; (c) 1. Pd(OAc)2, PPh3, Et3N, MeCN, 150 °C; (d) AlCl3, CHCl3, 0 °C.
phenyl)pyruvic acid (6b)2b and 2-(6-bromo-2-isopropoxy- Next we applied our method to the synthesis of a hybrid
3,4-dimethoxyphenyl)ethylamine (7b) occurred in only alkaloid 24, incorporating structural motifs from both
43% yield probably because of the two ortho substituents lukianol A and the lamellarins (Scheme 4). The starting
flanking the side chain. The subsequent cyclizations and diester 20 was obtained by reaction of ethyl 3-bromo-3-
the selective O-deprotection proceeded smoothly and af- (4-methoxyphenyl)pyruvate (17) with the sodium enolate
forded lamellarin K in four steps and 37% overall yield. of methyl 3-(3,4-dimethoxyphenyl)pyruvate (18), fol-
Lamellarin K has been synthesized before by the elegant lowed by in situ condensation with 2-(4-methoxyphen-
cycloaddition approaches of Banwell,13 Ruchirawat,14 and yl)ethylamine (19) to give pyrrole 20.2b Selective
Castedo.15
cleavage of the methyl ester was achieved with NaCN
in 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one
(DMPU),19 and treatment of the resulting acid 21 with
lead(IV) acetate yielded lactone 22 which was brominated
at the benzylic position with NBS. The ester moiety with-
in the bromo compound so formed was then hydrolyzed
and the second lactone ring produced by heating with a
catalytic amount of p-TsOH in toluene. The resulting di-
lactone 23 was treated with DDQ to yield the desired hy-
brid alkaloid in form of its permethyl ether 24.
Compounds of this type are as yet unknown as natural
products.
Lukianol A (32)20 was first synthesized by Fürstner21 via
lamellarin Q dimethyl ether (the so-called Fürstner inter-
mediate). Subsequently several other syntheses of luki-
anol A were reported and these all use the Fürstner
intermediate as a relay compound.22 We reasoned that our
biomimetic approach would allow us to develop a differ-
ent strategy, in which the lukianol skeleton is built up in a
single step.
The 2-(6-bromo-2-isopropoxy-3,4-dimethoxyphenyl)eth-
ylamine (7b), required for the synthesis of lamellarin K,
was obtained from 5-bromo-2,3-dimethoxybenzaldehyde
(12)16 in five steps and 37% yield as depicted in
Scheme 3. Thus, aldehyde 12 was treated with performic
acid and the resulting formate ester hydrolyzed with aque-
ous KOH to yield phenol 13. Formylation17 of the latter to
14 followed by O-protection with isopropyl bromide af-
forded aldehyde 15 which was condensed with ni-
tromethane to give nitrostyrene 16. Reduction of the latter
with chlorotrimethylsilane and lithium borohydride18
gave the desired amine 7b in high yield.
CHO
OH
OMe
OMe
a
b
75%
85%
Br
OMe
OMe
Br
OMe
12
OR
13
O2N
Oi-Pr
Our synthesis of lukianol A starts with pyrrole dicarboxy-
lic acid 26, which could be obtained in 81% yield from 3-
(4-methoxyphenyl)pyruvic acid and 2-hydroxy-2-(4-
methoxyphenyl)ethylamine (25) (Scheme 5). Compound
26 was converted into lactone 27 upon heating in toluene
in the presence of p-TsOH. Unfortunately, all attempts to
effect the direct conversion of this latter species into ox-
azinone 30 failed because of the sensitivity of the pyrrole
core towards oxidation. Similarly, we were unable to oxi-
dize the alcohol unit in 26 selectively to the corresponding
ketone using any of the commonly available reagents or
OHC
Br
OMe
e
d
7b
100%
97%
OMe
Br
OMe
14, R = H
15, R = i-Pr
16
c
78%
Scheme 3 Reagents and conditions: (a) 1. 25% H2O2, HCO2H,
H2SO4 (cat.), 2. aq KOH; (b) Cl2CHOCH3, TiCl4; (c) i-PrBr, K2CO3;
(d) MeNO2, NH4OAc; (e) TMSCl, LiBH4.
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

3050
C. Peschko et al.
PAPER
MeO
MeO
OMe
MeO
MeO
OMe
Br
NH2
a
b
EtO2C
CO2Me
EtO2C
CO2Me
N
O
O
93%
43%
17
18
19
20
OMe
OMe
MeO
MeO
OMe
MeO
MeO
OMe
O
c
d
EtO2C
CO2H
EtO2C
N
N
O
95%
71%
3 steps
21
OMe
22
OMe
MeO
MeO
OMe
MeO
OMe
MeO
O
O
O
O
N
N
e
O
O
O
O
70%
23
24
OMe
OMe
Scheme 4. Reagents and conditions: (a) 1. 18, NaH, 12 to –5 °C, then 17, –5 to 25 °C, CH2Cl2, 2. 19, 4 Å MS, reflux; (b) NaCN, DMPU,
115 °C; (c) Pb(OAc)4, EtOAc; (d) 1. NBS, CCl4, hn, 2. THF–H2O, 3. p-TsOH (cat.), toluene; (e) DDQ, 1,2-dichlorobenzene, 140 °C.
procedures (Dess–Martin periodinane, Swern oxidation,
Melting points (uncorrected): Büchi SMP 535 apparatus. IR spec-
etc.). This would have led to a most expeditious synthesis
of lukianol A. Nevertheless, the alkaloid could eventually
be obtained by esterification of lactone acid 27 with 2-(tri-
methylsilyl)ethanol, treatment of the resulting ester 28
with NBS and elimination of HBr from the ensuing bro-
mide to yield oxazinone 29. Deprotection of the ester
group with fluoride ion followed by decarboxylation of
the ensuing acid 30 afforded lukianol A trimethyl ether
31, which had previously been transformed into lukianol
A (32) by treatment with BBr3.21 Our sequence allowed
the synthesis of trimethyl ether 31 from 3-(4-methoxyphe-
nyl)pyruvic acid in just seven steps and 25% overall yield.
tra: PerkinElmer FT-IR Spectrum 1000. Abbreviations: s, strong;
m, medium; w, weak; br, broad. Mass spectra (EI, 70 eV): Finnigan
MAT 90 and Finnigan MAT 95Q. High-resolution mass spectra (EI,
70 eV): Finnigan MAT 95Q. NMR spectra: Bruker ARX 300 and
Bruker AMX 600. The spectra were recorded in CDCl3, DMSO-d6
or acetone-d6 using the residual solvent peak as an internal standard
(CDCl3, dH = 7.26 and dC = 77.10; DMSO-d6, dH = 2.49 and
dC = 39.50; acetone-d6, dH = 2.04 and dC = 29.80). Elemental analy-
ses were carried out by the Microanalytical Laboratory of the De-
partment of Chemistry, University of Munich. Flash
chromatography (FC): Merck Kieselgel 60 (0.040–0.063 mm).
TLC: Aluminum foils, silica gel 60 F254 (Merck). Solvents for flash
chromatography (FC) were distilled before use. THF was distilled
under argon from Na/benzophenone. CH2Cl2 was distilled under ar-
gon from Sicapent (Merck). Anhyd DMF was purchased from Flu-
ka.
The work presented in this paper demonstrates that our
biogenetic approach to marine pyrrole alkaloids can be
used for concise syntheses of many types of these bioge-
netically closely related compounds.
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

PAPER
Biomimetic Syntheses of Lamellarin and Lukianol-Type Alkaloids
3051
MeO
OMe
MeO
OMe
MeO
OMe
HO2C
CO2H
O
HO2C
CO2H
OH
RO2C
NH2
N
N
O
O
b
d
a
OH
O
83%
75%
81%
OMe
25
OMe
26
OMe
27, R = H
c
82%
28, R = CH2CH2SiMe3
RO
OR
MeO
OMe
MeO
OMe
O
e
f
O
O
O
HO2C
N
N
N
O
89%
70%
O
O
O
Me3Si
OR
OMe
OMe
31, R = Me
32, R = H
29
g
30
99%20
Scheme 5 Reagents and conditions: (a) 1. n-BuLi (2 equiv), THF, –78 °C, 2. I2 (0.5 equiv), –78 °C to r.t., 3. 25, r.t., 4 Å MS, 18 h; (b) p-
TsOH (cat.), toluene, reflux; (c) Me3SiCH2CH2OH, TBTU; (d) NBS, hn, then Et3N; (e) Bu4NF; (f) copper chromite, quinoline; (g) BBr3.
3,4-Diarylpyrrole-2,5-dicarboxylic Acids 2, 8a,b and 26; Gener-
al Procedure
13C NMR (75 MHz, DMSO-d6): d = 37.5 (CH2), 48.1 (CH2), 55.4
(CH3, several overlapping signals), 55.7 (CH3), 110.9 (CH), 112.3
(CH), 112.5 (CH), 114.9 (CH), 120.7 (CH), 122.8 (CH), 124.5,
127.3, 129.6, 130.9, 147.4, 147.5, 147.7, 148.9, 162.8.
A solution of n-BuLi (20 mL of 2.5 M in hexane, 50 mmol) was
added to a magnetically stirred solution of the appropriate 3-
arylpyruvic acid (25 mmol) in anhyd THF (400 mL) at –78 °C. Stir-
ring was continued for 30 min and the mixture was then treated,
over a period of 30 min, with a solution of I2 (3.17 g, 12.5 mmol) in
anhyd THF (30 mL). After removal of the cooling bath, the mixture
was stirred for another 1 h at r.t. The appropriate 2-arylethylamine
(20–65 mmol) and 4 Å molecular sieves (5 g) were added, and the
mixture was either stirred overnight at r.t. (2, 8a, 26) or at reflux for
80 min (8b). After filtration and washing the filter residue with H2O
(2 × 100 mL), the combined filtrates were acidified to pH 3 with 2
N HCl and extracted with EtOAc (3 × 200 mL). The combined or-
ganic extracts were washed with brine (200 mL), dried (Na2SO4),
and concentrated under reduced pressure. The crude product was
purified by recrystallization or flash chromatography.
EI-MS: m/z (%) = 591 (13, [M]+), 547 (11, [M – CO2]+), 503 (100,
[M – 2 × CO2]+), 352 (32, [M – 2 × CO2 – C9H11O2]+).
HRMS: m/z calcd for C32H33NO10: 591.2104; found: 591.2094.
Anal. Calcd for C32H33NO10: C, 64.97; H, 5.62; N, 2.37. Found: C,
65.07; H, 5.70; N, 2.29.
1-(3,4-Dimethoxyphenyl)-3-[2-(3,4-dimethoxyphenyl)ethyl]-
7,8-dimethoxy-4-oxo-3H-[1]benzopyrano[3,4-b]pyrrole-2-car-
boxylic Acid (3)
To a solution of 2 (2.95 g, 4.99 mmol) in anhyd EtOAc (300 mL)
was added Pb(OAc)4 (3.32 g, 7.5 mmol) and the resulting mixture
was heated under reflux for 45 min. After cooling to r.t., 1 M aq
KHSO4 (40 mL) was added and the mixture stirred for 5 min. The
precipitate was filtered off and the filtrate washed with 1 M aq
KHSO4 (20 mL) and brine (20 mL), then dried (Na2SO4), and con-
centrated under reduced pressure. Acid 3 (2.83 g, 96%) was ob-
tained as a yellow solid, which was recrystallized from MeOH; mp
220 °C (Lit.8a mp 219–220 °C).
3,4-Bis(3,4-dimethoxyphenyl)-1-[2-(3,4-dimethoxyphenyl)eth-
yl]pyrrole-2,5-dicarboxylic Acid (2)
From keto acid 1 (5.61 g, 25 mmol) and 2-(3,4-dimethoxyphen-
yl)ethylamine (11.78 g, 65 mmol) according to the general proce-
dure. The crude product was recrystallized from MeOH to afford 2
(4.85 g, 66%); mp 224 °C.
IR (KBr): 3437 (s, br), 2937 (m), 2838 (w), 1729 (s), 1624 (m),
1539 (m), 1516 (m), 1491 (m), 1465 (m), 1437 (m), 1406 (m), 1361
(w), 1263 (s), 1239 (m), 1193 (m), 1156 (s), 1075 (w), 1028 (m),
942 (w), 858 (w), 766 (w), 572 (w) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.97 (t, J = 7.6 Hz, 2 H), 3.52
(s, 6 H), 3.68 (s, 6 H), 3.71 (s, 3 H), 3.73 (s, 3 H), 4.80 (t, J = 7.6
3
Hz, 2 H), 6.55 (dd, J = 8.2 Hz, 4J = 1.8 Hz, 1 H), 6.57 (‘s’, 3 H),
4
6.72 (dd, 3J = 8.2 Hz, J = 1.8 Hz, 2 H), 6.75 (d, J = 8.2 Hz, 2 H),
6.88 (d, J = 8.2 Hz, 1 H).
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

3052
C. Peschko et al.
PAPER
1H NMR (300 MHz, DMSO-d6): d = 2.98 (t, J = 7.2 Hz, 2 H), 3.27,
3.67, 3.69, 3.72, 3.77, 3.79 (s each, 3 H), 4.97 (t, J = 7.2 Hz, 2 H),
1-[2-(2-Bromo-5-isopropoxy-4-methoxyphenyl)ethyl]-3,4-bis(3-
isopropoxy-4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylic
Acid (8a)
3
6.38 (s, 1 H), 6.68 (d, J = 1.9 Hz, 1 H), 6.69 (dd, J = 8.1 Hz,
4J = 1.9 Hz, 1 H), 6.85 (d, J = 8.1 Hz, 1 H), 6.86 (dd, 3J = 8.2 Hz,
4J = 1.8 Hz, 1 H), 6.92 (d, J = 1.8 Hz, 1 H), 7.03 (s, 1 H), 7.06 (d,
J = 8.2 Hz, 1 H), 13.22 (s, 1 H).
From 6a2b (5.05 g, 20 mmol) and 7a2b (5.19 g, 18 mmol) according
to the general procedure. The pale-yellow product was recrystal-
lized from Et2O to yield 8a (6.30 g, 84%) as a colorless powder; mp
151 °C.
13C NMR (75 MHz, DMSO-d6): d = 37.3 (CH2), 48.1 (CH2), 55.0
(CH3), 55.4 (CH3), 55.8 (2 × CH3), 55.9 (CH3), 56.1 (CH3), 100.9
(CH), 104.5 (CH), 109.1, 112.0 (CH), 112.3 (CH), 112.6 (CH),
114.2 (CH), 116.7, 120.9 (CH), 122.7 (CH), 123.7, 126.3, 126.7,
130.5, 130.6, 145.5, 145.6, 147.8, 148.7, 148.8, 149.2, 154.3, 162.0,
173.5.
EI-MS: m/z (%) = 589 (100, [M]+), 545 (31, [M – CO2]+), 513 (11,
[M – CO2 – CH3OH]+), 469 (14, [M – 2 × CO2 – CH3OH]+), 425 (57,
[M – C10H12O2]+), 407 (66), 381 (22).
1H NMR (600 MHz, DMSO-d6): d = 1.06 (d, J = 6.1 Hz, 12 H). 1.21
(d, J = 6.1 Hz, 6 H), 3.04 (t, J = 6.8 Hz, 2 H), 3.66 (s, 6 H), 3.72 (s,
3 H), 4.21 (sept, J = 6.1 Hz, 2 H), 4.38 (sept, J = 6.1 Hz, 1 H), 4.84
(t, J = 6.8 Hz, 2 H), 6.49 (d, J = 2.2 Hz, 2 H), 6.53 (dd, 3J = 8.5 Hz,
4J = 2.2 Hz, 2 H), 6.65 (s, 1 H), 6.74 (d, J = 8.5 Hz, 2 H), 7.06 (s, 1
H), 12.62 (br, 2 H).
13C NMR (150 MHz, DMSO-d6): d = 21.7 (CH3), 21.8 (CH3), 37.2
(CH2), 45.2 (CH2), 55.3 (CH3), 55.8 (CH3), 70.1 (CH), 70.6 (CH),
111.3 (CH), 113.9 (CH), 116.0, 117.3 (CH), 118.6 (CH), 123.1
(CH), 126.9, 129.1, 129.2, 145.3, 146.2, 148.6, 149.5, 162.5; one
UV (MeOH): lmax (e) = 203 (92791), 253 (31514), 283 (18126),
330 nm (11432).
Cquat obscured.
HRMS: m/z calcd for C32H31NO10: 589.1948; found: 589.1925.
EI-MS: m/z (%) = 754 (4, [M(81Br) – H]+), 752 (2, [M(79Br) – H]+),
668 (13, [M(81Br) – 2 × CO2]+), 666 (12, [M(79Br) – 2 × CO2]+), 587
(100, [M – Br – 2 × CO2]+), 545 (11), 503 (4).
1-(3,4-Dimethoxyphenyl)-3-[2-(3,4-dimethoxyphenyl)ethyl]-
7,8-dimethoxy-3H-[1]benzopyrano[3,4-b]pyrrole-4-one (4)
Compound 3 (2.74 g, 4.65 mmol) and copper chromite (0.406 g,
1.75 mmol) were heated in quinoline (70 mL) for 35 min at 180 °C.
After cooling to r.t., the mixture was treated with EtOAc (100 mL)
and filtered through a pad of Celite. The filtrate was washed with aq
2 N HCl (5 × 50 mL), H2O (2 × 50 mL) and brine (100 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was recrystallized from EtOAc to afford 4 (2.36 g, 93%) as a pale-
yellow powder; mp 193 °C (Lit.8a mp 186–187 °C, Lit.8c mp 183–
187 °C).
HRMS: m/z calcd for C38H4479BrNO10: 753.2149; found: 753.2138.
Anal. Calcd for C38H44BrNO10: C, 60.48; H, 5.88; N, 1.86; Br,
10.59. Found: C, 60.34; H, 5.77; N, 2.16; Br, 10.31.
1-[2-(6-Bromo-2-isopropoxy-3,4-dimethoxyphenyl)ethyl]-3,4-
bis-(4-isopropoxy-3-methoxyphenyl)-1H-pyrrole-2,5-dicarbox-
ylic Acid (8b)
From 6b2b (3.46 g, 13.7 mmol) and 7b (7.41 g, 23.3 mmol) accord-
ing to the general procedure. After addition of amine 7b and 4 Å
molecular sieves (5 g), the mixture was refluxed for 80 min. FC
(CH2Cl2-acetone, 3:1) yielded 8b (2.31 g, 43%) as a pale-yellow
foam.
1H NMR (600 MHz, DMSO-d6): d = 3.02 (t, J = 7.1 Hz, 2 H), 3.45,
3.64, 3.69, 3.75, 3.79, 3.80 (s each, 3 H), 4.60 (t, J = 7.1 Hz, 2 H),
4
6.68 (dd, 3J = 8.1 Hz, J = 1.8 Hz, 1 H), 6.69 (d, J = 1.8 Hz, 1 H),
6.85 (d, J = 8.1 Hz, 1 H), 6.92 (d, J = 1.8 Hz, 1 H), 6.96 (dd, 3J = 8.1
Hz, 4J = 1.8 Hz, 1 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.06, 7.09, 7.32 (s
each, 1 H).
1H NMR (300 MHz, DMSO-d6): d = 1.17 (d, J = 6 Hz, 6 H), 1.18
(d, J = 6 Hz, 12 H), 3.07 (t, J = 6 Hz, 2 H), 3.46 (s, 6 H), 3.60 (s, 3
H), 3.73 (s, 3 H), 4.39 (m, J = 6 Hz, 3 H), 4.92 (t, J = 6 Hz, 2 H),
6.48 (d, J = 2 Hz, 2 H), 6.49 (dd, 3J = 9 Hz, 4J = 2 Hz, 2 H), 6.72 (d,
J = 9 Hz, 2 H), 6.92 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 22.1 (CH3), 22.5 (CH3), 32.4
(CH2), 44.5 (CH2), 55.3 (CH3), 56.2 (CH3), 60.0 (CH3), 70.3 (CH),
75.0 (CH), 111.8 (CH), 114.5 (CH), 115.3 (CH), 118.5, 122.9 (CH),
124.4, 127.9, 129.2, 141.4, 145.2, 148.6, 150.9, 152.6, 162.7; one
13C NMR (150 MHz, DMSO-d6): d = 37.1 (CH2), 49.9 (CH2), 55.4
(CH3), 55.5 (CH3), 55.7 (2 × CH3), 55.9 (CH3), 56.1 (CH3), 101.2
(CH), 104.9 (CH), 110.0, 112.0 (CH), 112.7 (CH), 113.3 (CH),
114.4, 118.8, 121.0 (CH), 122.0 (CH), 126.1, 126.4, 130.6, 133.2
(pyrrole-CH), 145.4, 145.8, 147.7, 148.5, 148.8, 148.9 (2 ×), 149.1,
154.5.
EI-MS: m/z (%) = 545 (100, [M]+), 394 (20, [M – C9H11O2]+), 381
Cquat obscured.
(53, [M – C8H8O2 – CO]+), 334 (5), 151 (4).
EI-MS: m/z (%) = 785 (0.2, [M(81Br)]+), 783 (0.2, [M(79Br)]+), 741
(0.4, [M(81Br) – CO2]+), 739 (0.4, [M(79Br) – CO2]+), 697 (10,
[M(81Br) – 2 × CO2]+), 695 (9, [M(79Br) – 2 × CO2]+), 654 (9,
[M(81Br) – 2 × CO2 – C3H7]+), 652 (8, [M(79Br) – 2 × CO2 – C3H7]+),
617 (41, [M + H – 2 × CO2 – Br]+), 616 (100, [M – 2 × CO2 – Br]+),
615 (30, [M – H – 2 × CO2 – Br]+), 574 (16, [M – 2 × CO2 – C3H6 –
Br]+).
UV (MeOH): lmax (e) = 202 (33070), 282 (5674), 327 nm (5170).
HRMS: m/z calcd for C31H31NO8: 545.2050; found: 545.2048.
Ningalin B (5)
BBr3 (2.51 g, 10 mmol) was added dropwise to a magnetically
stirred solution of 4 (546 mg, 1.00 mmol) in anhyd CH2Cl2 (50 mL)
maintained at –78 °C. The ensuing mixture was maintained over-
night at r.t., then H2O (20 mL) was added, the CH2Cl2 removed un-
der reduced pressure, and the aq phase extracted with EtOAc (3 ×
10 mL). The combined extracts were washed with brine, dried
(Na2SO4), and concentrated. Recrystallization from H2O yielded 5
(410 mg, 89%) as an off-white solid; mp 303 °C (dec.). The spec-
troscopic data derived from 5 were in good agreement with those re-
ported for the natural product.7
HRMS: m/z calcd for C39H4679BrNO11: 783.2254; found: 783.2250.
3-[2-(2-Bromo-5-isopropoxy-4-methoxyphenyl)ethyl]-8-isopro-
poxy-1-(3-isopropoxy-4-methoxyphenyl)-7-methoxy-4-oxo-3H-
[1]benzopyrano[3,4-b]pyrrole-2-carboxylic Acid (9a)
Pb(OAc)4 (665 mg, 1.5 mmol) was added to a magnetically stirred
solution of 8a (755 mg, 1 mmol) in anhyd EtOAc (60 mL). The mix-
ture was stirred for 20 min at r.t., during which time the solution
gradually acquired a yellow-orange color. After addition of 1 M aq
KHSO4 (20 mL), the organic layer was separated and the aqueous
phase extracted with EtOAc (3 × 10 mL). The combined organic
phases were washed with brine (30 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The oily residue crystallized on
Anal. Calcd for C25H19NO8·0.5 H2O: C, 63.83; H, 4.28; N, 2.98.
Found: C, 63.73; H, 4.00; N, 2.98.
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

PAPER
Biomimetic Syntheses of Lamellarin and Lukianol-Type Alkaloids
3053
addition of MeOH. Product 9a was thus obtained as a lemon-yellow
solid (655 mg, 87%); mp 236 °C.
deep-red reaction mixture was cooled to r.t. and filtered through a
pad of Celite. The pad was rinsed with EtOAc (2 × 20 mL), and the
combined filtrates were adjusted to pH 4 with aq 2 N HCl. After
phase separation, the aqueous phase was extracted with EtOAc (3 ×
20 mL), and the combined organic layers were washed with concd
aq NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), dried
(Na2SO4) and concentrated under reduced pressure. Crystallization
from MeOH yielded 10a (100 mg, 80%) as a colorless solid; mp
224–227 °C.
1H NMR (600 MHz, DMSO-d6): d = 1.01 (d, J = 6 Hz, 3 H), 1.03
(d, J = 6 Hz, 3 H), 1.09 (‘t’, J = 6 Hz, 6 H), 1.21 (‘t’, J = 6 Hz, 6 H),
3.10 (t, J = 6.8 Hz, 2 H), 3.70, 3.76, 3.80 (s each, 3 H), 3.81 (sept,
J = 6 Hz, 1 H), 4.24 (sept, J = 6 Hz, 1 H), 4.48 (sept, J = 6 Hz, 1 H),
5.08 (t, J = 6.8 Hz, 2 H), 6.35, 6.61 (s each, 1 H), 6.82 (dd, 3J = 8.5
Hz, 4J = 2.3 Hz, 1 H), 6.84 (d, J = 2.3 Hz, 1 H), 7.02, 7.04 (s each,
1 H), 7.06 (d, J = 8.5 Hz, 1 H), 13.11 (br, 1 H).
1H NMR (600 MHz, CDCl3): d = 1.15, 1.17, 1.32, 1.33, 1.36, 1.37
(d each, J = 6.2 Hz, 3 H), 3.09 (‘t’, J = 6 Hz, 2 H), 3.34, 3.85, 3.93
(s each, 3 H), 3.96, 4.50, 4.54 (sept each, J = 6.2 Hz, 1 H), 4.75, 4.81
(m each, 1 H), 6.65, 6.73, 6.76, 6.90 (s each, 1 H), 7.02 (d, J = 1.8
Hz, 1 H), 7.05 (dd, 3J = 8.5 Hz, 4J = 1.8 Hz, 1 H), 7.06 (d, J = 8.5
Hz, 1 H).
13C NMR (150 MHz, DMSO-d6): d = 21.7 (CH3), 21.8 (CH3), 37.0
(CH2), 46.0 (CH2), 55.6 (CH3), 55.8 (CH3), 55.9 (CH3), 70.2 (CH),
70.4 (CH), 70.7 (CH), 100.9 (CH), 107.2 (CH), 108.9, 112.1 (CH),
114.1 (CH), 115.9, 116.4, 117.6 (CH), 117.4 (CH), 122.4 (CH),
123.4, 126.3, 126.4, 128.8, 143.2, 145.4, 146.1, 146.5, 149.4, 149.6,
149.8, 154.1, 161.5; one Cquat obscured.
13C NMR (75 MHz, CDCl3): d = 21.8 (CH3), 21.9 (CH3), 22.1
(CH3), 28.6 (CH2), 42.5 (CH2), 55.1 (CH3), 56.1 (CH3), 56.3 (CH3),
71.3 (CH), 71.4 (CH), 77.2 (CH), 100.8 (CH), 108.1 (CH), 109.2
(CH), 110.4, 112.8 (CH), 114.8 (CH), 117.6 (CH), 120.3, 123.5
(CH), 126.3, 128.1, 132.9, 136.0, 143.8, 146.1, 147.3, 148.3, 148.7,
149.9, 150.1, 155.6; one Cquat obscured.
EI-MS: m/z (%) = 755 (38, [M(81Br) + H]+), 754 (100, [M(81Br)]+),
753 (38, [M(79Br) + H]+), 752 (95, [M(79Br)]+), 710 (12, [M(81Br) –
CO2]+), 708 (8, [M(79Br) – CO2]+), 673 (16, [M – Br]+), 629 (12, [M
– Br – CO2]+), 587 (24, [M – Br – CO2 – C3H6]+), 545 (9), 503 (12).
UV (MeOH): lmax (e) = 205 (77202), 289 (13879), 330 nm (9832).
HRMS: m/z calcd for C38H4281BrNO10: 753.1972; found: 753.1975;
EI-MS: m/z (%) = 627 (100, [M]+), 585 (16, [M – C3H6]+), 543 (33,
m/z calcd for C38H4279BrNO10: 751.1992; found: 751.1935.
[M – 2 × C3H6]+), 501 (26, [M – 3 × C3H6]+).
Anal. Calcd for C38H42BrNO10·H2O: C, 59.23; H, 5.75; N, 1.82.
Found: C, 59.69; H, 5.71; N, 1.81.
UV (MeOH): lmax (e) = 202 (66581), 277 (35606), 315 (29997),
330 nm (28042).
HRMS: m/z calcd for C37H41NO8: 627.2832; found: 627.2831.
3-[2-(6-Bromo-2-isopropoxy-3,4-dimethoxyphenyl)ethyl]-7-iso-
propoxy-1-(4-isopropoxy-3-methoxyphenyl)-8-methoxy-4-
oxo[1]benzopyrano[3,4-b]pyrrole-2-carboxylic Acid (9b)
From 8b (78.5 mg, 0.10 mmol) and Pb(OAc)4 (66.5 mg, 0.15 mmol)
as described for 9a; reaction time 10 min. Purification by FC
(CH2Cl2–acetone, 4:1) yielded 9b (71 mg, 91%) as a yellowish sol-
id; mp 107 °C.
Anal. Calcd for C37H41NO8: C, 70.79; H, 6.58; N, 2.23. Found: C,
70.48; H, 6.80; N, 2.22.
3,10-Diisopropoxy-14-(4-isopropoxy-3-methoxyphenyl)-
2,11,12-trimethoxy-8,9-dihydro-6H-[1]benzofura-
no[4¢,3¢:4,5]pyrrolo[2,1-a]isoquinolin-6-one (10b)
A pressure tube containing a stirred mixture of Pd(OAc)2 (45 mg,
0.2 mmol) and Ph3P (105 mg, 0.4 mmol) in MeCN (6 mL) was
purged with argon and warmed to 50-60 °C until a deep-red solution
resulted. Immediately after addition of a solution of 9b (157 mg,
0.20 mmol) in MeCN (6 mL) and Et3N (1 mL), the reaction vessel
was sealed and immersed in an oil bath at 100 °C. After stirring for
5 h, the mixture was cooled to r.t. and filtered through a pad of
Celite. The pad was rinsed with EtOAc (3 × 20 mL), and the com-
bined filtrates were washed with 2 N HCl (2 × 15 mL), H2O, and
brine (30 mL), dried (MgSO4), and concentrated under reduced
pressure. Purification of the residue by FC (hexanes–EtOAc, 3:2)
afforded 10b (130 mg, 98%) as a slightly yellowish solid; mp
238 °C (Lit.13 mp 244–245 °C).
1H NMR (600 MHz, CDCl3): d = 1.31, 1.39, 1.41 (d each, J = 6 Hz,
6 H), 3.15 (t, J = 5 Hz, 2 H), 3.34, 3.42 (s each, 3 H), 3.83 (s, 6 H),
4.54, 4.55, 4.60 (m each, J = 6 Hz, 1 H), 4.74 (t, J = 5 Hz, 2 H),
6.60, 6.64, 6.92, (s each, 1 H), 7.04 (d, J = 2 Hz, 1 H), 7.05 (dd,
3J = 8 Hz, 4J = 2 Hz, 1 H), 7.10 (d, J = 8 Hz, 1 H).
1H NMR (300 MHz, DMSO-d6): d = 0.94 (d, J = 6 Hz, 6 H), 1.23
(d, J = 6 Hz, 12 H), 3.15 (t, J = 5 Hz, 2 H), 3.26, 3.44, 3.68, 3.72 (s
each, 3 H), 4.25 (m, J = 6 Hz, 1 H), 4.54 (m, J = 6 Hz, 1 H), 4.62
(m, J = 6 Hz, 1 H), 5.11 (t, J = 5 Hz, 2 H), 6.42 (s, 1 H), 6.78 (dd,
3J = 8 Hz, 4J = 2 Hz, 1 H), 6.83 (d, J = 2 Hz, 1 H), 6.92 (s, 1 H), 7.02
(d, J = 8 Hz, 1 H), 7.03 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 21.6 (CH3), 22.1 (CH3), 31.7
(CH2), 44.8 (CH2), 54.5 (CH3), 55.5 (CH3), 56.1 (CH3), 59.6 (CH3),
70.3 (CH), 70.4 (CH), 74.5 (CH), 102.9 (CH), 104.5 (CH), 109.2,
111.6 (CH), 114.4 (CH), 115.2 (CH), 117.0, 118.6, 122.4 (CH),
123.0, 123.7, 126.2, 127.0, 140.9, 145.3, 145.9, 146.2, 146.6, 149.5,
150.5, 152.3, 154.1, 161.6; one Cquat obscured.
EI-MS: m/z (%) = 784 (35, [M(81Br) + H]+), 783 (100, [M(81Br)]+),
782 (34, [M(79Br) + H]+), 781 (90, [M(79Br)]+), 741 (9, [M(81Br) –
C3H6]+), 739 (11, [M(79Br) – C3H6]+), 699 (9, [M(81Br) – 2 C3H6]+),
697 (9, [M(79Br) – 2 C3H6]+), 618 (8, [M – Br – 2 C3H6]+), 574 (6,
[M – Br – CO2 – 2 C3H6]+).
13C NMR (150 MHz, CDCl3): d = 21.81 (CH3), 21.89 (CH3), 21.91
(CH3), 22.66 (2 × CH3), 22.69 (CH3), 42.3 (CH2), 48.4 (CH2), 55.1
(CH3), 55.4 (CH3), 56.2 (CH3), 60.6 (CH3), 71.5 (CH), 71.8 (CH),
75.7 (CH), 103.5 (CH), 104.9 (CH), 105.0 (CH), 110.3, 113.9,
114.6 (CH), 115.6, 117.0 (CH), 121.1, 123.0, 123.4 (CH), 128.1,
128.6, 135.5, 142.5, 145.9, 146.5, 146.97, 147.04, 148.6, 151.3,
151.8, 155.6.
EI-MS: m/z (%) = 658 (41, [M + H]+), 657 (100, [M]+), 616 (14, [M
– C3H5]+), 615 (37, [M – C3H6]+), 573 (12, [M – 2 × C3H6]+), 558 (6,
[M – C7H15]+), 531 (9, [M – 3 × C3H6]+), 516 (10, [M – 3 × C3H6 –
CH3]+).
UV (MeOH): lmax (e) = 207 (85062), 254 (28624), 287 (16010),
334 nm (10997).
HRMS: m/z calcd for C39H4481BrNO11: 783.2077; found: 783.2101.
Anal. Calcd for C39H44BrNO11: C, 59.85; H, 5.67; N, 1.79. Found:
C, 59.26; H, 5.83; N, 1.73.
2,11-Diisopropoxy-14-(3-isopropoxy-4-methoxyphenyl)-3,12-
dimethoxy-8,9-dihydro-6H-[1]benzofurano[4¢,3¢:4,5]pyrro-
lo[2,1-a]isoquinolin-6-one (10a)
A pressure tube containing a stirred mixture of MeCN (11.5 mL)
and Et3N (4 mL) was charged with 9a (151 mg, 0.2 mmol),
Pd(OAc)2 (45 mg, 0.2 mmol) and Ph3P (131 mg, 0.5 mmol). After
purging with argon, the tube was sealed, immersed in an oil bath at
150 °C and maintained at this temperature for 2 h. The resulting
UV (MeOH): lmax (e) = 205 (59669), 278 (34256), 313 nm (30730).
HRMS: m/z calcd for C38H43NO9: 657.2938; found: 657.2932.
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

3054
C. Peschko et al.
PAPER
Anal. Calcd for C38H43NO9: C, 69.39; H, 6.59; N, 2.13. Found: C,
69.03; H, 6.81; N, 2.08.
(4 × 10 mL). The combined extracts were washed with 5% aq
NaHCO3 (2 × 50 mL) and brine (100 mL), dried (MgSO4), and con-
centrated under reduced pressure. Purification of the residue by FC
(CHCl3–MeOH, 100:1) yielded 14 (3.63 g, 85%) as pinkish crys-
tals; mp 76.5 °C.
1H NMR (300 MHz, CDCl3): d = 3.88, 3.95 (s each, 3 H), 6.78,
10.12, 12.23 (s each, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.5 (CH3), 60.8 (CH3), 109.3
(CH), 113.5, 123.2, 135.9, 158.0, 159.0, 196.6 (CH).
EI-MS: m/z (%) = 262 (96, [M(81Br)]+), 260 (100, [M(79Br)]+), 247
(28, [M(81Br) – CH3]+), 245 (30, [M(79Br) – CH3]+), 233 (6,
[M(81Br) – CHO]+), 231 (8, [M(79Br) – CHO]+), 219 (66), 217 (70),
216 (19), 214 (21).
Lamellarin G (11a)
Compound 10a (111 mg, 0.177 mmol) was added to a magnetically
stirred solution of AlCl3 (177 mg, 1.33 mmol) in anhyd CH2Cl2 (50
mL) at 0 °C. After stirring for 3 h, the mixture was quenched with
H2O (20 mL) and the CH2Cl2 removed under reduced pressure. The
remaining solution was diluted with H2O (25 mL) and extracted
with EtOAc (5 × 20 mL). After concentration of the combined ex-
tracts, the residue was triturated with MeOH to furnish 11a (86 mg,
97%) as a grayish amorphous powder; mp 264 °C (dec.) (Lit.11a mp
263–265 °C, dec.). The spectroscopic data derived from 11a were
in good agreement with those reported for the natural product.11a
Anal. Calcd for C28H23NO8: C, 67.06; H, 4.62; N, 2.79. Found: C,
66.69; H, 4.73; N, 2.74.
Anal. Calcd for C9H9BrO4: C, 41.41; H, 3.47; Br, 30.61. Found: C,
41.47; H, 3.46; Br, 30.15.
Lamellarin K (11b)
6-Bromo-2-isopropoxy-3,4-dimethoxybenzaldehyde (15)
A mixture of 14 (3.63, 13.9 mmol), isopropyl bromide (4 mL, 42.6
mmol), and DMF (55 mL) was degassed using ultrasonic tech-
niques and, after the establishment of an argon atmosphere, treated
with K2CO3 (8.84 g, 64 mmol). The suspension was stirred for 30
min at 60 °C and then overnight at r.t. The mixture was filtered and
the filter cake rinsed with EtOAc (3 × 50 mL). The combined fil-
trates were washed with H2O (100 mL) and brine (100 mL), dried
(Na2SO4) and concentrated under reduced pressure. Purification of
the residue by FC (hexanes–EtOAc, 4:1) furnished 15 (3.28 g, 78%)
as a pale-yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.32 (d, J = 6 Hz, 6 H), 3.85, 3.93
(s each, 3 H), 4.65 (sept, J = 6, 1 H), 6.96 (s, 1 H), 10.27 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.3 (2 × CH3), 56.4 (CH3), 60.7
(CH3), 77.7 (CH), 113.5 (CH), 118.5, 122.6, 142.1, 155.3, 157.7,
189.5 (CH).
From 10b (130 mg, 0.20 mmol) and AlCl3 (96 mg, 0.72 mmol) as
described above. The mixture was stirred for 24 h at r.t. Crude 11b
was obtained as a brown oil that became solid on treatment with
Et2O. Trituration with a small amount of acetone yielded 11b (101
mg, 96%) as an off–white amorphous powder; mp >180 °C (Lit.11a
mp 196–198 °C). The spectroscopic data of 11b were in agreement
with those of reported for the natural product.11a
HRMS: m/z calcd for C29H25NO9: 531.1529; found: 531.1556.
5-Bromo-2,3-dimethoxyphenol (13)
A freshly prepared mixture of 30% aq H2O2 (7.8 g), formic acid (22
mL) and concd H2SO4 (3 drops) was maintained for 1 h at r.t.. The
mixture was then cooled to 5 °C and treated with a solution of 5-
bromo-2,3-methoxybenzaldehyde (12;16 8.29 g, 33.8 mmol) in for-
mic acid (50 mL). The ensuing mixture was maintained overnight
at 5 °C, then treated with a solution of Na2SO3 (3.4 g) in H2O (100
mL), stirred, and extracted with EtOAc (3 × 50 mL). The combined
extracts were washed with H2O (50 mL) and brine (50 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was dissolved in Et2O (20 mL) and after addition of 25% aq KOH
(220 mL) vigorously stirred under argon. The organic layer was
separated, the aqueous phase acidified to pH 3 with aq 2 N HCl, and
extracted with EtOAc (3 × 100 mL). The combined organic phases
were washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure to yield an oily residue, which was purified by FC
(hexanes–EtOAc, 2:1). Recrystallization of the product from
MeOH yielded 13 (5.91g, 75%) as colorless cubic crystals; mp
72 °C.
1H NMR (300 MHz, CDCl3): d = 3.84, 3.87 (s each, 3 H), 5.82 (s, 1
OH), 6.61, 6.78 (d each, J = 2.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.1 (CH3), 61.0 (CH3), 108.0
(CH), 111.7 (CH), 116.4 (C–Br), 134.9 (C–OH), 150.0 (C–O),
152.9 (C–O).
EI-MS: m/z (%) = 234 (93, [M(81Br)]+), 232 (100, [M(79Br)]+), 219
(74, [M(81Br) – CH3]+), 217 (87, [M(79Br) – CH3]+), 191 (19), 189
(24).
EI-MS: m/z (%) = 304 (15, [M(81Br)]+), 302 (15, [M(79Br)]+), 262
(97, [M(81Br) – C3H6]+), 260 (100, [M(79Br) – C3H6]+), 247 (27,
[M(81Br) – C3H6 – CH3]+), 245 (30, [M(79Br) – C3H6 – CH3]+), 219
(27, [M(81Br) – C3H6 – CH3 – CO]+), 217 (31, [M(79Br) – C3H6 –
CH3 – CO]+), 216 (18), 214 (21).
HRMS: m/z calcd for C12H1579BrO4: 302.0154; found: 302.0144.
(E)-6-Bromo-b-nitro-2-isopropoxy-3,4-dimethoxystyrene (16)
A mixture of 15 (3.12 g, 10.3 mmol), NH4OAc (753 mg, 9.77
mmol) and nitromethane (50 mL) was stirred for 45 min at 100 °C.
The mixture was then cooled to r.t., treated with H2O (100 mL), and
extracted with Et2O (3 × 100 mL). The combined extracts were
washed with brine, dried (MgSO4), and concentrated under reduced
pressure. The crude product was recrystallized from EtOAc–hex-
anes to afford 16 (3.56 g, 100%) as yellow plates; mp 125 °C.
1H NMR (300 MHz, CDCl3): d = 1.30 (d, J = 6 Hz, 6 H), 3.82, 3.91
(s each, 3 H), 4.84 (sept, J = 6, 1 H), 7.00 (s, 1 H), 8.13, 8.33 (d each,
J = 13 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.6 (2 × CH3), 56.4 (CH3), 60.6
(CH3), 77.3 (CH), 112.6 (CH), 118.4, 122.3, 135.0 (CH), 139.8
(CH), 142.0, 152.8, 156.2.
EI-MS: m/z (%) = 347 (36, [M(81Br)]+), 345 (35, [M(79Br)]+), 305
(10, [M(81Br) – C3H6]+), 303 (10, [M(79Br) – C3H6]+), 258 (99,
[M(81Br) – C3H6 – HNO2]+), 256 (100, [M(79Br) – C3H6 – HNO2]+),
243 (64), 241 (66), 224 (85, [M – Br – C3H6]+), 196 (89), 192 (41),
178 (28), 164 (18), 134 (63).
Anal. Calcd for C8H9BrO3: C, 41.23; H, 3.89; Br, 34.28. Found: C,
41.10; H, 3.87; Br, 34.83.
6-Bromo-2-hydroxy-3,4-dimethoxybenzaldehyde (14)
A magnetically stirred solution of dichloromethyl methyl ether
(2.95 mL, 32.6 mmol) and TiCl4 (4.3 mL, 39.2 mmol) in anhyd
CH2Cl2 (60 mL) was treated with a solution of 13 (3.8 g, 16.3 mmol)
in anhyd CH2Cl2 (20 mL) at 0 °C. The ice-bath was removed and
the mixture stirred at r.t for 4 h. After the addition of cold 5% aq HCl
(16 mL), the stirring was continued for 15 min. The organic layer
was then separated and the aqueous solution extracted with CH2Cl2
UV (MeOH): lmax (e) = 212 (29249), 257 (sh, 7618), 347 nm
(15346).
Anal. Calcd for C13H16BrNO5: C, 45.11; H, 4.66; N, 4.05; Br, 23.08.
Found: C, 45.14; H, 4.63; N, 4.05; Br, 23.45.
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

PAPER
Biomimetic Syntheses of Lamellarin and Lukianol-Type Alkaloids
3055
2-(6-Bromo-2-isopropoxy-3,4-dimethoxyphenyl)ethylamine
(7b)
ed for 90 min to 115 °C, then cooled to r.t. and poured into 1 M aq
FeSO4 (250 mL). After vigorous stirring in air (formation of blue
color), the solution was acidified with 2 N HCl to pH 2 and extract-
ed with EtOAc. The DMPU was removed by repeated extraction of
the organic layer with 1 M aq KHSO4, H2O, and brine. The solution
was then dried (MgSO4), concentrated under reduced pressure, and
purified by FC (CH2Cl2–acetone, 7:1) to yield 21 (1.51 g, 93%) as
a yellow powder; mp 151–154 °C.
1H NMR (300 MHz, acetone-d6): d = 0.93 (t, J = 7.1 Hz, 3 H), 3.08
(t, J = 7.7 Hz, 2 H), 3.62, 3.74, 3.75, 3.78 (s each, 3 H), 4.02 (q,
J = 7.1 Hz, 2 H), 4.91 (t, J = 7.7 Hz, 2 H), 6.66 (d, J = 8.0 Hz, 1 H),
6.68 (s, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.77 (d, J = 8.9 Hz, 2 H),
6.88 (d, J = 8.7 Hz, 2 H), 6.99 (d, J = 8.9 Hz, 2 H), 7.18 (d, J = 8.7
Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 13.9 (CH3), 38.1 (CH2), 49.1
(CH2), 55.37 (CH3), 55.44 (CH3), 55.8 (CH3), 55.9 (CH3), 60.9
(CH2), 111.6 (CH), 113.4 (CH), 114.7 (CH), 116.0 (CH), 123.9
(CH), 124.8, 125.5, 128.16, 128.24, 130.7 (CH), 131.24, 131.28,
131.6, 132.5 (CH), 149.0, 159.4, 159.5, 162.2, 162.6, 163.0.
EI-MS: m/z (%) = 559 (16, [M]+), 516 (31), 515 (100, [M – CO2]+),
394 (8), 366 (8), 362 (5), 336 (5), 335 (11), 135 (6), 121 (7).
TMSCl (9.04 mL, 71.2 mmol) was added to a vigorously stirred
suspension of LiBH4 (776 mg, 35.6 mmol) in anhyd THF (50 mL)
over a period of 2 min (Caution! exothermic reaction with efferves-
cence). After the gas evolution had ceased, the trimethylsilane was
removed by purging the solution with argon. Then, over a period of
5 min, a solution of 16 (3.08 g, 8.9 mmol) in anhyd THF (40 mL)
was added and the mixture was heated for 6 h at reflux. After cool-
ing to r.t., the mixture was quenched carefully (at the beginning
dropwise) at 0 °C with MeOH (40 mL). The solvent was removed
with a rotatory evaporator, the resulting residue dissolved in 20% aq
KOH (100 mL), and extracted with CH2Cl2 (3 × 50 mL). The com-
bined extracts were dried (Na2SO4) and then concentrated under re-
duced pressure. The oily product was purified by Kugelrohr
distillation to yield amine 7b (2.74 g, 97%) as a clear, colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.29 (d, J = 6 Hz, 6 H), 1.72 (br,
2 H), 2.88 (‘s’, 4 H), 3.80, 3.83 (s each, 3 H), 4.68 (sept, J = 6 Hz,
1 H), 6.85 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.5 (CH3), 22.7 (CH3), 34.9
(CH2), 41.7 (CH2), 56.1 (CH3), 60.4 (CH3), 75.3 (CH), 111.4 (CH),
118.5, 126.6, 142.1, 150.6, 152.2.
HRMS: m/z calcd for C32H33NO8: 559.2206; found: 559.2194.
EI-MS: m/z (%) = 320 (1, [M(81Br) + H]+), 318 (1, [M(79Br) + H]+),
290 (8, [M(81Br) – CH2NH]+), 288 (8, [M(79Br) – CH2NH]+), 248
(53), 247 (43), 246 (55), 245 (39), 238 (100, [M – Br]+).
7,8-Dimethoxy-1-(4-methoxyphenyl)-3-[2-(4-methoxyphen-
yl)ethyl]-4-oxo-3H-[1]benzopyrano[3,4-b]pyrrole-2-carboxylic
Acid Ethyl Ester (22)
Anal. Calcd for C13H20BrNO3: C, 49.07; H, 6.33; N, 4.40. Found: C,
48.57; H, 6.24; N, 4.23.
Pb(OAc)4 (197 mg, 0.43 mmol) was added to a solution of 21 (200
mg, 0.36 mmol) in anhyd EtOAc (15 mL). The resulting suspension
was refluxed for 60 min, cooled to r.t. and quenched with 1 M aq
KHSO4 (10 mL). After a short period of stirring, the solid precipi-
tate was filtered off and rinsed with EtOAc. The organic phases
were washed with sat. aq NaHCO3, H2O and brine, dried (MgSO4),
and concentrated under reduced pressure. Purification by FC
(EtOAc–hexanes, 1:1) yielded 22 (190 mg, 95%) as a pale-yellow
powder; mp 189 °C.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 7.1 Hz, 3 H), 3.10 (t,
J = 7.5 Hz, 2 H), 3.43, 3.78, 3.86, 3.89 (s each, 3 H), 4.03 (q, J = 7.1
Hz, 2 H), 5.10 (t, J = 7.5 Hz, 2 H), 6.51 (s, 1 H), 6.83 (d, J = 8.7 Hz,
2 H), 6.88 (s, 1 H), 7.00 (d, J = 8.7 Hz, 2 H), 7.18, 7.26 (d each,
J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.5 (CH3), 37.5 (CH2), 48.6
(CH2), 55.25 (CH3), 55.45 (CH3), 55.48 (CH3), 56.1 (CH3), 60.8
(CH2), 100.4 (CH), 104.6 (CH), 109.8, 113.7 (CH), 113.9 (CH),
117.5, 124.2, 126.9, 127.0, 129.8, 130.1, 130.2 (CH), 131.5 (CH),
145.6, 146.0, 149.1, 155.2, 158.4, 159.3, 160.9.
EI-MS: m/z (%) = 558 (36, [M + H]+), 557 (100, [M]+), 436 (14),
423 (28), 408 (12), 378 (27), 377 (82), 121 (13).
Methyl 5-Ethoxycarbonyl-3-(3,4-dimethoxyphenyl)-4-(4-meth-
oxyphenyl)-1-[2-(4-methoxyphenyl)ethyl]-1H-pyrrole-2-car-
boxylate (20)
A solution of methyl 3-(3,4-dimethoxyphenyl)pyruvate (18; 1.20 g,
5.04 mmol) in anhyd CH2Cl2 (100 mL) was treated with NaH (133
mg, 5.54 mmol) at –10 °C. The resulting mixture was warmed to
0 °C and, after the gas evolution had ceased, a solution of ethyl 3-
bromo-3-(4-methoxyphenyl)pyruvate (17;23 1.78 g, 5.90 mmol) in
anhyd CH2Cl2 (30 mL) was added dropwise. After stirring for 1 h at
r.t., the mixture was treated with 2-(4-methoxyphenyl)ethylamine
(19; 0.87 mL, 5.90 mmol) and 4 Å molecular sieves, and the stirring
was continued for 18 h. The molecular sieves were filtered off and
rinsed with EtOAc (3 × 10 mL). The combined organic phases were
washed with 1 M aq KHSO4 (2 × 150 mL), H2O (2 × 150 mL) and
brine (150 mL), then dried (MgSO4) and concentrated under re-
duced pressure. Purification of the residue by FC (EtOAc–hexanes,
1:2) yielded 20 (1.24 g, 43%) as a dark-yellow oil.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7.1 Hz, 3 H), 3.10 (t,
J = 7.7 Hz, 2 H), 3.61, 3.64, 3.74, 3.77, 3.83 (s each, 3 H), 4.05 (q,
J = 7.1 Hz, 2 H), 4.86 (t, J = 7.7 Hz, 2 H), 6.51 (d, J = 1.9 Hz, 1 H),
4
6.60 (dd, 3J = 8.2 Hz, J = 1.9 Hz, 1 H), 6.70 (d, J = 8.2 Hz, 1 H),
HRMS: m/z calcd for C32H31NO8: 557.2050; found: 557.2042.
6.72 (d, J = 8.9 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.94 (d, J = 8.9
Hz, 2 H), 7.20 (d, J = 8.6 Hz, 2 H).
Anal. Calcd for C32H31NO8: C, 68.93; H, 5.60; N, 2.51. Found: C,
68.42; H, 5.68; N, 2.54.
13C NMR (75 MHz, DMSO-d6): d = 13.6 (CH3), 37.5 (CH2), 48.7
(CH2), 51.4 (CH3), 55.1 (CH3), 55.2 (CH3), 55.6 (2 × CH3), 60.4
(CH2), 110.1 (CH), 112.7 (CH), 113.9 (CH), 114.0 (CH), 122.9
(CH), 123.8, 124.4, 127.0, 127.2, 130.1 (CH), 130.56, 130.63,
130.7, 131.6 (CH), 147.5, 147.7, 158.26, 158.34, 161.6, 162.2.
EI-MS: m/z (%) = 573 (100, [M]+), 393 (21), 392 (20), 362 (26),
135 (7), 121 (12).
3,4-Dihydro-9,10-dimethoxy-3,12-bis(4-methoxyphenyl)-1H-
[1]benzopyrano[4¢,3¢:4,5]pyrrolo[2,1-c][1,4]oxazin-1-one (23)
NBS (33 mg, 0.19 mmol) was added to a solution of 22 (100 mg,
0.18 mmol) in CCl4 (20 mL). The mixture was irradiated with a 500
W lamp at 20 °C (water cooling!) until the consumption of NBS
was complete (~3 h). The resulting mixture was filtered, concentrat-
ed, and the residue dissolved in THF–H2O (20 mL, 4:1). The result-
ing solution was stirred for 18 h at r.t. and concentrated under
reduced pressure. The ensuing solid was dissolved in degassed tol-
uene (20 mL), treated with a catalytic amount of p-TsOH and heated
for 1 h at 110 °C. After cooling to r.t., the solution was washed with
sat. aq NaHCO3, H2O, and brine, dried (MgSO4), and concentrated.
Purification of the resulting residue by FC (CH2Cl2–acetone, 100:1)
yielded 23 (67 mg, 71%) as a beige powder; mp 152–154 °C.
HRMS: m/z calcd for C33H35NO8: 573.2363; found: 573.2364.
Ethyl 2-Carboxy-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphen-
yl)-1-[2-(4-methoxyphenyl)ethyl]-1H-pyrrole-5-carboxylate
(21)
A solution of 20 (1.66 g, 2.89 mmol) in DMPU (100 mL) was treat-
ed with NaCN (1.42 g, 28.98 mmol). The ensuing mixture was heat-
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

3056
C. Peschko et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 3.49, 3.84, 3.87, 3.89 (s each, 3
3J = 3 Hz, 1 H), 5.84 (dd, 3J = 11.5, 3 Hz, 1 H), 6.73 (d, J = 8.5 Hz,
4 H), 6.76 (d, J = 8.6 Hz, 4 H), 7.05 (‘m’, 6 H), 7.55 (d, J = 8.6 Hz,
2 H).
13C NMR (75 MHz, acetone-d6): d = 49.7 (CH2), 55.3 (2 × CH3),
55.7 (CH3), 78.7 (CH), 113.5 (2 × CH), 113.6 (2 × CH), 114.9 (2 ×
CH), 120.0, 126.1, 127.1, 128.1, 129.1 (2 × CH), 129.2, 130.0,
132.1, 132.76 (2 × CH), 132.79 (2 × CH), 158.4, 159.5, 159.6,
161.3, 162.3.
2
3
2
H), 4.52 (dd, J = 14.5 Hz, J = 11.0 Hz, 1 H), 5.36 (dd, J = 14.5
Hz, 3J = 3.2 Hz, 1 H), 5.76 (dd, 3J = 11.0, 3.2 Hz, 1 H), 6.75, 6.87
(s each, 1 H), 6.96 (d, J = 8.6 Hz, 2 H), 7.03, 7.36 (d each, J = 8.7
Hz, 2 H), 7.42 (d, J = 8.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 48.0 (CH2), 55.4 (2 CH3), 55.7
(CH3), 56.1 (CH3), 78.8 (CH), 100.6 (CH), 104.7 (CH), 109.3, 114.0
(CH), 114.1 (CH), 114.3 (CH), 116.6, 123.5, 124.1, 126.4, 126.6,
127.2, 128.0 (CH), 146.0, 149.5, 155.3, 158.2, 157.4, 159.8, 160.5.
EI-MS: m/z (%) = 499 (7, [M]+), 455 (15, [M – CO2]+), 412 (30, [M
EI-MS: m/z (%) = 528 (31, [M + H]+), 527 (100, [M]+), 483 (10, [M
+ H – 2 × CO2]+), 411 (100, [M – 2 × CO2]+) 410 (54), 396 (11).
– CO2]+), 423 (5), 378 (6), 377 (12), 135 (15).
HRMS: m/z calcd for C29H25NO7: 499.1631; found: 499.1643.
HRMS: m/z calcd for C30H25NO8: 527.1580; found: 527.1580.
3,7,8-Tris(4-methoxyphenyl)-1-oxo-3,4-dihydro-1H-pyrro-
lo[2,1-c][1,4]oxazine-6-carboxylic Acid 2-(Trimethylsilyl)ethyl
Ester (28)
9,10-Dimethoxy-3,12-bis(4-methoxyphenyl)-1H-[1]benzopyra-
no[4¢,3¢:4,5]pyrrolo[2,1-c][1,4]oxazin-1-one (24)
Compound 23 (30 mg, 57 mmol) and DDQ (64 mg, 28 mmol) were
dissolved in 1,2-dichlorobenzene (3 mL), and the resulting solution
was heated for 10 h at 140 °C. After cooling to r.t., the crude mix-
ture was separated by FC (EtOAc–hexanes, 1:1) to yield 24 (21 mg,
70%) as a pale-yellow solid; mp 151–153 °C.
1H NMR (300 MHz, CDCl3): d = 3.50, 3.86, 3.90 (2 ×), (s each, 3
H), 6.84, 6.90 (s each, 1 H), 6.97, 7.08, 7.73, 8.04 (d each, J = 8.9
Hz, 2 H), 8.63 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.79 (CH3), 55.81 (CH3), 56.1
(CH3), 56.6 (CH3), 101.1 (CH), 102.5 (CH), 105.3 (CH), 109.4,
114.4 (CH), 114.8 (CH), 120.3, 122.7, 123.9, 124.9, 126.6 (CH),
128.3, 132.0, 132.1 (CH), 146.5, 146.7, 150.5, 154.0, 155.5, 160.4,
161.4.
To a solution of 27 (0.30 g, 0.60 mmol) in MeCN (2 mL) at 0 °C,
were added 2-(trimethylsilyl)ethanol (0.13 mL, 0.90 mmol) and O-
benzotriazolyl-N,N,N¢,N¢-tetra(methyluronium) tetrafluoroborate
(TBTU) (0.29 g, 0.90 mmol). After a short period of stirring, Et3N
(0.17 mL, 1.20 mmol) was added and the stirring continued for 18
h at r.t. The mixture was dissolved in EtOAc (10 mL), washed with
1 M aq KHSO4, H2O, and brine, dried (MgSO4) and concentrated
under reduced pressure. Purification of the residue by FC (EtOAc–
hexanes, 2:3) afforded 28 (0.30 g, 82%) as a yellow-ochre powder;
mp 69–71 °C.
1H NMR (300 MHz, CDCl3): d = –0.04 (s, 9 H), 0.75 (‘t’, J = 8.8
Hz, 2 H), 3.76, 3.78, 3.84 (s each, 3 H), 4.14 (‘t’, J = 8.8 Hz, 2 H),
3
2
4.37 (dd, 2J = 14.6 Hz, J = 11.2 Hz, 1 H), 5.16 (dd, J = 14.6 Hz,
3J = 3.1 Hz, 1 H), 5.69 (dd, 3J = 11.2, 3.1 Hz, 1 H), 6.75, 6.76, 6.96,
6.99, 7.08, 7.43 (d each, J = 8.6 Hz, 2 H).
EI-MS: m/z (%) = 526 (32, [M + H]+), 525 (100, [M]+), 263 (10),
135 (9).
13C NMR (75 MHz, acetone-d6): d = –1.7 (CH3), 17.0 (CH2), 48.8
(CH2), 55.0 (CH3), 55.1 (CH3), 55.3 (CH3), 63.2 (CH2), 78.1 (CH),
112.9 (CH), 113.0 (CH), 114.2 (CH), 118.8, 122.5, 124.4, 125.9,
127.4, 128.0 (CH), 131.7 (CH), 131.8 (CH), 132.9, 158.1, 158.5,
158.6, 160.3, 161.3.
HRMS: m/z calcd for C30H23NO8: 525.1424; found: 525.1408.
1-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-3,4-bis(4-methoxy-
phenyl)-1H-pyrrole-2,5-dicarboxylic Acid (26)
From 3-(4-methoxyphenyl)pyruvic acid (3.8 g, 19.6 mmol) and 2-
hydroxy-2-(4-methoxyphenyl)ethylammonium acetate (25;24 (6.81
g, 30 mmol) according to the general procedure. Recrystallization
of the crude product from MeOH yielded 26 (4.1 g, 81%) as a col-
orless solid; mp 133 °C (dec.).
1H NMR (400 MHz, CDCl3): d = 3.68 (s, 6 H) 3.74 (s, 3 H), 4.92
(m, 3 H), 6.72 (d, J = 8.8 Hz, 4 H), 6.91 (d, J = 8.8 Hz, 6 H, two
overlapping signals), 7.24 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 52.7 (CH2), 55.0 (2 × CH3), 55.3
(CH3), 72.6 (CH), 112.8 (4 × CH), 113.7 (2 × CH), 125.3 (br),
126.9, 127.1, 129.0 (2 × CH), 130.3, 131.6 (4 × CH), 157.8 (2 ×),
158.7, 163.2.
EI-MS: m/z (%) = 600 (42, [M + H] +), 599 (100, [M] +), 571 (15),
499 (33), 436 (27), 73 (16), 58 (20).
HRMS: m/z calcd for C34H37NO7Si: 599.2339; found: 599.2318.
Anal. Calcd for C34H37NO7Si: C, 68.09; H, 6.22; N, 2.34. Found: C,
67.78; H, 6.28; N, 2.26.
3,7,8-Tris(4-methoxyphenyl)-1-oxo-1H-pyrrolo[2,1-c][1,4]ox-
azine-6-carboxylic Acid 2-(Trimethylsilyl)ethyl Ester (29)
A solution of 28 (70 mg, 0.12 mmol) and NBS (23 mg, 0.13 mmol)
in anhyd CCl4 (15 mL) was irradiated at 20 °C with a halogen lamp
(500 W) until complete consumption of the NBS had occurred.
Then Et3N (0.20 mL, 1.44 mmol) was added dropwise, inducing the
immediate precipitation of Et3N·HBr. The mixture was stirred for 2
h at r.t. and then concentrated under reduced pressure. The residue
was dissolved in EtOAc (10 mL) and worked up as usual. Purifica-
tion by FC (EtOAc–hexanes, 1:3) afforded 29 (58 mg, 83%) as an
orange oil.
ESI-MS: m/z (%) = 540 (54, [M + Na]+), 522 (100, [M + Na –
H2O]+), 500 (45), 482 (8).
3,7,8-Tris(4-methoxyphenyl)-1-oxo-3,4-dihydro-1H-pyrro-
lo[2,1-c][1,4]oxazine-6-carboxylic Acid (27)
To a suspension of 26 (1 g, 1.93 mmol) and a catalytic amount of p-
TsOH in anhyd toluene (400 mL) was added DMF until a clear so-
lution resulted. This mixture was refluxed for 5 h under a water sep-
arator. Then the solution was concentrated to half of its volume and
washed exhaustively with H2O. After drying (MgSO4) and removal
of the toluene under reduced pressure, the residual DMF was re-
moved under high vacuum. The residue can be directly used for the
next reaction step or purified by FC (benzene–HCO2Et–HCO2H,
5:4:1) to yield 27 (0.73 g, 75%) as a colorless solid; mp 117–
120 °C.
1H NMR (300 MHz, CDCl3): d = –0.02 (s, 9 H), 0.78 (‘t’, J = 8.3
Hz, 2 H), 3.78, 3.80, 3.86 (s each, 3 H), 4.21 (‘t’, J = 8.3 Hz, 2 H),
6.78 (d, J = 9 Hz, 4 H), 6.97, 7.02, 7.12, 7.72 (d each, J = 9 Hz, 2
H), 8.73 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = –1.66 (CH3), 17.0 (CH2), 55.1
(CH3), 55.2 (CH3), 55.4 (CH3), 63.4 (CH2), 102.7 (CH), 112.9 (CH),
113.0 (CH), 114.3 (CH), 115.7, 119.3, 123.1, 123.7, 125.6, 126.1
(CH), 131.2, 131.9 (CH), 132.1 (CH), 133.6, 142.4, 154.2, 158.77,
158.81, 160.7, 161.4.
1H NMR (300 MHz, acetone-d6): d = 3.73 (s, 6 H), 3.83 (s, 3 H),
EI-MS: m/z (%) = 598 (40, [M + H]+), 597 (100, [M]+), 569 (32),
497 (47).
3
2
4.47 (dd, 2J = 14.1 Hz, J = 11.5 Hz, 1 H), 5.17 (dd, J = 14.1 Hz,
Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York

PAPER
Biomimetic Syntheses of Lamellarin and Lukianol-Type Alkaloids
3057
HRMS: m/z calcd for C34H35NO7Si: 597.2183; found: 597.2175.
(4) (a) Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995,
51, 9941. (b) Winklhofer, C.; Terpin, A.; Peschko, C.;
Steglich, W. Synthesis, preceding paper (DOI: 10.1055/s-
2006-950190).
3,7,8-Tris(4-methoxyphenyl)-1-oxo-1H-pyrrolo[2,1-c][1,4]ox-
azine-6-carboxylic Acid (30)
To a solution of 29 (62 mg, 0.104 mmol) in THF (3 mL) at 0 °C was
added Bu4NF (1 M in THF, 0.15 mL). After 1 h, EtOAc (10 mL)
was added and the organic phase washed and dried as usual. Purifi-
cation by FC (CH2Cl2–acetone, 50:1) yielded 30 (46 mg, 89%) as a
pale-yellow solid; mp 217–218 °C.
1H NMR (300 MHz, acetone-d6): d = 3.85, 3.87, 3.98 (s each, 3 H),
6.84, 6.96, 7.14, 7.19, 7.24, 7.84 (d each, J = 9 Hz, 2 H), 8.11 (s, 1
H), 8.93 (s, 1 CO2H).
13C NMR (75 MHz, acetone-d6): d = 55.29 (CH3), 55.34 (CH3), 55.6
(CH3), 103.5 (CH), 113.5 (CH), 113.6 (CH), 114.9, 115.3 (CH),
120.3, 124.1, 125.1, 126.5, 126.8, 131.8 (CH), 132.5 (CH), 133.0
(CH), 143.0, 153.9, 159.8, 161.8, 162.4.
EI-MS: m/z (%) = 498 (32, [M + H]+), 497 (100, [M]+), 454 (20, [M
+ H – CO2]+), 453 (62, [M – CO2]+), 427 (10), 411 (13), 410 (11),
396 (11), 292 (13), 279 (12), 135 (48).
(5) Kreipl, A. T.; Reid, C.; Steglich, W. Org. Lett. 2002, 4, 3287.
(6) Ebel, H.; Terpin, A.; Steglich, W. Tetrahedron Lett. 1998,
39, 9165.
(7) Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254.
(8) (a) Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick, M.
P.; Jin, Q. J. Org. Chem. 2000, 65, 2479. (b) Bullington, J.
L.; Wolff, R. R.; Jackson, P. F. J. Org. Chem. 2002, 67,
9439. (c) Gupton, J. T.; Clough, S. C.; Miller, R. B.; Lukens,
J. R.; Henry, C. A.; Kanters, R. P. F.; Sikorski, J. A.
Tetrahedron 2003, 59, 207. (d) Iwao, M.; Takeuchi, T.;
Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron Lett.
2003, 44, 4443.
(9) (a) Soenen, D. R.; Hwang, I.; Hedrick, M. P.; Boger, D. L.
Bioorg. Med. Chem. Lett. 2003, 13, 1777. (b) Tao, H.;
Hwang, I.; Boger, D. L. Bioorg. Med. Chem. Lett. 2004, 14,
5979.
(10) (a) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org.
Chem. 1998, 63, 9139. (b) Sala, T.; Sargent, M. V. J. Chem.
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HRMS: m/z calcd for C29H23NO7: 497.1475; found: 497.1501.
3,7,8-Tris(4-methoxyphenyl)pyrrolo[2,1-c][1,4]oxazin-1-one
(31)
To a solution of 30 (30 mg, 0.060 mmol) in quinoline (5 mL) was
added a small amount of copper chromite. The ensuing mixture was
heated for 15 min at 220 °C and then cooled to r.t. After addition of
EtOAc (10 mL), the solution was washed with 1 N HCl and brine,
dried (MgSO4) and concentrated under reduced pressure. FC of the
residue (EtOAc–hexanes 2:3) afforded 31 (19 mg, 70%) as color-
less crystals; mp 206–207 °C (Lit.21 mp 206–207 °C, Lit.22d mp
207 °C).
1H NMR (300 MHz, CDCl3): d = 3.78, 3.82, 3.84 (s each, 3 H),
6.80, 6.87 (d each, J = 8.9 Hz, 2 H), 6.95 (d, J = 9.1 Hz, 2 H), 7.08
(d, J = 8.9 Hz, 2 H), 7.19 (s, 1 H), 7.28 (d, J = 8.9 Hz, 2 H), 7.31 (s,
1 H), 7.64 (d, J = 9.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.16 (CH3), 55.22 (CH3), 55.4
(CH3), 102.7 (CH), 113.0, 113.4 (CH), 113.7, 113.9 (CH), 114.3
(CH), 119.0 (CH), 123.1, 124.7, 125.86 (CH), 125.89, 128.2, 129.8
(CH), 132.1 (CH), 142.0, 154.4, 158.6, 159.0, 160.5.
EI-MS: m/z (%) = 454 (27, [M + H]+), 453 (100, [M]+), 306 (6), 305
(20), 135 (43).
(14) Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.;
Wongbundit, S.; Ruchirawat, S. Angew. Chem. Int. Ed.
2004, 43, 866; Angew. Chem. 2004, 116, 884.
(15) Díaz, M.; Guitián, E.; Castedo, L. Synlett 2001, 1164.
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1990, 503.
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308.
(18) Giannis, A.; Sandhoff, K. Angew. Chem., Int. Ed. Engl.
HRMS: m/z calcd for C28H23NO5: 453.1576; found: 453.1573.
1989, 28, 218; Angew. Chem. 1989, 101, 220.
(19) Müller, P.; Siegfried, B. Helv. Chim. Acta 1974, 57, 987.
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Helv. Chim. Acta 1992, 75, 1721.
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60, 6637.
Acknowledgment
The authors thank the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie for financial support of this work
and Prof. M. G. Banwell (ANU, Canberra) for helpful discussions
and improvements in the manuscript.
(22) (a) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C.
R. Chem. Commun. 1997, 207. (b) Boger, D. L.; Boyce, C.
W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 54. (c) Gupton, J. T.; Krumpe, K. E.; Burnham,
B. S.; Webb, T. M.; Shuford, J. S.; Sikorski, J. A.
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3587. (e) Kim, S.; Son, S.; Kang, H. Bull. Korean Chem.
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(23) Compound 17 was prepared from ethyl 3-(4-methoxy-
phenyl)pyruvate according to ref. 2b in quantitative yield.
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H. M. J. Heterocycl. Chem. 1986, 23, 1805.
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Synthesis 2006, No. 18, 3048–3057 © Thieme Stuttgart · New York