Attempts to mimic key bond-forming events associated with the proposed biogenesis of the pentacyclic lamellarins

Article abstract of DOI:10.1071/CH07402

The pyrrole-tethered veratroles 16 and 27 each engage in PIFA-induced oxidative cyclization reactions to give compounds 22 and 29, respectively, which incorporate a key tricyclic fragment associated with the title natural products. In contrast, the corresponding catechols 11 and 12 only produce polymeric materials on subjection to analogous reaction conditions. Efforts to study lactone ring formation by the oxidative cyclization of catechol 30 and veratrole 38 have been thwarted by an inability to prepare the former substrate and decomposition of the latter. The reported conversions 44 ? 45 and 46 ? 47 suggest that a C2-carboxy group attached to the pyrrole ring can ?direct' the oxidative cyclization of N-tethered aryl groups. The acquisition of compound 22 by the means described herein provides an adventitious and concise route to the racemic modification of the pyrrolo[2,1-a]isoquinoline alkaloid crispine A (52). CSIRO 2008.

Full text of DOI:10.1071/CH07402

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 80–93
www.publish.csiro.au/journals/ajc
Attempts to Mimic Key Bond-Forming Events Associated with
the Proposed Biogenesis of the Pentacyclic Lamellarins
Lorraine C. Axford,A Kate E. Holden,A Katrin Hasse,A Martin G. Banwell,A,C
Wolfgang Steglich,B Jörg Wagler,A and Anthony C. WillisA
AResearch School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra, ACT 0200, Australia.
BDepartment Chemie, Ludwig-Maximilians-Universität, Butenandtstr. 5-13 (Haus F),
81377 München, Germany.
CCorresponding author. Email: mgb@rsc.anu.edu.au
The pyrrole-tethered veratroles 16 and 27 each engage in PIFA-induced oxidative cyclization reactions to give compounds
22 and 29, respectively, which incorporate a key tricyclic fragment associated with the title natural products. In contrast,
the corresponding catechols 11 and 12 only produce polymeric materials on subjection to analogous reaction conditions.
Efforts to study lactone ring formation by the oxidative cyclization of catechol 30 and veratrole 38 have been thwarted
by an inability to prepare the former substrate and decomposition of the latter. The reported conversions 44 → 45 and
46 → 47 suggest that a C2-carboxy group attached to the pyrrole ring can ‘direct’ the oxidative cyclization of N-tethered
aryl groups. The acquisition of compound 22 by the means described herein provides an adventitious and concise route
to the racemic modification of the pyrrolo[2,1-a]isoquinoline alkaloid crispine A (52).
Manuscript received: 21 November 2007.
Final version: 3 January 2008.
Introduction
OH
HO
The lamellarins are a large group of marine alkaloids that show a
range of interesting biological activities with some having been
investigated as agents for the treatment of HIVAIDS and various
cancers.[1] Structurally speaking, the lamellarins can be divided
into two subclasses with the simpler ones being comprised of
a central pyrrole ring to which is attached a C2-carbomethoxy
group, C3- and C4-aryl groups, as well as an N1-β-phenethyl
moiety.[1,2] The aryl groups are always at least mono-oxygenated
as can be seen in lamellarin Q (1, Fig. 1),[3] a representative
member of this subclass.The structurally more complex variants
incorporate a pentacyclic framework as encountered, for exam-
ple, in lamellarin K (2).[4] Given the limited supply of many
of these compounds from natural sources, a great deal of effort
has been devoted to establishing total syntheses of them.[2,5,6]
Some such work has been potentially biomimetic in nature[6]
and served to reinforce the notion that the pyrrole ring of the
lamellarins as well as the associated C3- and C4-aryl groups
are derived, biosynthetically, from two molecules of tyrosine or
l-DOPA. However, much remains to be determined about the
biogenesis of these alkaloids, especially the pentacyclic mem-
bers of the family. The establishment of a fuller understanding
of the manner in which nature produces these fascinating com-
pounds might well assist with the development of even more
highly efficient methods for their chemical synthesis.
OMe
OMe
HO
OH
CO2Me
O
Bond B
N
Bond A
O
MeO
MeO
N
O
OH
MeO
1
2
Fig. 1.
the formation of bonds A and B (no order of formation implied)
as indicated in structure 2. In particular, a simpler lamellarin car-
rying an N1-β-[(3ꢀ,4ꢀ-dihydroxyphenyl)ethyl] side chain, e.g. 3
(Scheme 1), might be oxidized to the corresponding o-quinone,
4, that then engages in an intramolecular Michael addition
reaction[8] as indicated to give, via the zwitterion 5, product
6 that incorporates the pivotal bond A encountered in the more
complex lamellarins.
Based on a consideration of, amongst other things, the
oxygenation patterns observed in the structurally more com-
plex members of the family, it has been suggested[7] that the
pentacyclic forms of these alkaloids are generated from their
simpler counterparts through oxidation processes that lead to
In a related manner, oxidation of a 3ꢀ,4ꢀ-dihydroxylated C3-
aryl group within the simpler lamellarin framework, e.g., 7
(Scheme 2), would lead to the corresponding o-quinonoid sys-
tem 8 that could engage in a hetero-Michael addition reaction
with the C2-carboxylic acid residue and so produce zwitterion
© CSIRO 2008
10.1071/CH07402
0004-9425/08/020080

Biogenesis of the Pentacyclic Lamellarins
81
Ar
Arꢀ
Ar
Arꢀ
O
O
HO
HO
CO2R
CO2R
N
N
HO
HO
HO
HO
[O]
N
N
3
4
Intramolecular
Michael
11
12
addition
Fig. 2.
Bond A
Ar
Arꢀ
Ar
Arꢀ
MeO
MeO
HO
HO
ꢂO
CO2R
CO2R
N
N
Nꢁ
Prototropic
shifts
O
16
6
5
N
H
ꢁ
Scheme 1.
13
NH
MeO
MeO
Base
HO
OH
O
O
O
ꢁ
MeO
MeO
17
Arꢀ
Arꢀ
X
O
ꢁ
[O]
2
14 X ꢃ Br
15 X ꢃ OTs
N
R
N
R
OH
OH
MeO
MeO
7
8
Intramolecular
hetero-Michael
addition
18
HO
O
OH
O–
Scheme 3.
Bond B
because the reaction only gives compound 11 in 8% yield we
sought alternate methods for the preparation of this material.
Our first attempts to do so involved (Scheme 3) treatment of the
parent pyrrole (13) with either the commercially available bro-
mide 14 or the readily prepared tosylate 15[10] in the presence
of base and a phase-transfer catalyst.[11] However, the desired
N-alkylation product 16[12] was always accompanied by varying
quantities of what is tentatively assigned as the corresponding
C-alkylated isomer 17 as well as the H–X elimination product
3,4-dimethoxystyrene (18).[13]
The difficulties associated with separating these products
from one another prompted us to pursue a variation on the orig-
inal Paal–Knorr synthesis (Scheme 4).[12] In particular, reaction
of commercially available 2,5-dimethoxytetrahydrofuran (19)
andcommerciallyavailableβ-(3,4-dimethoxyphenyl)ethylamine
(20) in refluxing acetic acid provided the expected pyrrole 16 in
58% yield. This product was subjected to two-fold demethyla-
tion using boron tribromide in dichloromethane at −78◦C, and
in this manner the originally targeted catechol 11 was obtained
in 34% yield.
The spectroscopic and physical properties of this crystalline
material matched those reported[9] in the literature and were in
complete accord with the assigned structure, but final confir-
mation of this came from a single-crystal X-ray analysis. The
derived ORTEP plot is shown in Fig. 3 and other data arising
from this analysis are provided in the Experimental section.
With compound 11 in hand the capacity of it to
undergo oxidative cyclization in the manner indicated in
Scheme 1 was explored. Ag2CO3 on Celite,[14] Ag2O,[15]
NaIO4,[16] dichlorodicyanoquinone (DDQ),[17] o-chloranil,[18]
Arꢀ
Arꢀ
O
O
O
Prototropic
shifts
N
R
N
R
O
H
ꢁ
10
9
Scheme 2.
9 that would then undergo prototropic shifts and accompanying
re-aromatization to give compound 10. Thus, this process would
result in the formation of bond B and the associated lactone ring
encountered in the more complex lamellarins.
The purpose of the present work was to attempt to establish
the validity, or otherwise, of such proposals and to do so using
substituted pyrroles that incorporate the relevant substituents for
studying the above-mentioned conjugate addition processes.The
outcomes of such studies are detailed below.
Results and Discussion
Investigations of the Proposed Pathway
for Bond A Formation
Both the pyrrole 11 incorporating an N-tethered catechol residue
and the corresponding 3,4-diphenylated system 12 (Fig. 2) were
considered relevant model systems for a study of the bond A-
forming process proposed in Scheme 1.
The former compound has been reported previously[9] and
was prepared using a Paal–Knorr pyrrole synthesis involv-
ing the reaction of 2,5-dimethoxytetrahydrofuran and β-(3,4-
dihydroxyphenyl)ethylamine in the presence of acid. However,

82
L. C. Axford et al.
OMe
MeO
O
19
ꢁ
MeO
MeO
HO
HO
BBr3
AcOH
N
N
MeO
16
11
MeO
NH2
[O]
PIFA, BF3·Et2O
X
20
MeO
MeO
HO
HO
BBr3
N
N
22
21
Scheme 4.
was exposed to either DDQ or PIFA it underwent smooth
and near quantitative conversion into the corresponding o-
benzoquinone (i.e., N-acetyldopaminequinone).[24] A further
interesting contrast stems from the observation, originally made
byTellitu et al.,[22,25] that treatment of the veratrole 16 with PIFA
and BF3·Et2O in dichloromethane at −40◦C afforded the corre-
sponding cyclized product 22,[25] albeit in just 24% yield. The
structure of compound 22 was confirmed by single crystal X-
ray analysis and treatment of this material with BBr3 resulted in
two-fold demethylation and formation of an authentic sample of
the originally targeted tricyclic catechol 21 (31%). The spectro-
scopic data derived from this last compound were in full accord
with the assigned structure. In particular, the 13C NMR spectrum
displayed the expected 12 resonances while the 70 eV electron-
impact mass spectrum revealed the molecular ion, at m/z 201, as
base peak. The 300 MHz 1H NMR spectrum displayed distinct
resonances for the five aromatic protons within the molecule as
well as two mutually coupled two-proton triplets at δ 3.16 and
2.17, that are assigned to the methylene protons associated with
the newly created heterocyclic ring. The origins of our inability
to effect oxidative cyclization of compound 11 remain unclear
but may arise from the lack of the aryl groups at the C3 and
C4 positions on the pyrrole ring. Accordingly, the preparation of
a potentially ‘more realistic’ model system incorporating such
substituents was pursued.
The 3,4-diphenylated analogue, 12, of compound 11 was pre-
pared using the reaction sequence shown in Scheme 5. Thus,
parent pyrrole 13 was converted into the corresponding N-
trisisopropylsilyl (TIPS)-substituted derivative 23 (99%) using
the conditions related to those defined by Muchowski et al.[26]
Two-fold iodination of this material using molecular iodine
in the presence of mercury(ii) acetate afforded the previously
reported 3,4-diiodinated pyrrole 24 (58%),[26] which was sub-
jected to a two-fold Kumada cross-coupling reaction[27] with
phenylmagnesium bromide. The resulting 3,4-diphenylated pyr-
role 25 (77%)[28] was then treated with tetra-n-butylammonium
fluoride (TBAF) so as to remove the TIPS group at the ring
nitrogen. The resulting 3,4-diphenylpyrrole (26)[29] (99%) was
N-alkylated with bromide 14 in the presence of sodium hydride
C3
C4
C2
C5
N1
C6
C7
C8
C13
C12
C9
C10
C11
O15
O14
Fig. 3. Molecular structure of compound 11 with labelling of selected
atoms. Anisotropic displacement ellipsoids show 30% probability levels.
Hydrogen atoms are drawn as circles with small radii.
ceric ammonium nitrate (CAN) on silica,[19] horseradish
peroxidase,[20] (diacetoxyiodo)benzene,[21] andphenyliodine(iii)
bis(trifluoroacetate) (PIFA)/BF3·Et2O[22] are all known to con-
vert catechols into the corresponding o-benzoquinone. However,
upon exposing substrate 11 to such reagents only complex mix-
tures of products were obtained, and none of these appeared
to contain the cyclized product 21, an authentic sample of
which was available by the pathway described immediately
below. In contrast, when a sample of the related catechol
N-(3,4-dihydroxyphenethyl)acetamide (N-acetyldopamine)[23]

Biogenesis of the Pentacyclic Lamellarins
83
X
X
N
R
13 R ꢃ X ꢃ H
Ref. [26]
23 R ꢃ TIPS, X ꢃ H
24 R ꢃ TIPS, X ꢃ I
25 R ꢃ TIPS, X ꢃ Ph
26 R ꢃ H, X ꢃ Ph
I2, Hg(OAc)2
TBAF
MeO
MeO
HO
HO
BBr3
NaH
PhMgBr,
Pd0
N
N
27
12
ꢁ
MeO
PIFA, BF3·Et2O
[O]
X
MeO
Br
14
MeO
MeO
HO
HO
BBr3
N
N
29
28
Scheme 5.
HO
OH
to give the veratrole 27 in 61% yield. Treatment of this last com-
pound with BBr3 in dichloromethane between −78 and 18◦C
then afforded the target catechol 12 in 95% yield. While all
attempts to effect oxidative cyclization of this last compound to
the corresponding tricyclic system 28 failed (only complex mix-
tures of products were obtained), treatment of veratrole 27 with
PIFA and BF3·Et2O in dichloromethane at −40◦C afforded the
oxidative coupling product 29 in 40% yield. This last compound
could then be demethylated with BBr3 in dichloromethane to
give the targeted tricyclic catechol 28 in 53% yield. The spectro-
scopic data derived from this material were in complete accord
with the assigned structure and rather similar in nature to those
obtained for its non-phenylated congener 21. In particular, the
300 MHz 1H NMR spectrum revealed one-proton singlets at
δ 6.87, 6.63, and 6.45 that are attributed to the isolated aro-
matic protons associated with the catechol and pyrrole rings of
compound 28.
O
N
OH
Me
30
Fig. 4.
with N-bromosuccinimide (NBS) in carbon tetrachloride under
conditions related to those defined by Easton et al.[32] provided
the 3-bromo-2-carbomethoxypyrrole 34 in 69% yield. The
1
300 MHz H NMR spectrum of this material displays a diag-
nostic pair of mutually coupled one-proton doublets (J 3.6 Hz)
at δ 6.24 and 7.22 arising from the adjacent pyrrolic ring pro-
tons. Treatment of compound 34 with zinc bromide resulted in
removal of the Boc-group and formation of pyrrole 35 (89%).
The structure of this compound follows from the derived spectro-
scopic data but was confirmed by a single-crystal X-ray analysis.
The derived ORTEP plot is shown in Fig. 5 while other data are
presented in the Experimental section. Compound 35 could be
N-methylated in 93% yield using methyl iodide in the presence
of NaH as base. Compound 36 so-formed was then subjected
to a microwave-promoted Suzuki–Miyaura cross-coupling reac-
tion with commercially available 3,4-dimethoxyphenylboronic
acid and thus gave the required arylated compound 37 in 96%
yield. Saponification of this ester using sodium hydroxide fol-
lowed by acidic workup then gave the acid 38 (73%) that was
immediately subjected to two-fold demethylation with BBr3
in dichloromethane. While this reaction produced the desired
catechol subunit it was accompanied by decarboxylation and
The origins of the lack of success associated with our efforts
to effect oxidative cyclization of catechol 12 to its tricyclic coun-
terpart 28 are not clear but may be attributable to the capacity
of the pyrrole ring within such compounds to undergo oxidative
polymerization.[30]
Investigations of the Proposed Pathway
for Bond B Formation
In an effort to study the bond B forming process associated
with the proposed biogenesis of the pentacyclic lamellarins
(Scheme 2), the catechol 30 (Fig. 4) was sought. The route
followed to prepare this compound is shown in Scheme 6 and
starts with the near quantitative conversion of S-proline (31)
into the corresponding methyl ester (32) using thionyl chlo-
ride in methanol. Reaction of compound 32 with Boc2O and
Hünig’s base then afforded, in quantitative yield, the previously
reported[31] carbamate 33. Treatment of this last compound

84
L. C. Axford et al.
Br
(Boc)2O
NBS
CO2R
CO2Me
CO2Me
N
H
N
N
R
Hünig’s
base
Boc
31 R ꢃ H
32 R ꢃ Me
34 R ꢃ Boc
35 R ꢃ H
36 R ꢃ Me
33
SOCl2, MeOH
ZnBr2
NaH, MeI
3,4-(MeO)2C6H3B(OH)2,
Pd0, K2CO3
HO
OH
MeO
OMe
MeO
HO
OMe
OH
BBr3, DCM
O
O
X
N
N
N
N
O
O
Me
Me
Me
Me
41
40
39
37 X ꢃ CO2Me
38 X ꢃ CO2H
NaOH, H2O
MeOH
Scheme 6.
Br10
O
B
O
OH
34
Pd0, K2CO3
C4
O
O
C3
N
R
O8
42 R ꢃ Boc
43 R ꢃ H
ZnBr2
C2
C5
C9
C6
N1
NaH
14
PIFA
O7
BF3·Et3O
OH
O
OMe
MeO
Fig. 5. Molecular structure of compound 35 with labelling of selected
atoms. Anisotropic displacement ellipsoids show 30% probability levels.
Hydrogen atoms are drawn as circles with small radii.
N
N
O
OMe
MeO
45
44
so delivered compound 39 (73%) rather than the target com-
pound 30 required for the foreshadowed oxidative cyclization
studies. Consequently, we have been unable to examine the
proposed oxidative cyclization of the latter compound into the
corresponding lactone 40.
GiventheearliersuccessencounteredinusingPIFA/BF3·Et2O
to effect the oxidative cyclization of veratroles, compound 38
was treated with this reagent combination in an effort to pro-
duce the lactone 41. However, only rapid decomposition of the
substrate was observed. Similarly, when veratrole 38 was treated
with 1.1 molar equivalents of thallium tris(trifluoroacetate)[33]
and BF3·Et2O (4 molar equivalents) in trifluoroacetic acid
(TFA)/CH2Cl2 at −20◦C the reaction mixture turned black
almost instantaneously, and quenching it after just 20 seconds
only delivered highly polar and intractable materials.
Scheme 7.
outcomes of a series of experiments undertaken in an effort
to circumvent the difficulties created by the unwanted con-
version 38 → 39. Thus, for example, attempts were made to
establish whether or not the incorporation of the C2-carboxy
group into a lactone ring might prevent this type of decar-
boxylation reaction. To such ends, compound 34 was subjected
to Suzuki–Miyaura cross-coupling with commercially available
2-hydroxyphenylboronic acid pinacol ester (Scheme 7) so as to
give lactone 42 (78%), the structure of which was established by
single-crystal X-ray analysis.The Boc-group associated with the
last compound was removed using zinc bromide and reaction of
the ensuing pyrrole 43 (93%) with bromide 14 in the presence of
sodium hydride then gave the substrate 44 (78%) required for use
in the pivotal oxidative cyclization study. In the event, exposure
The propensity of pyrroles that incorporate a C2-carboxy
group to undergo decarboxylation has been emphasized by the

Biogenesis of the Pentacyclic Lamellarins
85
Br
RO
RO
OR
O
OR
Rꢀ
Rꢀ
MeO
CO2Me
N
NaH
35 ꢁ 14
O
MeO
RO
RO
RO
RO
N
46
N
O
Br
OH
PIFA
BF3·Et3O
OMe
N
48 R ꢃ H
50 R ꢃ Me
49 R ꢃ H
51 R ꢃ Me
Rꢀ ꢃ OH or OMe
OMe
47
Fig. 7.
Scheme 8.
MeO
N
Br18
C13
O12
MeO
52
C10
C3
C4
C11
C14
Fig. 8.
C5
C6
O15
the carboxylic acid residue, be less prone to polymerization and
could, in principle, undergo a now competitive two-fold oxida-
tive cyclization reaction to give the corresponding pentacyclic
system 49 that embodies the full carbon framework of the more
complex lamellarins. Even if such an outcome was not obtained,
the bis-veratrole precursor, 50, to compound 48 might be capable
of undergoing an equivalent tandem oxidative cyclization pro-
cesstogivecompoundssuchas51andthusprovideanewrouteto
the pentacyclic framework associated with the title natural prod-
ucts. Work directed towards examining these possibilities is now
underway in these laboratories. The biogenetic significance, or
otherwise, of the directed oxidative cyclization 46 → 47 is also
under investigation.
C2
N1
C9
C17
C7
C8
C16
Fig. 6. Molecular structure of compound 47 with labelling of selected
atoms. Anisotropic displacement ellipsoids show 50% probability levels.
Hydrogen atoms are drawn as circles with small radii.
of this last compound to PIFA/BF3·Et2O, under the same sorts
of conditions as employed earlier, led to a complex mixture of
products, the only characterizable component of which proved
to be the cyclized product 45 (9%).
An Adventitious Synthesis of the Pyrrolo[2,1-a]isoquinoline
The apparent capacity of the C2-carboxy group to ‘direct’
the regioselectivity of the oxidative cyclization process is rein-
forced by the observation that when compound 46, which is
readily derived by N-alkylation of pyrrole 35 with bromide 14,
is subjected to the same type of oxidative cyclization process
(Scheme 8) then the only isolable reaction product is the annu-
lated pyrrole 47 (29%). The structure of this rather unstable
product has been confirmed by a single-crystal X-ray analysis
(Fig. 6).
Alkaloid Crispine A
The pyrrolo[2,1-a]isoquinoline alkaloid (+)-crispine A (52,
Fig. 8) was isolated from extracts of the Chinese medicinal
plant Carduus crispus Linn. (welted thistle) by Zhao et al. in
2002.[34] The racemic modification of this compound, which
appears to possess some interesting activities, particularly at the
dopamine/serotonin receptor,[35] has been prepared on several
occasions,[36,37] most recently (2007) by King[36e] in three steps
from commercially available materials. Knölker’s earlier (2005)
synthesis[36c] relied on a ∼five step synthesis of compound 22
and the hydrogenation of this material with dihydrogen in the
presence of 5% Rh on carbon to give ( )-crispine A in 66%
yield.Accordingly, the acquisition of compound 22 by the means
described above constitutes a three-step synthesis (from com-
mercially available materials) of the racemic modification of the
title alkaloid. Given the sluggish nature of the hydrogenation step
used in Knölker’s synthesis (8 days at room temperature in 1:1
acetic acid/methanol) and our own interest in the reduction of
pyrroles,[38] weinvestigatedalternateconditionsforeffectingthe
conversion 22 → ( )-52. Exposure of an acetic acid solution of
compound 22 to dihydrogen at 18◦C for 18 h in the presence of
Adam’s catalyst (PtO2) failed to provide any useful quantities
of the target natural product, as did several variations on this
type of approach. Ultimately, we found that a two-stage reduc-
tion proved most effective in achieving the desired conversion.
Conclusions
The foregoing studies, involving attempts to effect the oxida-
tive cyclization of catechols 11 and 12, have failed to provide
any support for the proposed mode of formation of the A bond
associated with the biogenesis of the pentacyclic lamellarins.
These outcomes may be attributed to the facility with which such
model compounds can undergo oxidative polymerization. The
inability to prepare compound 30, because of the unexpectedly
facile decarboxylation of congener 38, has thwarted attempts to
investigate the proposed mode of formation of the B bond. As
such, compounds 11, 12, and 30/38 should probably be regarded
as inadequate models for the actual substrate(s) involved in
the in vivo production of the pentacyclic lamellarins. A more
appropriate compound to study might be the tetra-substituted
pyrrole 48 (Fig. 7), which should, by virtue of the presence of

86
L. C. Axford et al.
Specifically, subjection of compound 22 to reaction with acti-
vated zinc powder in refluxing ethanol for 3 h and in the presence
of aqueous HCl provided a mixture of compound ( )-52 and a
dehydroprecursor.[39] Subjection of this mixture to dihydrogen
(1 atm) in the presence of 10% palladium on carbon (Pd on C)
at 18◦C for 40 min then gave ( )-crispine A as a white crys-
talline solid. A one-pot modification of this procedure wherein
the zinc metal, mineral acid, and 10% Pd on C were present at
the outset, and the dihydrogen was being generated through reac-
tion between the first two of these reagents, led to an 88% yield
of target ( )-52 after just 1.5 h. The spectroscopic data derived
from this material were in full accord with those reported for the
natural product but final confirmation of the structure followed
from a single-crystal X-ray analysis of this material.∗
147.8 (C), 144.6 (C), 132.8 (C), 129.7 (CH), 128.6 (C), 127.8
(CH), 120.9 (CH), 111.8 (CH), 111.0 (CH), 70.8 (CH2), 55.8
(CH3), 55.7 (CH3), 34.9 (CH2), 21.6 (CH3). νmax (NaCl)/cm−1
2955, 2835, 1595, 1517, 1464, 1420, 1356, 1262, 1238, 1175,
1157, 1096, 1028, 967, 908, 812, 763, 663. m/z (ESI) 359 [76%,
(M + Na)+], 165 (100).
1-[2-(3,4-Dimethoxyphenyl)ethyl]-1H-pyrrole (16)
Method A: A magnetically stirred mixture of pyrrole
(13) (250 mg, 3.72 mmol), potassium hydroxide (245 mg,
3.73 mmol), and 18-crown-6 (31 mg, 0.12 mmol) in benzene
(2.5 mL) was heated at reflux for 2 h and then treated with
bromide 14 (1.21 g, 4.92 mmol). After a further 2 h the reac-
tion mixture was cooled to 18◦C, diluted with water (20 mL),
and extracted with CH2Cl2 (2 × 20 mL). The combined organic
phases were washed with water (1 × 20 mL) and then dried
(MgSO4), filtered, and concentrated under reduced pressure.The
resulting light-yellow oil was subjected to flash chromatography
(silica, 5/1 v/v pentane/diethyl ether → diethyl ether gradient
elution) affording three fractions, A–C.
Concentration of fractionA (RF 0.4 in 3/1 v/v pentane/diethyl
ether) afforded styrene 18[13] (218 mg, 27%) as a clear,
colourless oil [Found: M+• 164.0838. C10H12O2 requires M+•
164.0837]. δH (300 MHz, CDCl3) 6.96 (s, 1H), 6.94 (d, J 8.1,
1H), 6.81 (d, J 8.1, 1H), 6.65 (dd, J 17.7 and 10.8, 1H), 5.61 (d,
J 17.7, 1H), 5.15 (d, J 10.8, 1H), 3.40 (s, 3H), 3.87 (s, 3H). δC
(75.5 MHz, CDCl3) 149.2 (C), 149.1 (C), 136.7 (CH), 130.9 (C),
119.7 (CH), 112.0 (CH), 111.2 (CH2), 108.6 (CH), 56.1 (CH3),
56.0 (CH3). νmax (NaCl)/cm−1 2935, 2835, 1602, 1580, 1512,
1462, 1417, 1261, 1237, 1155, 1138, 1025, 898, 854, 810, 765.
m/z (EI, 70 eV) 164 (100%, M+•).
Experimental
General
Melting points were measured on a Stanford Research Systems
Optimelt–Automated Melting Point system and are uncorrected.
Proton (1H) and carbon (13C) NMR spectra were recorded on
either a Varian Inova 600 MHz or a Varian Gemini 300 MHz
NMR spectrometer. Unless otherwise specified, spectra were
acquired at 20◦C in deuterochloroform (CDCl3) that had been
filtered through basic alumina immediately before use. Chem-
ical shifts are recorded as δ values in parts per million (ppm).
Infrared spectra (νmax) were recorded on a Perkin–Elmer 1800
FTIR spectrometer and samples were analyzed as NaCl disks
(for solids) or as thin films on NaCl plates (for oils). Mass
spectra were recorded on a Micromass–Waters LC-ZMD single
quadrupole liquid chromatograph-MS or a VG Autospec instru-
ment using electron impact electrospray and ionization electron
impact techniques. High-resolution mass spectra were recorded
on an AUTOSPEC spectrometer. Dichloromethane (CH2Cl2)
was distilled from calcium hydride, and tetrahydrofuran (THF)
was distilled, under nitrogen, from sodium benzophenone ketyl.
Where necessary, reactions were performed under a nitrogen
atmosphere.
Concentration of fraction B (RF 0.3 in 3/1 v/v pentane/diethyl
ether) afforded the N-alkylated pyrrole 16[12] (232 mg, 27%) as
a clear, colourless oil [Found: (M + H)+ 232.1333. C14H17NO2
requires (M + H)+ 232.1338]. δH (CDCl3, 300 MHz) 6.78 (d,
J 8.1, 1H), 6.66 (dd, J 8.1 and 2.0, 1H), 6.58 (br s, 2H), 6.42
(d, J 2.0, 1H), 6.12 (br s, 2H), 4.07 (t, J 6.9, 2H), 3.86 (s, 3H),
3.79 (s, 3H), 2.98 (t, J 6.9, 2H). δC (CDCl3, 75.5 MHz) 148.5
(C), 147.4 (C), 130.8 (C), 120.3(3) (CH), 120.3(2) (CH), 111.6
(CH), 110.9 (CH), 107.8 (CH), 55.6 (CH3), 55.5 (CH3), 51.1
(CH2), 37.7 (CH2). νmax (NaCl)/cm−1 3097, 2998, 2934, 2833,
1607, 1590, 1517, 1464, 1419, 1359, 1333, 1263, 1236, 1155,
1140, 1089, 1069, 1028, 970, 808, 763, 725. m/z (ESI) 254 [15%,
(M + Na)+], 232 [43, (M + H)+], 165 (100).
Synthetic Studies
3,4-Dimethoxyphenethyl p-Toluenesulfonate (15)
Triethylamine (625 µL, 4.5 mmol), 4-(N,N-dimethylamino)
pyridine (DMAP, 73 mg, 0.6 mmol), and p-toluenesulfonyl chlo-
ride (686 mg, 3.6 mmol) were added to a magnetically stirred
solution of β-(3,4-dimethoxyphenyl)ethyl alcohol (547 mg,
3.0 mmol) in dry CH2Cl2 (15 mL) maintained at 0◦C under a
nitrogen atmosphere. After 5 min the cooling bath was removed
and the reaction mixture allowed to warm to 18◦C over 2 h.
The ensuing mixture was diluted with CH2Cl2 (10 mL) and
extracted with water (3 × 10 mL). The combined organic phases
were then dried (MgSO4), filtered, and concentrated under
reduced pressure. The resulting yellow oil was subjected to
flash chromatography (1/1 v/v ethyl acetate/hexane elution)
and concentration of the relevant fractions (RF 0.5) under
reduced pressure afforded the tosylate 15[10] (904 mg, 90%)
as a cream-coloured solid, mp 48–50◦C (lit.[10] mp 49–50◦C)
[Found: (M + Na)+ 359.0942. C17H20O5S requires (M + Na)+
359.0929]. δH (CDCl3, 300 MHz) 7.67 (d, J 8.1, 2H), 7.27 (d, J
8.1, 2H), 6.75 (d, J 8.1, 1H), 6.65 (dd, J 8.1 and 2.1, 1H), 6.59
(d, J 2.1, 1H), 4.18 (t, J 6.9, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.90
(t, J 6.9, 2H), 2.43 (s, 3H). δC (CDCl3, 75.5 MHz) 148.7 (C),
Concentration of fraction C (RF 0.1 in 3/1 v/v pentane/diethyl
ether) afforded a light-yellow oil that was tentatively identified
as the C-alkylated pyrrole 17 (198 mg, 23%).
Method B: Reaction of pyrrole (13) with tosylate 15 under
the same conditions as specified in Method A but using tetra-
n-butylammonium bromide (TBAB) in place of 18-crown-6
afforded a mixture of products 16 (9%), 17 (4%), and 18 (4%).
Method C: 2,5-Dimethoxytetrahydrofuran (518 µL, 4.0
mmol) was added dropwise to a magnetically stirred solution of
3,4-dimethoxyphenethylamine (675 µL, 4.0 mmol, ex Aldrich)
in acetic acid (1.0 mL) maintained under a nitrogen atmosphere.
The ensuing mixture was heated at reflux for 2 h and then
cooled and the acetic acid removed under reduced pressure.
The residue thus obtained was dissolved in ethyl acetate (5 mL)
and the resulting solution washed with water (2 × 5 mL), NaOH
(2 × 5 mL of a 0.1 M aqueous solution), and HCl (2 × 5 mL
of a 0.05 M aqueous solution) before being dried (Na2SO4),
∗ The X-ray crystal structure of the picrate salt of (+)-crispine A has been reported previously – see ref. [37b].

Biogenesis of the Pentacyclic Lamellarins
87
filtered, and concentrated under reduced pressure. Subjection
of the resulting oil to flash chromatography (silica, 1/1 v/v
ethyl acetate/hexane elution) and concentration of the relevant
fractions (RF 0.5) under reduced pressure afforded the title com-
pound 16[12] (539 mg, 58%) as a clear, colourless oil. This
material was identical, in all respects with that obtained by
Method A.
0.27 mmol) in 2,2,2-trifluoroethanol (2 mL) maintained at 18◦C.
1H NMR analysis (300 MHz) of an aliquot of the reaction
mixture, withdrawn 5 min after the addition mentioned above,
revealed the clean formation of the title quinone.
8,9-Dimethoxypyrrolo[2,1-a]isoquinoline (22)
Boron trifluoride diethyl etherate (143 mg, 0.10 mmol) was
added to a magnetically stirred solution of PIFA (505 mg,
1.174 mmol) in anhydrous CH2Cl2 (40 mL) maintained under
a nitrogen atmosphere and the resulting solution was cooled to
0◦C. This solution was then added, through a cannula, to a mag-
netically stirred solution of pyrrole 16 (197 mg, 0.85 mmol) in
anhydrous CH2Cl2 (40 mL) maintained at −35◦C. The ensuing
mixture was stirred at −35◦C for 3 h and then quenched with
ammonia (5 mL of a 12% aqueous solution) and water (20 mL)
before being allowed to warm to 18◦C. The resulting mix-
ture was extracted with CH2Cl2 (3 × 30 mL) and the combined
organic phases were then washed with brine (1 × 30 mL) before
being dried (Na2SO4), filtered, and concentrated under reduced
pressure. Subjection of the residue thus obtained to flash
chromatography (silica, 2/1 v/v pentane/diethyl ether elu-
tion) and concentration of the relevant fractions (RF 0.35)
under reduced pressure afforded the title compound 22[25]
(48 mg, 24%) as a white powder, no melting point, decompo-
sition from 120◦C (lit.[25] mp 132–133◦C) [Found: (M + H)+
230.1176. C14H15NO2 requires (M + H)+ 230.1181]. δH
(CDCl3, 300 MHz) 7.03 (s, 1H), 6.70 (s, 1H), 6.65 (m, 1H),
6.40 (m, 1H), 6.20 (app. t, J 3.4, 1H), 4.06 (t, J 6.6, 2H), 3.92
(s, 3H), 3.90 (s, 3H), 3.00 (t, J 6.6, 2H). δC (CDCl3, 75.5 MHz)
148.2(C), 147.2(C), 129.9(C), 122.7(C), 122.5(C), 120.4(CH),
111.2 (CH), 108.3 (CH), 105.8 (CH), 102.2 (CH), 55.9(8) (CH3),
55.9(7) (CH3), 44.2 (CH2), 29.0 (CH2). νmax (NaCl)/cm−1 2950,
1553, 1508, 1465, 1340, 1266, 1209, 1167, 1131, 1015, 845, 730.
m/z (ESI) 252 [12%, (M + Na)+], 230 [100, (M + H)+].
4-[2-(1H-Pyrrol-1-yl)ethyl]benzene-1,2-diol (11)
Boron tribromide (2.88 mL of a 2 M solution in CH2Cl2,
5.75 mmol) was added dropwise to a magnetically stirred solu-
tion of pyrrole 16 (539 mg, 2.3 mmol) in dry CH2Cl2 (50 mL)
maintained at −78◦C under a nitrogen atmosphere. The reac-
tion mixture was allowed to warm to 18◦C overnight and then
quenched with water (15 mL) and the ensuing mixture was
concentrated under reduced pressure. The residue so obtained
was extracted with ethyl acetate (4 × 20 mL) and the combined
organic phases were washed with brine (1 × 15 mL) before being
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure to afford a yellow oil. Trituration of this material (ethyl
acetate/hexane) gave the catechol 11[9] (157 mg, 34%) as white
crystals, mp 102–103◦C (RF 0.4 in 1/1 v/v ethyl acetate/hexane)
[Found: C 70.8, H 6.4, N 6.8; (M + H)+ 204.1015. C12H13NO2
requires C 70.9, H 6.5, N 6.9%; (M + H)+ 204.1025]. δH
(CDCl3, 300 MHz) 6.76 (d, J 8.0, 1H), 6.60 (t, J 2.1, 2H), 6.56–
6.50 (complex m, 2H), 6.14 (t, J 2.1, 2H), 5.42 (s, OH), 5.28 (s,
OH), 4.05(t, J7.2, 2H), 2.93(t, J7.2, 2H). δC (CDCl3, 75.5 MHz)
143.5 (C), 142.1 (C), 131.7 (C), 121.3 (CH), 120.8 (CH), 115.9
(CH), 115.6 (CH), 108.0 (CH), 51.4 (CH2), 37.7 (CH2). νmax
(NaCl)/cm−1 3401, 2928, 2872, 1603, 1520, 1499, 1444, 1357,
1281, 1189, 1111, 1089, 1069, 815, 726. m/z (ESI) 204 [100%,
(M + H)+].
N-Acetyldopamine
Treatment of N-(3,4-dimethoxyphenethyl)acetamide with
boron tribromide in CH2Cl2 at −78◦C under the same condi-
tions as used in the conversion described immediately above
afforded, after workup, the title compound[23] (45%) as a clear,
colourless oil (RF 0.2 in 1/9 v/v methanol/CH2Cl2) [Found:
(M + H)+ 196.0961. C10H13NO3 requires (M + H)+ 196.0794].
δH [(CD3)2SO, 300 MHz] 7.89 (m, 1H), 6.63 (d, J 7.1, 1H),
6.57 (d, J 2.1, 1H), 6.42 (dd, J 7.1 and 2.1, 1H), 3.16 (m,
2H), 2.50 (t, J 7.5, 2H), 1.78 (s, 3H), signals due to OH pro-
tons not observed. δC (CD3OD, 75.5 MHz) 173.2 (C), 146.3
(C), 144.8 (C), 132.0 (C), 121.0 (CH), 116.8 (CH), 116.3 (CH),
42.4 (CH2), 35.9 (CH2), 22.6 (CH3). νmax (NaCl)/cm−1 3273,
2927, 2855, 1643, 1528, 1443, 1374, 1287, 1198, 1117, 1046,
1023, 1000, 819. m/z (ESI) 218 [45%, (M + Na)+], 196 [35,
(M + H)+], 85 (100).
Pyrrolo[2,1-a]isoquinoline-8,9-diol (21)
Boron tribromide (0.70 mL of a 1 M solution in CH2Cl2,
0.694 mmol) was added dropwise to a magnetically stirred solu-
tion of pyrrole 22 (53 mg, 0.231 mmol) in dry CH2Cl2 (40 mL)
maintained at −78◦C under a nitrogen atmosphere. The ensu-
ing mixture was allowed to warm to 18◦C overnight and was
then quenched with water (20 mL) and NaHCO3 (10 mL of a
saturated aqueous solution).The resulting mixture was extracted
with CH2Cl2 (3 × 30 mL) and the combined organic phases were
washed with brine (1 × 20 mL), before being dried (Na2SO4),
filtered, and concentrated under reduced pressure to afford a
yellow oil. Subjection of this material to flash chromatography
(silica, CH2Cl2 elution) and concentration of the relevant frac-
tions (RF 0.3) under reduced pressure afforded catechol 21
(14 mg, 31%) as a light-yellow oil [Found: M+• 201.0790.
C12H11NO2 requires M+• 201.0790]. δH (300 MHz, CDCl3)
6.67 (s, 1H), 6.37 (s, 1H), 6.32 (s, 1H), 6.28–6.23 (complex
m, 2H), 4.62 (br s, 2H), 3.16 (t, J 6.3, 2H), 2.17 (t, J 6.3, 2H).
δC (75 MHz, CDCl3) 142.7 (C), 142.1 (C), 129.9 (C), 124.0 (C),
123.3 (C), 120.6 (CH), 115.3 (CH), 110.0 (CH), 108.5 (CH),
102.6 (CH), 44.5 (CH2), 29.1 (CH2). δC (75.5 MHz, C6D6) 142.7
(C), 142.6 (C), 129.9 (C), 123.8 (C), 123.2 (C), 120.3 (CH),
115.2 (CH), 109.7 (CH), 108.7 (CH), 102.9 (CH), 43.9 (CH2),
28.8 (CH2). νmax (NaCl)/cm−1 3401, 2918, 2849, 1601, 1558,
1509, 1461, 1334, 1278, 1201, 1126, 1072, 871, 803, 714. m/z
(EI, 70 eV) 201 (100%, M+•), 184 (4), 172 (5), 154 (6), 100 (6),
77 (11).
N-Acetyldopaminequinone
Method A: A solution of DDQ (45 mg, 0.20 mmol) in
CD3OD (0.5 g) was added to a 5 mm (i.d.) NMR tube contain-
ing N-acetyldopamine (39 mg, 0.20 mmol) in CD3OD (0.5 g)
maintained at 18◦C. 1H NMR analysis (300 MHz) of the
resulting solution, undertaken immediately after mixing, sug-
gested complete and clean conversion of the substrate into
N-acetyldopaminequinone.[24] δH (CD3OH, 300 MHz) 7.11 (dd,
J 10.2 and 2.1, 1H), 6.36 (d, J 10.2, 1H), 6.22 (br s, 1H), 3.45 (t,
J 6.6, 2H), 2.61 (broad t, J 6.6, 2H), 1.93 (s, 3H), signal due to
NH proton not observed.
Method B: PIFA[22] (128 mg, 0.28 mmol) was added to
a magnetically stirred solution of N-acetyldopamine (53 mg,

88
L. C. Axford et al.
3,4-Diiodo-1-(triisopropylsilyl)-1H-pyrrole (24)
bromide (14) (345 mg, 1.41 mmol) was added and the resulting
solution was stirred at room temperature for 2 h.A further aliquot
of 3,4-dimethoxyphenethyl bromide (115 mg, 0.05 mmol) was
added and the ensuing solution was stirred for an addi-
tional 2 h. The reaction mixture was then treated with water
(20 mL) and extracted into ethyl acetate (4 × 15 mL). The com-
bined organic phases were washed with water (1 × 50 mL)
and brine (1 × 50 mL) and then dried (MgSO4) and the sol-
vent removed under reduced pressure. The residue so obtained
was subject to flash chromatography (silica, 3/7 → 1/1 v/v
CH2Cl2/hexanegradientelution)andconcentrationoftheappro-
priate fractions (RF 0.2 in 1/1 v/v CH2Cl2/hexane) furnished
the title compound 27 (110 mg, 61%) as a white foam [Found:
(M + H)+ 384.1968. C26H25NO2 requires (M + H)+ 384.1964].
δH (300 MHz, CDCl3) 7.31–7.19 (complex m, 10H), 6.86 (d, J
8.1, 1H), 6.79–6.73 (complex m, 3H), 6.49 (d, J 2.0, 1H), 4.15
(app. t, J 6.9, 2H), 3.92 (s, 3H), 3.81 (s, 3H), 3.09 (app. t, J 6.9,
2H). δC (75.5 MHz, CDCl3) 148.8, 147.7, 135.8, 130.8, 128.3,
128.1, 125.5, 123.1, 120.5, 120.3, 111.8, 111.1, 55.9, 55.6, 51.6,
37.7. νmax (NaCl)/cm−1 3027, 2932, 2833, 1702, 1601, 1539,
1515, 1463, 1441, 1262, 1155, 1028, 762, 699. m/z (ESI) 406
[79%, (M + Na)+], 384 [94, (M + H)+], 165 (100), 125 (26).
A solution of molecular iodine (4.46 g, 17.56 mmol) in
CH2Cl2 (100 mL) was added, dropwise over 1 h, to a magneti-
cally stirred suspension of N-trisisopropylsilyl (23)[26] (1.78 g,
7.98 mmol) and mercury (II) acetate (5.60 g, 17.56 mmol) in
CH2Cl2 (100 mL) maintained at 0◦C. The resulting yellow sus-
pension was stirred for a further 1.5 h and the solvent was then
removed under reduced pressure to give a yellow oil. Hexane
(20 mL) was added to this material and the resulting suspension
was filtered through a pad of Celite.The filtrate was concentrated
underreducedpressureandtheresiduesoobtainedwassubjected
to flash chromatography (neutral alumina, hexane elution). Con-
centration of the appropriate fractions (RF 0.4) furnished the title
compound 24[26] (2.18 g, 58%) as a white, crystalline solid, mp
74–76◦C (lit.[26] mp 75–78◦C). The spectroscopic data derived
from this material were in good agreement with those reported
in the literature.[26]
3,4-Diphenyl-1-(triisopropylsilyl)-1H-pyrrole (25)
Phenyl magnesium bromide (0.45 mL of a 3 M solution
in diethyl ether, 1.34 mmol) was added to a magnetically
stirred solution of pyrrole 24 (159 mg, 0.335 mmol) and
palladium (II) chloride·1,1ꢀ-bis(diphenylphosphino)ferrocene
[PdCl2(dppf)] (complex with CH2Cl2, 14 mg, 0.017 mmol) in
THF (5 mL) maintained under argon. The resulting mixture was
heated at 60◦C for 5 h and then allowed to cool to 18◦C and
treated with NH4Cl (5 mL of a saturated aqueous solution). The
ensuing mixture was extracted with diethyl ether (4 × 15 mL)
and the combined organic phases were washed with brine
(1 × 50 mL) and then dried (MgSO4), filtered, and concentrated
under reduced pressure. Subjection of the resulting oil to flash
chromatography (silica, hexane → 2/98 v/v CH2Cl2/hexane elu-
tion) and concentration of appropriate fractions (RF 0.35 in 1/5
v/v CH2Cl2/hexane) under reduced pressure afforded a solid
that upon recrystallization (hexane) gave the title compound
25[28] (97 mg, 77%) as white crystals, mp 135–136◦C (lit.[28] mp
134–135◦C) [Found: (M + H)+ 376.2478. C25H33NSi requires
(M + H)+ 376.2461]. δH (CDCl3, 300 MHz) 7.34–7.14 (com-
plex m, 10H), 6.86 (s, 2H), 1.50 (heptet, J 7.5, 3H), 1.16 (d, J
7.5, 18H). δC (CDCl3, 75.5 MHz) 136.2 (C), 128.4 (CH), 128.1
(CH), 125.4(CH), 125.4(C), 123.8(CH), 17.9(CH3), 11.6(CH).
νmax (NaCl)/cm−1 2946, 2866, 1602, 1532, 1461, 1362, 1338,
1240, 1106, 1072, 1017. m/z (ESI) 376 [100%, (M + H)+].
1-[(3ꢀ,4ꢀ-Dihydroxyphenyl)ethyl]-3,4-diphenylpyrrole
(12)
Boron tribromide (180 µL, 1 M in CH2Cl2, 0.180 mmol)
was added dropwise to a magnetically stirred solution of pyr-
role 27 (23 mg, 0.060 mmol) in anhydrous CH2Cl2 (10 mL)
maintained under nitrogen at −78◦C. The resulting yellow
solution was allowed to warm to 18◦C over 15 h and then
quenched with water (20 mL) and NaHCO3 (20 mL of a
2 M aqueous solution). The resulting mixture was extracted
into CH2Cl2 (4 × 10 mL) and the combined organic phases
were then washed with brine (1 × 50 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure.
The yellow oil thus obtained was subjected to flash chro-
matography (silica, 1/1 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (RF 0.7) furnished
the title compound 12 (20 mg, 95%) as a pale-yellow oil
[Found: (M + H)+ 356.1665; (M + Na)+ 378.1465. C24H22NO2
requires (M + H)+ 356.1651; (M + Na)+ 378.1470]. δH
(300 MHz, CDCl3) 7.19–7.29 (complex m, 10H), 6.82 (d, J
8.1, 1H), 6.73 (s, 2H), 6.61–6.66 (complex m, 2H), 5.28 (s,
1H), 5.19 (s, 1H), 4.09 (app. t, J 7.4, 2H), 3.02 (app. t, J 7.4,
2H). δC (75.5 MHz, CDCl3) 143.8, 142.4, 136.2, 131.6, 128.6,
128.4, 125.8, 123.4, 121.5, 120.5, 116.1, 115.8, 51.7, 37.8.
νmax (NaCl)/cm−1 3401, 3053, 2926, 1601, 1538, 1518, 1441,
1395, 1358, 1281, 1179, 909, 761, 699. m/z (ESI) 378 [18%,
(M + Na)+], 356 [100, (M + H)+], 220 (18), 149 (27), 137 (45),
71 (25).
3,4-Diphenyl-1H-pyrrole (26)
TBAF (6.40 mL of a 1.0 M inTHF, 6.40 mmol) was added to a
magnetically stirred solution of pyrrole 25 (480 mg, 1.28 mmol)
in THF (50 mL). After 5 min the volatile components were
removed under reduced pressure and the residue subjected to
flash chromatography (silica, 1/1 v/v CH2Cl2/hexane elution).
Concentration of the appropriate fractions (RF 0.2) furnished
the title compound 26[29] (278 mg, 99%) as a pale-orange solid,
mp 95–96◦C (lit.[29] mp 94.5–95.5◦C). The spectroscopic data
derived from this material were in good agreement with those
reported in the literature.[29]
5,6-Dihydro-8,9-dimethoxy-1,2-diphenylpyrrolo
[2,1-a]isoquinoline (29)
Boron trifluoride diethyl etherate (178 mg, 0.465 mmol) was
added to a magnetically stirred solution of PIFA (240 mg,
0.558 mmol) in anhydrous CH2Cl2 (30 mL) maintained under
nitrogen and the resulting solution was cooled to 0◦C. This solu-
tion was added, through a cannula, to a magnetically stirred solu-
tion of pyrrole 27 (178 mg, 0.465 mmol) in anhydrous CH2Cl2
(30 mL) maintained at −40◦C (MeCN/dry ice). The ensuing
mixture was stirred at −40◦C for 3 h and then additional PIFA
(20 mg) was added.After another 2.5 h, the reaction mixture was
treated with ammonia (3 mL of 12% aqueous solution) and water
1-[(3ꢀ,4ꢀ-Dimethoxyphenyl)ethyl]-3,4-diphenylpyrrole
(27)
Sodium hydride (21 mg, 60% in mineral oil, 0.52 mmol) was
added to a magnetically stirred solution of pyrrole 26 (103 mg,
0.47 mmol) in anhydrous N,N-dimethylformamide (DMF, 3 mL)
maintainedundernitrogen.After2 min, 3,4-dimethoxyphenethyl

Biogenesis of the Pentacyclic Lamellarins
89
(10 mL) and then extracted into CH2Cl2 (4 × 20 mL). The com-
bined organic phases were washed with brine (1 × 80 mL) and
then dried (MgSO4), filtered, and concentrated under reduced
pressure. The resulting light-yellow oil was subjected to flash
chromatography (silica, 1/4 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (RF 0.3) furnished the
title compound 29 (70 mg, 40%) as a white crystalline solid, mp
147–149◦C [Found: (M + H)+ 382.1817. C26H23NO2 requires
(M + H)+ 382.1807]. δH (300 MHz, CDCl3) 7.49–7.19 (com-
plex m, 10H), 6.98 (br s, 1H), 6.80 (s, 1H), 6.62 (s, 1H), 4.21
(t, J 6.6, 2H), 3.96 (s, 3H), 3.42 (s, 3H), 3.17 (app. t, J 6.6,
2H). δC (75.5 MHz, CDCl3) 147.2, 146.7, 136.8, 135.5, 131.2,
128.5, 128.0, 127.8, 126.5, 125.2, 124.1, 123.9, 122.2, 118.3,
111.0, 107.4, 55.8, 55.0, 44.7, 29.4, signals due to two carbons
obscured or overlapping. νmax (NaCl)/cm−1 2930, 1601, 1549,
1535, 1506, 1465, 1407, 1334, 1264, 1216, 1182, 1124, 1026,
910, 863, 801, 700. m/z (ESI) 404 [28%, (M + Na)], 382 [100,
(M + H)+], 165 (40), 149 (70), 102 (32).
resulting pale-yellow oil was subjected to flash chromatogra-
phy (silica, 1/1 v/v ethyl acetate/hexane elution). Concentration
of the appropriate fractions (RF 0.5, 1/1 v/v pentane/diethyl
ether, visualized using a KMnO4-based stain) furnished the title
compound 33[31] (4.47 g, 100%) as a pale-yellow oil. The spec-
troscopic data derived from this material matched those reported
in the literature.[31]
Methyl 3-Bromo-1-(tert-butoxycarbonyl)pyrrole-
2-carboxylate (34)
NBS (139 mg, 0.78 mmol) was added to a solution of the
proline derivative 33 (51 mg, 0.22 mmol) in carbon tetrachlo-
ride (25 mL) and the resulting suspension was heated to 85◦C
for 1 h. The reaction mixture was then cooled to 0◦C and
the precipitated succinimide removed by filtration. The fil-
trate was concentrated under reduced pressure and the yellow
oil thus obtained was subjected to flash chromatography (sil-
ica, 3/7 v/v ethyl acetate/hexane elution). Concentration of the
appropriate fractions (RF 0.9 in 1/1 v/v ethyl acetate/hexane)
furnished the title compound 34 (47 mg, 69%) as a pale-yellow
oil [Found: (M + Na)+ 326.0014. C11H1479BrNO4 requires
(M + Na)+ 326.0004]. δH (300 MHz, CDCl3) 7.22 (d, J 3.6, 1H),
6.24 (d, J 3.6, 1H), 3.91 (s, 3H), 1.57 (s, 9H). δC (75.5 MHz,
CDCl3) 161.0, 147.1, 124.0, 123.4, 114.0, 106.2, 85.5, 52.2,
27.4. νmax (NaCl)/cm−1 3147, 2982, 2952, 1756, 1732, 1542,
1457, 1405, 1371, 1311, 1254, 1220, 1154, 1092, 926, 844, 771,
741. m/z (ESI) 328 and 326 [both 37%, (M + Na)+], 272 and
270 (both 64), 228 (31), 218 and 216 (both 30), 60 (100).
5,6-Dihydro-8,9-dihydroxy-1,2-diphenylpyrrolo
[2,1-a]isoquinoline (28)
Boron tribromide (340 µL of a 1 M solution in CH2Cl2,
0.34 mmol) was added dropwise to a magnetically stirred solu-
tion of pyrrole 29 (43 mg, 0.11 mmol) in anhydrous CH2Cl2
(20 mL) maintained under nitrogen at −78◦C. The resulting yel-
low solution was allowed to warm to 18◦C over 14 h and then
quenched with water (20 mL) and NaHCO3 (20 mL of saturated
aqueous solution). The resulting mixture was extracted with
CH2Cl2 (4 × 15 mL) and the combined organic phases were then
washed with brine (1 × 80 mL) before being dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The yellow oil
thus obtained was subjected to flash chromatography (silica, 1/4
v/v ethyl acetate/hexane) to afford two fractions, A and B.
Concentration of fraction A (RF 0.3 in 1/4 v/v ethyl acetate/
hexane) afforded the starting pyrrole 29 (5 mg, 12% recovery) as
a white crystalline solid that was identical, in all respects, with
an authentic sample.
Concentration of fraction B (RF 0.4 in 1/1 v/v ethyl acetate/
hexane) furnished the title compound 28 (21 mg, 53% at 88%
conversion) as a pale-orange oil [Found: (M + H)+ 354.1480;
(M + Na)+ 376.1320. C24H19NO2 requires(M + H)+ 354.1494;
(M + Na)+ 376.1313]. δH (300 MHz, CD3OD) 7.34–7.20 (com-
plex m, 5H), 7.10–6.98 (complex m, 5H), 6.87 (s, 1H), 6.63 (s,
1H), 6.45 (s, 1H), 4.03 (t, J 6.3, 2H), 2.92 (t, J 6.3, 2H), sig-
nals due to OH protons not observed. δC (75.5 MHz, CD3OD)
144.6(5), 144.5(9), 138.7, 137.5, 132.3, 129.5, 129.0, 128.8,
127.6, 127.4, 125.9, 125.7, 125.3, 122.9, 119.5, 119.4, 116.0,
112.7, 45.7, 30.6. νmax (NaCl)/cm−1 3479, 1599, 1506, 1394,
1330, 1274, 1174, 1118, 876, 809, 739, 702. m/z (ESI) 391 [8%,
(M + K)+], 376 [8, (M + Na)+], 354 [100, (M + H)+], 149 (46),
102 (48).
Methyl 3-Bromopyrrole-2-carboxylate (35)
Zinc bromide (860 mg, 3.82 mmol) was added to a mag-
netically stirred solution of pyrrole 34 (583 mg, 1.91 mmol) in
CH2Cl2 (60 mL) maintained under nitrogen at 18◦C. Further
aliquots of zinc bromide (200 mg) were added after 2 h and after
4 h. After a total of 5 h, the reaction mixture was treated with
NaHCO3 (50 mL of a saturated aqueous solution) and water
(50 mL), and then extracted with ethyl acetate (4 × 60 mL). The
combined organic phases were washed with water (1 × 200 mL)
and brine (1 × 200 mL) before being dried (MgSO4), filtered,
and concentrated under reduced pressure. The ensuing light-
yellow oil was subjected to flash chromatography (silica, 1/4
v/v ethyl acetate/hexane) and concentration of the appropri-
ate fractions (RF 0.6 in 1/1 v/v ethyl acetate/hexane) afforded
a solid that upon recrystallization (ethyl acetate/hexane) fur-
nished the title compound 35 (347 mg, 89%) as white blocks,
mp 202–204◦C [Found: (M + Na)+ 225.9476. C6H679BrNO2
requires (M + Na)+ 225.9480]. δH (300 MHz, CDCl3) 9.59 (br
s, 1H), 6.89 (t, J 3.0, 1H), 6.34 (t, J 3.0, 1H), 3.90 (s, 3H). δC
(75.5 MHz, CDCl3) 160.8, 122.8, 119.9, 114.7, 103.6, 51.7. δmax
(NaCl)/cm−1 3302, 3136, 2951, 1684, 1541, 1445, 1399, 1316,
1210, 1129, 1075, 1006, 933, 889, 775. m/z (ESI) 228 and 226
[both 7%, (M + Na)+], 206 and 204 (both 58), 174 and 172 (both
100), 102 (32).
L-N-tert-Butoxycarbonyl Proline Methyl Ester (33)
Hünig’s base (16.9 mL, 97.3 mmol) was added to a
magnetically stirred solution of proline methyl ester hydrochlo-
ride (32)[31] (3.22 g, 19.5 mmol), di-tert-butyl dicarbonate
(8.48 g, 38.9 mmol), and DMAP (240 mg, 1.95 mmol) in anhy-
drous DMF (20 mL) maintained under a nitrogen atmosphere.
The resulting solution was stirred at 18◦C for 15 h and then
treated with water (100 mL) and extracted with diethyl ether
(5 × 40 mL). The combined organic phases were washed with
water (2 × 100 mL) and brine (1 × 100 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure.The
Methyl 3-Bromo-1-methylpyrrole-2-carboxylate (36)
Sodium hydride (87 mg, 60% dispersion in mineral oil,
2.18 mmol) was added to a magnetically stirred solution of
pyrrole 35 (404 mg, 1.98 mmol) in anhydrous DMF (10 mL)
maintained under nitrogen. Methyl iodide (0.25 mL, 3.96 mmol)
was then added and the ensuing mixture stirred for 17 h at
18◦C. The resulting mixture was treated with water (50 mL)
and extracted into ethyl acetate (4 × 25 mL). The combined
organic phases were washed with water (2 × 50 mL) and brine

90
L. C. Axford et al.
(1 × 50 mL) before being dried (MgSO4), filtered, and con-
centrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica, 1/4 v/v ethyl
acetate/hexane elution) and concentration of the appropriate
fractions (RF 0.6) furnished the title compound 36 (400 mg,
93%) as a clear, colourless oil [Found: (M + H)+ 217.9818.
C7H879BrNO2 requires (M + H)+ 217.9817]. δH (300 MHz,
CDCl3) 6.68 (d, J 2.7, 1H), 6.19 (d, J 2.7, 1H), 3.86 (s, 3H), 3.85
(s, 3H). δC (75.5 MHz, CDCl3) 160.8, 128.6, 120.1, 112.4, 104.5,
51.0, 38.4. νmax (NaCl)/cm−1 3116, 2952, 1700, 1513, 1435,
1403, 1320, 1259, 1110, 1026, 924, 807, 771. m/z (ESI) 242 and
240 [both 6%, (M + Na)+], 220 and 218 (both 60), 188 and 186
(both 100), 161 and 159 (both 10), 149 (16), 139 (16), 95 (52).
acetate/hexane/acetic acid elution) and concentration of the
appropriate fractions (RF 0.2 in 1/1 v/v ethyl acetate/hexane) fur-
nished a solid that was recrystallized (methanol) to give the title
compound 38 (74 mg, 73%) as white crystals, no mp, decom-
position above 230◦C [Found: (M − H)− 260.0911. C14H15NO4
requires (M − H)− 260.0923]. δH (300 MHz, CDCl3) 7.04–7.00
(complex m, 2H), 6.89 (d, J 8.1, 1H), 6.84 (d, J 2.6, 1H), 6.18
(d, J 2.6, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), signal
of CO2H proton not observed. δC (75.5 MHz, CDCl3) 166.3,
148.0, 147.9, 135.9, 129.6, 128.8, 121.7, 117.5, 113.2, 110.7,
110.4, 55.8 (two signals overlapping), 38.3. νmax (NaCl)/cm−1
2996, 1660, 1583, 1543, 1512, 1450, 1373, 1350, 1302, 1252,
1233, 1132, 1024, 944, 803, 725. m/z (ESI, −ve ion) 543 {55%,
2[(M − H)− + Na+)]}, 397 (25), 280 (42), 260 (38), 216 (70),
62 (100).
Methyl 3-(3,4-Dimethoxyphenyl)-1-methyl-1H-pyrrole-
2-carboxylate (37)
In each of three 12 (i.d.) × 85 mm2 glass reaction tubes
were placed pyrrole 36 (94 mg, 0.43 mmol) in toluene
(1.5 mL), K2CO3 (476 mg, 3.45 mmol) in water (1.5 mL),
tetra-n-butylammonium bromide (14 mg, 0.04 mmol), and 3,4-
dimethyoxyphenyl boronic acid (118 mg, 0.65 mmol). The tubes
were flushed with argon, (PPh3)4Pd (13 mg, 0.01 mmol) was
added, and the tubes were flushed with argon once more. Each
of the tubes was subjected to microwave irradiation (100W,
110◦C, 2 min ramp time) for 1 h. The contents of the tubes
were combined, Na2CO3 (5 mL of a saturated aqueous solution)
was added, and the mixture was extracted with ethyl acetate
(4 × 30 mL). The combined organic phases were washed with
brine (1 × 50 mL) before being dried (MgSO4), filtered, and
concentrated under reduced pressure. The ensuing light-yellow
oil was subjected to flash chromatography (silica, 1/9 → 1/5
v/v ethyl acetate/hexane gradient elution). Concentration of the
appropriate fractions (RF 0.2 in 1/4 v/v ethyl acetate/hexane)
affordedasolidthatuponrecrystallization(ethylacetate/hexane)
gave the title compound 37 (343 mg, 96%) as a white crys-
talline solid, mp 195–196◦C [Found: (M + Na)+ 298.1059.
C15H17NO4 requires (M + Na)+ 298.1055]. δH (300 MHz,
CDCl3) 7.12–6.94 (complex m, 2H), 6.87 (d, J 8.7, 1H), 6.78
(d, J 2.7, 1H), 6.15 (d, J 2.7, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.88
(s, 3H), 3.68 (s, 3H). δC (75.5 MHz, CDCl3) 162.1, 147.8, 147.7,
133.7, 129.3, 128.3, 121.4, 119.0, 112.9, 110.3, 110.1, 55.7(1),
55.6(7), 50.7, 37.7. νmax (NaCl)/cm−1 2997, 2950, 2834, 1697,
1606, 1584, 1541, 1510, 1438, 1395, 1293, 1252, 1232, 1111,
1028, 784. m/z (ESI) 298 [48%, (M + Na)+], 276 [9, (M + H)+],
244 (100), 213 (22), 102 (36).
4-(1-Methyl-1H-pyrrol-3-yl)benzene-1,2-diol (39)
Boron tribromide (0.83 mL of a 1.0 M solution in CH2Cl2,
0.83 mmol) was added, dropwise, to a magnetically stirred solu-
tion of pyrrole 38 (72 mg, 0.28 mmol) in anhydrous CH2Cl2
(40 mL) maintained under nitrogen at −78◦C. The resulting
yellow solution was allowed to warm to 18◦C over 13 h and
then quenched with water (50 mL). The ensuing mixture was
extracted into CH2Cl2 (4 × 20 mL) and the combined organic
phases were washed with brine (1 × 100 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure.
The residue thus obtained was subjected to flash chromato-
graphy (silica, 1/1 v/v ethyl acetate/hexane elution) and con-
centration of the appropriate fractions (RF 0.7) furnished the
title compound 39 (38 mg, 73%) as a yellow solid [Found:
(M + H)+ 190.0869. C11H11NO2 requires (M + H)+ 190.0868].
δH (300 MHz, CDCl3) 7.02 (d, J 2.0, 1H), 6.96 (dd, J 8.1 and 2.0,
1H), 6.83 (d, J 8.1, 1H), 6.80 (t, J 2.0, 1H), 6.61 (t, J 2.5, 1H), 6.34
(dd, J 2.5 and 2.0, 1H), 5.25 (br s, 1H), 5.11 (br s, 1H), 3.67 (s,
3H). δC (75.5 MHz, CDCl3) 143.6, 141.2, 129.8, 124.5, 122.6,
118.0, 117.7, 115.7, 112.3, 106.0, 36.3. νmax (NaCl)/cm−1 3425,
2940, 1602, 1561, 1513, 1441, 1365, 1274, 1255, 1199, 1164,
1111, 866, 777. m/z (ESI) 190 [100%, (M + H)+], 172 (43), 160
(36), 144 (21), 102 (20), 82 (35).
tert-Butyl 4-Oxochromeno[3,4-b]pyrrole-3(4H)-
carboxylate (42)
A mixture of pyrrole 34 (70 mg, 0.231 mmol), potassium
carbonate (160 mg, 1.155 mmol), tetra-n-butylammonium bro-
mide (15 mg, 0.046 mmol), 2-hydroxyphenylboronic acid pina-
col ester (70 mg, 0.318 mmol), Pd(PPh3)4 (13 mg, 0.012 mmol),
THF (3 mL), and water (1 mL) was subjected to microwave
irradiation (150 W, 70◦C, 2 min ramp time) for 1 h in a CEM
Discover apparatus. The cooled reaction mixture was then
treated with Na2CO3 (10 mL of a saturated aqueous solu-
tion) and the ensuing mixture extracted with ethyl acetate
(3 × 30 mL). The combined organic phases were washed with
brine (1 × 30 mL) and then dried (Na2SO4), filtered, and con-
centrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica, 5/1 v/v pentane/
diethyl ether elution) and concentration of the appropriate
fractions (RF 0.2) yielded a white solid. Recrystallization
(pentane/diethyl ether) of this material furnished the title lac-
tone 42 (51 mg, 78%) as colourless prisms, mp 94–96◦C [Found:
(M + H)+ 286.1080. C16H15NO4 requires (M + H)+ 286.1079].
δH (300 MHz, CDCl3) 7.78 (d, J 3.3, 1H), 7.78–7.71 (complex
m, 1H), 7.48–7.36 (complex m, 2H), 7.34–7.24 (complex m,
1H), 6.77 (d, J 3.3, 1H), 1.68 (s, 9H). δC (75.5 MHz, CDCl3)
3-(3,4-Dimethoxyphenyl)-1-methyl-1H-pyrrole-
2-carboxylic Acid (38)
Sodium hydroxide solution (2 mL of a 2 M solution in water)
was added to a solution of pyrrole 37 (106 mg, 0.39 mmol) in
MeOH (6 mL) and the ensuing mixture stirred magnetically
at 18◦C for 4 h. Any insoluble material so-formed was then
dissolved by the addition of acetonitrile (2 mL). The resulting
solution was stirred for a further 1 h at 18◦C and then heated
to 85◦C for 4 h. The now light-yellow solution was cooled
to 18◦C and stirred at this temperature for an additional 12 h
before being concentrated under reduced pressure. The ensuing
residue was acidified to pH 1 with hydrochloric acid (1 M aque-
ous solution) and extracted with ethyl acetate (4 × 20 mL). The
combined organic phases were washed with brine (1 × 100 mL)
and then dried (MgSO4), filtered, and concentrated under
reduced pressure. The ensuing light-yellow oil was subjected
to flash chromatography (silica using 50/49.5/0.5 v/v/v ethyl

Biogenesis of the Pentacyclic Lamellarins
91
152.6, 152.4, 148.0, 135.9, 132.6, 129.8, 129.6, 124.3, 123.8,
117.1, 116.8, 104.7, 86.3, 30.0. νmax (NaCl)/cm−1 2979, 2869,
1775, 1743, 1353, 1295, 1258, 1145, 1066, 754, 713. m/z (ESI)
308 [(M + Na)+, 77%], [(M + H)+, ∼0.1], 252 (65), 230 (100).
0◦C. This solution was added, through a cannula, to a magnet-
ically stirred solution of pyrrole 44 (110 mg, 0.314 mmol) in
anhydrous CH2Cl2 (150 mL) maintained at −40◦C.The ensuing
mixturewasstirredat−40◦Cfor3 handthentreatedwithammo-
nia (4 mL of a 12% w/v aqueous solution) and water (20 mL)
before being extracted with CH2Cl2 (3 × 20 mL). The combined
organic phases were washed with brine (1 × 20 mL) and then
dried (Na2SO4) and the solvent removed under reduced pressure.
The residue thus obtained was subjected to flash chromato-
graphy (silica, 1/1 v/v pentane/diethyl elution). Concentration
of the appropriate fractions (RF 0.2) then furnished compound
45 (9 mg, 9%) as a clear, colourless oil [Found: (M + Na)+
344.1267. C20H19NNaO3 requires (M + Na)+ 344.1263]. δH
(300 MHz, CDCl3) 7.34–7.15 (complex m, 2H), 7.04–6.91
(complex m, 2H), 6.77 (d, J 2.7, 1H), 6.68 (s, 1H), 6.63 (s, 1H),
6.21 (d, J 2.7, 1H), 5.51 (s, 1H), 4.11 (t, J 6.3, 2H), 3.85 (s, 3H),
3.38 (s, 3H), 3.05 (t, J 6.3, 2H). δC (75.5 MHz, CDCl3) 153.9,
148.0, 147.4, 131.5, 129.1, 126.6, 123.8, 122.0, 121.1, 120.6,
115.1, 113.1, 111.3, 110.6, 106.8, 56.1, 55.4, 45.1, 29.6 (one
signal obscured or overlapping). νmax (NaCl)/cm−1 3436, 1643,
1508, 1463, 1330, 1285, 1251, 1208, 1138, 1029, 864, 795, 757,
731. m/z (ESI) 344 [(M + Na)+, 100%], 322 [(M + H)+, 95].
Chromeno[3,4-b]pyrrole-4(3H)-one (43)
Zinc bromide (250 mg, 1.110 mmol) was added to a mag-
netically stirred solution of lactone 42 (77 mg, 0.269 mmol) in
CH2Cl2 (10 mL) maintained under nitrogen. The ensuing mix-
ture was stirred for 20 h at 18◦C and then treated with sodium
hydrogen carbonate (20 mL of a saturated aqueous solution) and
water (20 mL). The ensuing mixture was extracted with ethyl
acetate (4 × 20 mL). The combined organic phases were washed
with water (1 × 50 mL) and brine (1 × 50 mL) before being dried
(Na2SO4), filtered, and concentrated under reduced pressure.
The ensuing residue was subjected to flash chromatography
(silica, 1/1 v/v pentane/diethyl ether elution). Concentration of
the appropriate fractions (RF 0.2) then furnished compound 43
(46 mg, 93%) as a white solid, mp 191–193◦C (Found M+•
185.0479. C11H7NO2 requires M+• 185.0477). δH (300 MHz,
CDCl3) 10.46 (br s, 1H), 7.82 (ddd, J 7.8, 1.8 and 0.9, 1H),
7.49–7.29 (complex m, 4H), 6.78 (dd, J 2.7 and 2.1, 1H). δC
(75.5 MHz, CDCl3) 156.2, 151.5, 130.3, 129.2, 128.2, 124.7,
123.6, 118.2, 117.6, 117.3, 103.7. νmax (NaCl)/cm−1 3438, 3251,
2962, 1718, 1705, 1424, 1258, 1108, 1068, 799, 786, 758, 724,
706. EI MS m/z 185 (M+•, 45%), 81 (50), 69 (100).
Methyl 1-(3,4-Dimethoxyphenethyl)-3-bromo-
1H-pyrrole-2-carboxylate (46)
Sodium hydride (13 mg of a 60% dispersion in mineral oil,
0.325 mmol) was added to a magnetically stirred solution of pyr-
role 35 (40 mg, 0.119 mmol) in DMF (1.5 mL) and the ensuing
slurry was stirred at 18◦C for 0.5 h. 3,4-Dimethoxyphenethyl
bromide (14) (152 mg, 0.597 mmol) was then added to the reac-
tion mixture, which was stirred at 18◦C for 14 h before being
treated with water (20 mL). The resulting mixture was extracted
with ethyl acetate (4 × 10 mL) and the combined organic phases
were washed with water (2 × 5 mL) and brine (1 × 10 mL), and
then dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue thus obtained was subjected to flash
chromatography (silica, 1/1 v/v pentane/diethyl elution) and
concentration of the appropriate fractions (RF 0.2) afforded
compound 46 (44 mg, 61%) as a clear, colourless oil [Found:
(M + Na)+ 392.0291. C16H1881BrNNaO4 requires (M + Na)+
392.0296]. δH (300 MHz, CDCl3) 6.76 (d, J 8.1, 1H), 6.63 (dd, J
8.1 and 2.1, 1H), 6.48–6.41 (complex m, 2H), 6.14 (d, J 3.0, 1H),
4.45 (t, J 6.9, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 2.93
(t, J 6.9, 2H). δC (75.5 MHz, CDCl3) 161.2, 149.0, 147.9, 130.8,
128.8, 121.0, 119.6, 112.7, 112.1, 111.4, 105.5, 56.1, 56.0, 53.0,
51.5, 37.9. νmax (NaCl)/cm−1 2998, 2953, 2834, 1704, 1591,
1516, 1465, 1437, 1404, 1325, 1262, 1238, 1029, 806, 775, 633.
m/z (ESI) 392 and 390 [(M + Na)+, 100 and 98%], 338 and 336
(both 70).
3-(3,4-Dimethoxyphenethyl)chromeno[3,4-b]pyrrole-
4(3H)-one (44)
Sodium hydride (16 mg of a 60% dispersion in mineral
oil, 0.398 mmol) was added to a magnetically stirred solu-
tion of lactone 43 (46 mg, 0.249 mmol) in DMF (2 mL) and
the ensuing slurry was stirred at 18◦C for 0.25 h. After this
time 3,4-dimethoxyphenethyl bromide (190 mg, 0.747 mmol)
was added to the reaction mixture which was then stirred for 4 h
at 18◦C. The ensuing mixture was treated with water (20 mL)
and then extracted with ethyl acetate (4 × 10 mL). The com-
bined organic phases were washed with water (2 × 5 mL) and
brine (1 × 20 mL) before being dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica, 1/1 v/v pentane/
diethyl ether elution) and concentration of the appropriate frac-
tions (RF 0.2) furnished the title compound 44 (68 mg, 78%)
as a white solid, mp 120–139◦C [Found: (M + Na)+ 372.1209.
C21H19NNaO4 requires (M + Na)+ 372.1212]. δH (300 MHz,
CDCl3) 7.74 (dd, J 8.1 and 1.5, 1H), 7.43–7.24 (complex m,
3H), 6.85 (d, J 2.7, 1H), 6.76 (d, J 8.1, 1H), 6.65 (dd, J 8.1
and 2.1, 1H), 6.57 (d, J 1.8, 1H), 6.54 (d, J 2.7, 1H), 4.57 (t,
J 6.9, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.02 (t, J 6.9, 2H). δC
(75.5 MHz, CDCl3) 155.3, 151.5, 149.0, 147.9, 133.1, 130.8,
130.6, 128.0, 124.3, 123.1, 121.1, 118.3, 117.3, 115.8, 112.2,
111.4, 101.5, 56.1, 56.0, 51.2, 38.0. νmax (NaCl)/cm−1 3114,
2953, 1704, 1591, 1516, 1262, 1029, 807, 776, 633. m/z (ESI)
388 [(M + K)+, 5%], 372 [(M + Na)+, 100], 350 [(M + H)+,
95], 318 (10), 186 (10), 165 (15), 102 (11).
1-Bromo-5,6-dihydro-8,9-dimethoxypyrrolo
[2,1-a]isoquinoline (47)
Boron trifluoride diethyl etherate (19 mg, 0.134 mmol) was
added to a magnetically stirred solution of bis(trifluoroacetoxy)
iodobenzene (PIFA) (59 mg, 0.137 mmol) in anhydrous CH2Cl2
(25 mL) maintained under nitrogen. The resulting solution was
cooled to 0◦C and then added to a magnetically stirred solu-
tion of pyrrole 46 (42 mg, 0.114 mmol) in anhydrous CH2Cl2
(25 mL) maintained at −40◦C. The ensuing mixture was stirred
at −40◦C for 3 h and then treated with ammonia (4 mL of a 12%
w/v aqueous solution) and water (10 mL) before being extracted
into CH2Cl2 (3 × 30 mL). The combined organic phases were
2-(5,6-Dihydro-8,9-dimethoxypyrrolo[2,1-a]isoquinolin-
1-yl)phenol (45)
Boron trifluoride diethyl etherate (49 mg, 0.345 mmol) was
added to a magnetically stirred solution of PIFA (148 mg,
0.345 mmol) in anhydrous CH2Cl2 (100 mL) maintained under
a nitrogen atmosphere and the resulting solution was cooled to

92
L. C. Axford et al.
washed with brine (1 × 30 mL) and then dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography (silica,
1/1 v/v pentane/diethyl ether elution) and concentration of
the appropriate fractions (RF 0.2) afforded a solid that upon
recrystallization (pentane/diethyl ether) afforded compound 47
(10 mg, 29%) as clear, colourless crystals [Found: (M + Na)+
330.0123. C14H1479BrNNaO2 requires (M + Na)+ 330.0106].
δH (300 MHz, CDCl3) 6.97 (s, 1H), 6.70 (s, 1H), 6.60 (d, J 2.7,
1H), 6.23 (d, J 2.7, 1H), 4.00 (t, J 6.3, 2H), 3.92 (s, 3H), 3.88
(s, 3H), 2.97 (t, J 6.3, 2H). m/z (ESI) 332 and 330 [(M + Na)+,
both 40%], 301 (50), 229 (60), 149 (60), 130 (61), 102 (100).
The instability of this material precluded acquisition of the usual
range of spectroscopic data.
Dx 1.308 g cm−3, 2636 unique data (2θmax 55◦), 1982 with
I > 2.0σ(I), R 0.040; Rw 0.116, S 0.96.
Compound 35: C6H6BrNO2, M 204.02,T 200 K, orthorhom-
bic, space group Pna21, Z 4, a 5.7890(7), b 21.253(2),
c 5.8374(7) Å, V 718.20(14) Å3, Dx 1.887 g cm−3, 1544 unique
data (2θmax 55◦), 1337 with I > 2.0σ(I), R 0.037; Rw 0.061,
S 1.12.
Compound 42: C16H15NO4, M 285.30, T 200 K, tri-
clinic, space group P1, Z 4, a 8.5419(2), b 13.3119(2), c
13.6091(3) Å, α 67.8584(13)◦, β 77.1770(13)◦, γ 81.8995(14)◦,
V 1394.80(5) Å3, Dx 1.359 g cm−3, 6407 unique data (2θmax
55◦), 4538 with I > 2.0σ(I), R 0.034; Rw 0.086, S 0.89.
Compound 47: C14H14BrNO2, M 308.17,T 100(2) K, mono-
clinic, space group P21/c, Z 4, a 11.0145(7), b 13.8140(8),
c 8.4559(5) Å, β 104.029(3)◦, V 1248.23(13) Å3, Dx
1.640 g cm−3, 2183 unique data (2θmax 50◦), 1742 with
I > 2.0σ(I), R 0.057; Rw 0.169, S 1.12.
( )-Crispine A [( )-52]
A magnetically stirred solution of compound 22 (29 mg,
0.13 mmol) in ethanol (2 mL) that contained zinc (100 mg of
activated powder) and 10% Pd on C (14 mg) was heated to
reflux and then treated dropwise with HCl (1 mL of a 2 M aque-
ous solution). After 1 h, further quantities of zinc (90 mg) and
HCl (1 mL) were added and the ensuing mixture was heated
at reflux for an additional 0.5 h. The cooled reaction mixture
was filtered through a pad of Celite and the solids thus retained
were washed with dichloromethane (20 mL). The combined fil-
trates were washed with water (1 × 30 mL) and the separated
aqueous phase was treated with sufficient Na2CO3 (2 M aque-
ous solution) to attain a pH of 10. The resulting mixture was
extracted with dichloromethane (3 × 10 mL) and the combined
organic phases were then dried (Na2SO4), filtered, and con-
centrated under reduced pressure to give a light-grey solid.
Subjectionofthismaterialtocolumnchromatography(basicalu-
mina, 79/20/1 v/v/v ethyl acetate/hexane/triethylamine elution)
afforded, after concentration of the relevant fractions (RF 0.3),
( )-crispine A [( )-52] (26 mg, 88%) as a white solid. Recrys-
tallization (diethyl ether–pentane) of this material afforded a
spectroscopically clean sample of the title compound[36] as
colourless crystals, mp 77–85◦C (lit.[36c] 76–78◦C) [Found:
(M + H)+ 234.1484. C14H19NO2 requires (M + H)+ 234.1494].
δH (600 MHz, CDCl3) 6.61 (s, 1H), 6.57 (s, 1H), 3.85 (s, 3H),
3.84 (s, 3H), 3.40 (t, J 8.3, 1H), 3.18 (ddd, J 11.3, 6.2 and 2.9,
1H), 3.08 (m, 1H), 3.02 (m, 1H), 2.72 (dt, J 16.3 and 2.8, 1H),
2.63 (ddd, J 11.2, 10.6 and 4.8, 1H), 2.54 (dd, J 16.8 and 8.9,
1H), 2.32 (m, 1H), 1.92–1.83 (complex m, 1H), 1.83–1.74 (com-
plex m, 1H), 1.72 (m, 1H). δC (75.5 MHz, CDCl3) 147.5, 147.4,
131.3, 126.4, 111.5, 109.0, 63.2, 56.2, 56.1, 53.4, 48.6, 30.7,
28.3, 22.4. νmax 2934, 2832, 2788, 1609, 1511, 1463, 1375, 1261,
1229, 1213, 1137, 1089, 1015, 856, 763. m/z (ESI) 234 [100%,
(M + H)+].
Compound ( )-52: C14H19NO2, M 233.31, T 295 K, mono-
clinic, space group P21/n, Z 4, a 10.1600(3), b 7.8418(3), c
15.9492(5)Å, β 101.791(2)◦,V1243.90(7)Å3, Dx 1.246 g cm−3
,
2186 unique data (2θmax 50◦), 1196 with I > 2.0σ(I), R 0.036;
Rw 0.107, S 1.08.
Structure Determination
Images were measured on a Nonius Kappa CCD diffracto-
meter (MoKα, graphite monochromator, λ 0.71073 Å) and data
extracted using the DENZO package.[40] Structure solution
was by direct methods (SIR92).[41] The structures of com-
pounds 11, 22, 35, 42, 47, and ( )-52 were refined using the
CRYSTALS or SHELXL97 program packages.[42,43] Atomic
coordinates, bond lengths and angles, and displacement para-
meters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC numbers 653446, 657220, 653447, 665772,
664959, and 657221 for compounds 11, 22, 35, 42, 47, and
( )-52, respectively). These data can be obtained free-of-
charge from www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
Acknowledgements
We thank the Institute of Advanced Studies and the Australian Research
Council for generous financial support and the Gottlieb Daimler und Karl
Benz-Stiftung for the provision of a scholarship to K.H. J.W. is the grateful
recipient of a DAAD-supported postdoctoral fellowship.
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