Modular total syntheses of lamellarin G trimethyl ether and lamellarin S

Article abstract of DOI:10.1002/ejoc.201001133

Modular total syntheses of the title compounds 2 and 3 are reported. The key pyrrolic building block 8 was prepared from the readily accessible pyrrole 6 via a di-iodination/mono-deiodination sequence. Suzuki-Miyaura cross-coupling of compound 8 with boronate ester 9 afforded lactone 10. Bromination of compound 10 followed by N-alkylation under Mitsunobu conditions afforded the fully substituted pyrrole 13 that engaged in a second Suzuki-Miyaura cross-coupling reaction with boronic acid 14 to give compound 15. Hydrolysis of the ester moiety within the last compound afforded acid 16 that engaged in a decarboxylative Heck cyclization process to give lamellarin G trimethyl ether (3). A related sequence of reactions starting from building block 8 and using the isopropoxy-substituted arenes 22, 25 and 27 has allowed for the completion of the first total synthesis of lamellarin S (2). The first total synthesis of the marine alkaloid lamellarin S is described.

Full text of DOI:10.1002/ejoc.201001133

FULL PAPER
DOI: 10.1002/ejoc.201001133
Modular Total Syntheses of Lamellarin G Trimethyl Ether and Lamellarin S
Katrin Hasse,[a] Anthony C. Willis,[a] and Martin G. Banwell*[a]
Keywords: Natural products / Alkaloids / Pyrroles / Cross-coupling
Modular total syntheses of the title compounds 2 and 3 are
reported. The key pyrrolic building block 8 was prepared
from the readily accessible pyrrole 6 via a di-iodination/
coupling reaction with boronic acid 14 to give compound 15.
Hydrolysis of the ester moiety within the last compound af-
forded acid 16 that engaged in a decarboxylative Heck cycli-
mono-deiodination sequence. Suzuki–Miyaura cross-cou- zation process to give lamellarin G trimethyl ether (3). A re-
pling of compound 8 with boronate ester 9 afforded lactone
10. Bromination of compound 10 followed by N-alkylation
under Mitsunobu conditions afforded the fully substituted
pyrrole 13 that engaged in a second Suzuki–Miyaura cross-
lated sequence of reactions starting from building block 8
and using the isopropoxy-substituted arenes 22, 25 and 27
has allowed for the completion of the first total synthesis of
lamellarin S (2).
As part of our group’s continuing efforts to develop new
routes to pyrrole-containing marine natural products,[6] we
now describe a modular total synthesis of the trimethyl
ether 3[7] of natural product 1 and a related study that has
resulted in the first total synthesis of lamellarin S (2). The
present work parallels that of Iwao[8] in so far as a symmet-
rical, penta-substituted pyrrolic system is used as the “plat-
form” through which to assemble the pentacyclic lamellarin
framework via a sequence of Pd0-catalyzed cross-coupling
and cyclization processes. However, the necessary desymme-
trization process used in the present work is quite distinct
from that employed by the Japanese group as is the se-
quence of ring-forming events. Details are provided in the
following sections.
Introduction
Lamellarins G[1] and S,[2] 1 and 2 respectively, are repre-
sentative members of a group of pentacyclic pyrrolic alka-
loids that have been isolated from various marine organisms
including molluscs, ascidians and sponges.[3] A range of
screening regimes has revealed that many of these lam-
ellarins display a fascinating array of potentially useful bio-
logical properties including selective cytotoxicities, a ca-
pacity to reverse multi-drug resistance (MDR) now being
encountered in certain cancer cell lines and an ability to
inhibit HIV-1 integrase.[3,4] Some of the lamellarins also dis-
play immunomodulatory activity.[3,4] As a consequence, sig-
nificant effort has been devoted to the development of con-
cise syntheses of the lamellarins and various analogs, not
only for the purposes of identifying new drug leads but also
because of the need to address the problems of the limited
supply of these compounds available from the natural
sources. Very useful new routes to the lamellarins have
emerged from such studies and much of the work in the
area has been the subject of recent and comprehensive re-
views.[3–5]
Results and Discussion
Part 1: Total Synthesis of Lamellarin G Trimethyl Ether
Our initial studies on the development of the modular
lamellarin syntheses described herein focused on establish-
ing a route to the well-known[7] trimethyl ether, 3, of the
natural product 1. The choice of compound 3 as the initial
target derived from the simplifications to the synthesis aris-
[a] Research School of Chemistry, Institute of Advanced Studies,
The Australian National University,
Canberra, ACT 0200, Australia
Fax: +61-2-6125-8114
E-mail: mgb@rsc.anu.edu.au
88
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 88–99

Modular Total Syntheses of Lamellarins
ing from avoiding the need to establish a combination of desymmetrization process we could identify involved treat-
methoxy and hydroxy substituents around the periphery of ing compound 7 with 1.15 g-atom equiv. of activated zinc
this pentacyclic framework. Given that simplification, the powder in N,N-dimethylacetamide (DMA) at 120 °C for
most challenging aspect of the work was the identification 2.5 h. By such means the mono-iodinated derivative 8 was
of a protocol for establishing an unsymmetrical substitution obtained in 69% yield. Efforts to obtain compound 8 di-
pattern around the pyrrolic core of the target. The reaction rectly from compound 6 using ca. 1 equiv. of molecular io-
sequence that has led to the present synthesis of lamellarin dine were ineffective – only mixtures of compounds 6 and
G trimethyl ether (3) is shown in Scheme 1 and starts with 7 were obtained.
the readily available N-Boc derivative 4 of pyrrole. Follow-
At the start of the next significant stage of the synthesis,
ing protocols used by Fürstner,[9] compound 4 was treated namely the introduction of the various aryl groups that
with ca. 2 equiv. of N-bromosuccinimide (NBS) and the re- need to be assembled around the pyrrole core of target 3,
sulting 2,4-dibromopyrrole 5 was treated with 3.8 equiv. of mono-iodide 8 was subjected to Suzuki–Miyaura cross-cou-
tert-butyllithium then ca. 10 equiv. of methyl chloroformate. pling[10] with the previously reported[6e] boronate ester 9. A
In this way the previously reported[9] diester 6 was obtained spontaneous and highly efficient lactonization process fol-
in ca. 50% overall yield from the starting compound 4. lowed the cross-coupling process such that the lactone 10
Heating product 6 in DMF at 130 °C for 12 h resulted in was obtained in 90% yield. This compound was readily and
cracking of the Boc group and the ensuing solution of the selectively brominated on the pyrrole ring using NBS in
deprotected pyrrole was then cooled to 80 °C and treated DMF at 0–18 °C and the mono-bromide 11 thereby ob-
with 2.2 molar equiv. of N-iodosuccinimide (NIS) in DMF. tained (59%) was subjected to N-alkylation with the readily
In this way the previously unreported di-iodinated pyrrole available β-phenethyl alcohol 12 under Mitsunobu condi-
di-ester 7 was obtained in 97% yield and its structure con- tions[11] using diisopropyl azodicarboxylate (DIAD) and
firmed through a single-crystal X-ray analysis, details of triphenylphosphane. The spectroscopic data acquired on
which are presented in the Exp. Sect. The most effective product 13, which was obtained in 62% yield, were in
Scheme 1.
Eur. J. Org. Chem. 2011, 88–99
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
89

K. Hasse, A. C. Willis, M. G. Banwell
FULL PAPER
1
complete accord with the assigned structure. It is interesting Table 1. Comparison of the H NMR spectroscopic data recorded
on samples of lamellarin G trimethyl ether (3) derived from the
to note the ordering of the reaction sequence 8 + 9 Ǟ 10
Ǟ 11 Ǟ 13 is crucial to success. Thus, for example, if prod-
uct 10 is subjected to N-alkylation with alcohol 12 and the
product of this process is treated with NBS then the aro-
present work and the work of Liermann and Opatz.[7e]
1H NMR data for dompound 3 (δH, CDCl3)
(400 MHz)[a]
(400 MHz)[b]
matic ring of the β-phenethyl residue rather than the pyrrole 7.12 (dd, J = 8.4 and 2.0 Hz, 1 H) 7.11 (dd, J = 8.1 and 1.8 Hz, 1 H)
7.08 (d, J = 8.4 Hz, 1 H)
7.05 (d, J = 2.0 Hz, 1 H)
6.91 (s, 1 H)
6.76 (s, 1 H)
6.72 (s, 1 H)
6.66 (s, 1 H)
4.86–4.72 (m, 2 H)
3.94 (s, 3 H)
3.88 (s, 3 H)
3.87 (s, 3 H)
7.07 (d, J = 8.1 Hz, 1 H)
7.05 (d, J = 1.8 Hz, 1 H)
6.90 (s, 1 H)
6.76 (s, 1 H)
6.71 (s, 1 H)
6.66 (s, 1 H)
4.85–4.73 (m, 2 H)
3.95 (s, 3 H)
3.89 (s, 3 H)
3.87 (s, 3 H)
ring is brominated. The installation of the final aromatic
group associated with target 3 involved Suzuki–Miyaura
cross-coupling of bromide 13 with the commercially avail-
able aryl boronic acid 14 and thereby generating compound
15 in 80% yield. The spectroscopic data recorded on this
material matched those reported by Boger et al.[12] who gen-
erated the same compound (by quite a different route) dur-
ing the course of their development of the first total synthe-
sis of ningalin B.
3.84 (s, 3 H)
3.44 (s, 3 H)
3.86 (s, 3 H)
3.45 (s, 3 H)
The final steps of the reaction sequence leading to target
3 were concerned with constructing the C10a–C10b linkage
and relied upon a protocol first developed by Steglich[7a]
and subsequently exploited, in modified form, by Iwao.[7b]
Thus, lactone-ester 15 was subjected to saponification using
potassium hydroxide and after acidic work-up the corre-
sponding bis-acid arising from cleavage of both the ester
and lactone residues in the starting material was obtained.
Accordingly, it was necessary to treat this product with
catalytic quantities of p-toluenesulfonic acid (pTsOH) mono-
hydrate as well as molecular sieves (4 Å) in refluxing tolu-
ene so as to re-install the lactone ring and thereby generat-
ing compound 16 that was obtained in 57% over the two
steps involved.
3.35 (s, 3 H)
3.13 (t, J = 7.2 Hz, 2 H)
[a] Data derived from present work. [b] Data derived from ref.[7e]
3.36 (s, 3 H)
3.12 (t, J = 6.8 Hz, 2 H)
Table 2. Comparison of the 13C NMR spectroscopic data recorded
on samples of lamellarin G trimethyl ether (3) derived from the
present work and the work of Liermann and Opatz.[7e]
13C NMR data for dompound 3 (δC, CDCl3)
The 13C NMR spectrum recorded on compound 16
matched the data reported for this compound by Boger et
al.[12] save for the appearance of a signal at δ = 48.7 in our
spectrum and the absence of one at δ = 29.7 as recorded by
the Scripps group. Since an HSQC-correlation experiment
established that the signal observed at δ = 48.7 is coupled
to the two protons resonating at δ = 5.03, the former reso-
nance must be “real”. On this basis, we believe that the
signal observed at δ = 29.7 by Boger et al.[12] is not due to
compound 16 and could, in fact, arise from grease contami-
nating their sample.
(200 MHz)[a]
(100 MHz)[b]
155.6 (C)
149.7 (C)
149.0 (C)
148.8 (C)
148.8 (C)
147.5 (C)
146.1 (C)
145.5 (C)
136.0 (C)
128.2 (C)
128.0 (C)
126.6 (C)
123.6 (CH)
120.0 (C)
114.8 (C)
113.9 (CH)
113.8 (C)
111.8 (CH)
111.0 (CH)
110.3 (C)
108.6 (CH)
104.5 (CH)
100.5 (CH)
56.2 (CH3)
56.2 (CH3)
56.1 (CH3)
56.1 (CH3)
55.9 (CH3)
55.5 (CH3)
55.2 (CH3)
42.4 (CH2)
28.7 (CH2)
155.5 (C)
149.7 (C)
149.0 (C)
148.8 (C)
148.8 (C)
147.5 (C)
146.1 (C)
145.5 (C)
135.9 (C)
128.2 (C)
128.0 (C)
126.6 (C)
123.6 (CH)
120.0 (C)
114.7 (C)
114.0 (CH)
113.7 (C)
111.9 (CH)
111.0 (CH)
110.3 (C)
108.7 (CH)
104.5 (CH)
100.5 (CH)
56.2 (CH3)
56.1 (CH3)
56.0 (CH3)
55.9 (CH3)
55.5 (CH3)
55.2 (CH3)
55.2 (CH3)
42.4 (CH2)
28.7 (CH2)
The completion of the synthesis of compound 3 involved
treating precursor 16 with 1.1 equiv. of Pd(OAc)2 in re-
fluxing acetonitrile so as to effect the required decarbox-
ylative Heck reaction. By such means target 3 was obtained
in 48% yield as a white crystalline solid, the melting range
for which (m.p. 233–234 °C) was in good agreement with
that recorded by Steglich et al.[7a] (m.p. 235 °C). Further-
1
more, as revealed in Table 1 and Table 2, the derived H
and 13C NMR spectroscopic data were in good agreement
with those recorded by Liermann and Opatz.[7e]
A comparison of key features of the various total synthe-
ses of lamellarin G trimethyl ether (3) reported so far is
provided in Table 3 and this reveals that the one described
recently by Yadav is the shortest and most efficient. The
present synthesis does not compare particularly favorably
in terms of overall yield but, as revealed in the following
section, its modular nature does allow hitherto inaccessible
members of the lamellarin family to be synthesized.
[a] Data derived from present work. [b] Data derived from ref.[7e]
90
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 88–99

Modular Total Syntheses of Lamellarins
Table 3. Comparison of key aspects of the reported syntheses of lamellarin G trimethyl ether (3).
Lead author
Year
Steps
Overall yield (%) Ring-forming sequence
Steglich
Ruchirawat
Iwao
Handy
Opatz
Gupton
Yadav
Present work
1997
2001
2003
2004
2008
2009
2009
2010
four
six
seven
eleven
eight
ten
32
27
9
9
20
7
E + F Ǟ EF + A Ǟ EFAC Ǟ EFACD Ǟ EFACDB
ABF + E Ǟ ABFEC Ǟ ABFECD
A Ǟ AC + F Ǟ ACF + E Ǟ ACFED Ǟ ACFEDB
C + F Ǟ CF + A Ǟ CFA Ǟ CFAB + E Ǟ CFABED
AB + F Ǟ ABF + E Ǟ ABFEC Ǟ ABFECD
EF + A Ǟ EFAC Ǟ EFACD Ǟ EFACDB
four
eight
45
5
E + F Ǟ EF Ǟ EFD + AB Ǟ EFDABC
C + E Ǟ CED + A Ǟ CEDA + F Ǟ CEDAF Ǟ CEDAFB
Part 2: Total Synthesis of Lamellarin S
The work described above served to establish the validity
of our modular approach to the pentacyclic lamellarins. Ac-
cordingly, we turned our attention to its use in the synthesis
of lamellarin S (2), a target that incorporates five hydroxy
groups and one methoxy group around its outer perimeter.
Following our earlier work on the total synthesis of lam-
ellarin K,[6b] we chose to use isopropoxy ethers as precur-
sors to the required free hydroxy groups which would be
revealed by treating the ethers with either AlCl3 or BCl3
under conditions that do not readily cleave the correspond-
ing methoxy unit.
Scheme 2.
A necessary prelude to carrying out the synthesis of lam-
ellarin S was the preparation of the di-iso-propoxy equiva-
lent of the dimethoxy-substituted aryl boronic ester 9. The readily synthesized β-phenethyl alcohol 25 afforded the ex-
reaction sequence used for this purpose is shown in pected product 26 in 96% yield. Cross-coupling of com-
Scheme 2 and started with the conversion of commercially pound 26 with the readily prepared (see Exp. Sect.) aryl
available 3,4-dihydroxybenzaldehyde (17) into the corre- boronic acid 27 then gave pyrrole 28 in 67% yield. Follow-
sponding diisopropoxybenzaldehyde (18)[13] (89%) using ing the procedures used earlier (Scheme 1), the last com-
isopropyl bromide in the presence of potassium carbonate. pound was subjected to a saponification/re-lactonization se-
Treatment of the latter compound with hydrogen peroxide quence but in addition to this producing the acid 30 (49%)
in the presence of sulfuric acid effected a Dakin oxidation required for the decarboxylative Heck reaction, the twofold
and resulted in the formation of phenol 19[13] (98%) that decarboxylation product 29 (16%) was obtained. The
was converted into the corresponding tetrahydropyranyl- or reasons for the formation of this unwanted material remain
THP-ether 20 (quant.) upon reaction with 3,4-dihydro-2H- unclear especially when no analogous by-product was gen-
pyran (DHP) in the presence of pyridinium p-toluenesulfo- erated during the conversion 15Ǟ16 (Scheme 1). Treatment
nate (PPTS). Reaction of arene 20 with 1.4 mol equiv. of of compound 30 with Pd(OAc)2 in refluxing acetonitrile ef-
NBS afforded the bromide 21 (86%) that was subjected to fected its conversion into the pentacyclic system 31 (56%)
treatment with triisopropylborate and n-butyllithium. which represents the pentaisopropyl ether of lamellarin S.
Treatment of the material so formed with hydrochloric acid Finally, treatment of a dichloromethane solution of com-
and pinacol resulted in cleavage of the THP-ether unit and pound 31 with BCl3 at –78 °C to 18 °C for ca. 3 h resulted
a transesterification reaction at boron and thereby forming in the cleavage of all five isopropyl aryl ether units and,
the target boronate ester 22 in 55% yield.[14] The spectro- therefore, the formation of lamellarin S (2) which was ob-
scopic data obtained on compound 22 were in complete tained as a pale-brown solid in 97% yield.
1
accord with the assigned structure with, for example, the
A comparison (Table 4) of the H NMR spectroscopic
EI mass spectrum showing a molecular ion at m/z 336. An data derived from synthetic lamellarin S with those re-
accurate mass measurement on this species established that ported for the natural product as reported by Urban and
it had the expected composition, viz. C18H28BO5.
Capon[2] reveal a good match, although in the spectrum
Following the same sequence as employed in the synthe- derived from the synthetic material each of the tabulated
sis of lamellarin G trimethyl ether (3), ester 22 was sub- signals had a small “mirror” peak which was always at
jected to Suzuki–Miyaura cross-coupling with pyrrole 8 and slightly higher field. The precise origins of these remain un-
1
this resulted (Scheme 3) in the formation of the lactone 23 clear. Since analogous features are not apparent in the H
(92%). Bromination of this last compound with NBS fol- NMR spectrum of precursor 31 it seems unlikely that they
lowed by engagement of the product bromide 24 (94%) in are the result of conformational effects. The 13C NMR
a Mitsunobu reaction with the previously reported[15] and spectroscopic data (Table 5) proved to be an excellent
Eur. J. Org. Chem. 2011, 88–99
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
91

K. Hasse, A. C. Willis, M. G. Banwell
FULL PAPER
Scheme 3.
match. In particular, the chemical shifts of many of the sig- Table 5. Comparison of the 13C NMR spectroscopic data recorded
on synthetically and naturally derived samples of lamellarin S (2).
nals are identical or only different by Δδ 0.1 ppm. In the
13C NMR Data (δC, CD3OD)
Synthetic 2 (125 MHz)[a]
latter case those signals arising from the synthetic material
have the consistently higher value (numerically speaking).
Natural 2 (75 MHz)[b]
157.7 (C)
148.1 (C)
147.5 (C)
147.4 (C)
147.3 (C)
146.8 (C)
146.7 (C)
143.4 (C)
138.6 (C)
130.0 (C)
128.7 (C)
128.1 (C)
123.7 (CH)
120.2 (C)
119.1 (C)
117.5 (CH)
116.5 (C)
115.8 (CH)
113.8 (CH)
111.3 (C)
110.4 (CH)
109.9 (CH)
104.2 (CH)
55.6 (CH3)
43.6 (CH2)
29.3 (CH2)
157.6 (C)
148.0 (C)
147.4 (C)
147.4 (C)
147.2 (C)
146.7 (C)
146.6 (C)
143.4 (C)
138.5 (C)
129.9 (C)
128.7 (C)
128.1 (C)
123.7 (CH)
120.2 (C)
119.0 (C)
117.5 (CH)
116.4 (C)
115.8 (CH)
113.8 (CH)
111.3 (C)
110.4 (CH)
109.8 (CH)
104.2 (CH)
55.6 (CH3)
43.5 (CH2)
29.3 (CH2)
1
Table 4. Comparison of the H NMR spectroscopic data recorded
on synthetically and naturally derived samples of lamellarin S (2).
1H NMR Data (δH, CD3OD)
Synthetic 2 (500 MHz)[a]
Natural 2 (300 MHz)[b]
7.00 (d, J = 8.0 Hz, 1 H)
6.88 (m, 1 H)
6.84 (s, 1 H)
6.96 (d, J = 8.0 Hz, 1 H)
6.86 (s, 1 H)
6.81 (s, 1 H)
6.78 (d, J = 8.0 Hz, 1 H)
6.76 (s, 1 H)
6.71 (s, 1 H)
6.75 (d, J = 8.0 Hz, 1 H)
6.72 (s, 1 H)
6.67 (s, 1 H)
6.64 (s, 1 H)
4.72–4.60 (m, 2 H)
3.40 (s, 3 H)
6.59 (s, 1 H)
4.67–4.53 (m, 2 H)
3.36 (s, 3 H)
3.02 (m, 2 H)
2.97 (m, 2 H)
[a] Data derived from present work. [b] Data derived from ref.[2]
An HPLC comparison of our synthetically derived sam-
ple of lamellarin S with the natural product was kindly car-
ried out by Prof. Rob Capon and Dr. Fabien Plisson (Uni-
versity of Queensland) and has established that the two ma-
terials were identical, both in terms of retention times and
UV absorption spectra (the latter being acquired using a
diode array detection system). HPLC analysis of a mixture
[a] Data derived from present work. [b] Data derived from ref.[2]
of the two compounds also led to a single peak in the chro- several lamellarins that vary in the number of associated
matogram. It should be noted that the HPLC method used methoxy and hydroxy substituents. It also resolves various
(see Exp. Sect. for details) has proven effective in separating isomeric systems such as lamellarins E and K.
92
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 88–99

Modular Total Syntheses of Lamellarins
Synthetic Studies
Conclusions
Compound 6: The dimethyl pyrroledicarboxylate 6 was prepared in
ca. 50% yield over two steps from compound 4 according to the
method of Fürstner et al.[9] The derived spectroscopic data matched
those reported previously.[9]
A modular synthesis of lamellarin G trimethyl ether (3)
and the first total synthesis of the natural product lam-
ellarin S (2) have been accomplished. This involves the se-
quential assembly of the benzenoid rings of the target
around the highly functionalized pyrrole 8 using Suzuki–
Miyaura and Heck reactions to establish the key carbon-
carbon double bonds of the target framework. As such, this
“pyrrole core to benzenoid periphery” approach stands in
complete contrast to our earlier synthesis of lamellarin K
wherein the periphery of this natural product was as-
sembled first and the pyrrole ring then constructed in the
closing stages using an intramolecular azomethine ylide cy-
cloaddition reaction. The two approaches are quite comple-
mentary and each offers the capacity to provide a wide-
range of novel lamellarin analogs.
Compound 7: A solution of compound 6 (477 mg, 1.68 mmol) in
DMF (4 mL) was heated at 130 °C for 12 h then cooled to 80 °C
and treated with NIS (834 mg, 3.71 mmol). The ensuing mixture
was kept at 80 °C for 4 h then cooled and concentrated to dryness
(50 °C under high vacuum). The byproduct of the reaction, suc-
cinimide, was removed by sublimation at 60 °C under high vacuum
for 24 h. The resulting light-brown solid was recrystallized (dichlo-
romethane/pentane) to give 7 (707 mg, 97%) as white crystals, no
melting point, decomposition above 240 °C (found [M]+·, 434.8467.
C8H7127I2NO4 requires [M]+·, 434.8465). 1H NMR (300 MHz,
CDCl3): δ = 10.07 (br. s, 1 H), 3.95 (s, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.9 (2ϫC), 127.6 (2ϫC), 85.7 (2ϫC),
52.7 (2ϫCH ) ppm. IR (KBr): ν
= 3379, 2951, 1708, 1510,
˜
3
max
1432, 1264, 1033, 943, 799, 776, 624 cm–1. MS (EI, 70 eV): m/z (%)
= 435 (100) [M]+·, 403 (26), 372 (40), 345 (24).
Experimental Section
General Experimental Procedures: Proton (1H) and carbon (13C)
Compound 8: Molecular iodine (29 mg, 0.115 mmol) was added to
zinc powder (86 mg, 1.322 mmol) maintained under a nitrogen at-
mosphere and the ensuing mixture was stirred magnetically at
18 °C for 2 min before being treated with DMA (0.8 mL). The re-
sulting suspension was stirred for a further 2 min at 18 °C before
compound 7 (500 mg, 1.150 mmol) was added to the reaction mix-
ture which was then heated at 120 °C for 2.5 h. After this time the
reaction mixture was cooled to 18 °C then treated with TLC-grade
silica gel (3.0 g) and concentrated under reduced pressure. The free-
flowing solid thus obtained was subjected to flash chromatography
(silica, 6:1 v/v pentane/diethyl etherǞ1:2 v/v pentane/diethyl ether
gradient elution) and concentration of the appropriate fractions (Rf
= 0.4 in 1:3 v/v pentane/diethyl ether) gave 8 (247 mg, 69%) as a
white solid, m.p. 139–140 °C (found [M]+·, 308.9495. C8H8127INO4
NMR spectra were recorded on a Varian Gemini 300 machine (op-
1
erating at 300 and 75 MHz for H and 13C spectra, respectively), a
1
Varian MR400 instrument (operating at 400 and 100 MHz for H
and 13C spectra, respectively), a Varian VXR500 machine with an
Inova console (operating at 500 and 125 MHz for 1H and 13C spec-
tra, respectively) or a Bruker AM-800 instrument (operating at 800
1
and 200 MHz for H and 13C spectra, respectively). Unless other-
wise specified, spectra were acquired at 20 °C in deuteriochloro-
form (CDCl3) that had been stored over anhydrous sodium carbon-
ate. Chemical shifts are recorded as δ values in parts per million
(ppm). Infrared spectra (νmax) were normally recorded on a Perkin–
˜
Elmer 1800 Series FTIR Spectrometer and samples were analyzed
as thin films on NaCl or KBr plates (for liquids) or as a KBr disk
(for solids). Low-resolution ESI mass spectra were recorded in pos-
itive-ion mode on a Micromass–Waters LC-ZMD single quadru-
pole liquid chromatograph-mass spectrometer while low- and high-
resolution EI mass spectra were recorded on a VG Fisions AUTO-
SPEC three-sector, double-focusing instrument. Melting points
were measured on a Stanford Research Systems Optimelt-Auto-
mated melting point system and are uncorrected. Analytical thin-
layer chromatography (TLC) was performed on aluminum-backed
0.2 mm thick silica gel 60 F254 plates as supplied by Merck. Eluted
plates were visualized using a 254 nm UV lamp and/or by treatment
with a suitable dip followed by heating. These dips included a mix-
ture of vanillin/sulfuric acid/ethanol (1 g:1 g:18 mL) or phos-
phomolybdic acid/ceric sulfate/sulfuric acid (concd.)/water
1
requires [M]+·, 308.9498). H NMR (300 MHz, CDCl3): δ = 10.11
(br. s, 1 H), 7.03 (s, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.9 (C), 159.8 (C), 126.9 (C), 126.3
(C), 124.5 (CH), 68.6 (C), 52.3 (CH3), 52.1 (CH3) ppm. IR (KBr):
ν
= 3440, 3280, 2953, 1729, 1703, 1544, 1438, 1272, 776 cm–1.
˜
max
MS (EI, 70 eV): m/z (%) = 309 (100) [M]+·, 277 (34), 246 (79), 219
(53), 199 (12).
Compound 10: A solution of pyrrole 8 (111 mg, 0.359 mmol) in
THF/H2O (7.2 mL of 3:1 v/v mixture) was treated with potassium
carbonate (213 mg, 1.54 mmol), tetra-n-butylammonium bromide
(TBAB) (22 mg, 20 mol-%), and boronate ester
9 (241 mg,
0.86 mmol). The resulting mixture was flushed with nitrogen, then
(37.5 g:7.5 g:37.5 g:720 mL). The retardation factor (Rf) values Pd(PPh3)4 (41 mg, 10 mol-%) was added and the reaction vessel
cited here have been rounded to the first decimal point. Flash chro-
matographic separations were carried out following protocols de-
fined by Still et al.[16] with silica gel 60 (40–63 μm) as the stationary
phase and using the AR- or HPLC-grade solvents indicated. Start-
ing materials and reagents were generally available from the Sigma–
Aldrich, Merck, TCI, Strem or Lancaster Chemical Companies
and were either used as supplied or, in the case of liquids, distilled
when required. Drying agents and other inorganic salts were pur-
chased from the AJAX, BDH or Unilab Chemical Companies.
THF, dichloromethane, acetonitrile and benzene were dried using
a Glass Contour solvent purification system that is based upon a
technology originally described by Grubbs et al.[17] Spectroscopic
grade solvents were used for all analyses. Where necessary, reac-
tions were performed under a nitrogen or an argon atmosphere.
again flushed with nitrogen before being sealed then subjected to
microwave irradiation (150 W, 60 °C, 1 min ramp time) for 1 h. The
cooled reaction mixture was then diluted with H2O (20 mL) and
extracted with ethyl acetate (4ϫ20 mL). The combined organic
phases were washed with brine (1ϫ30 mL) before being dried
(Na2SO4), filtered and concentrated under reduced pressure. The
ensuing yellow solid was washed with dichloromethane to give 10
(98 mg, 90%) as a white, crystalline solid, m.p. 253–258 °C (found
[M]+·, 303.0744. C15H13NO6 requires [M]+·, 303.0743). 1H NMR
(300 MHz, CDCl3): δ = 9.98 (s, 1 H), 7.26 (s, 1 H), 7.14 (s, 1 H),
6.95 (s, 1 H), 3.981 (s, 3 H), 3.977 (s, 3 H), 3.94 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 160.4 (C), 155.1 (C), 149.9 (C), 146.6
(C), 146.2 (C), 130.6 (C), 129.8 (C), 118.7 (C), 109.3 (C), 107.0
(CH), 104.2 (CH), 101.0 (CH), 56.4 (CH3), 56.3 (CH3), 52.6 (CH3)
Eur. J. Org. Chem. 2011, 88–99
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
93

K. Hasse, A. C. Willis, M. G. Banwell
FULL PAPER
ppm. IR (KBr): ν
= 3441, 3288, 2953, 2924, 2463, 1735, 1278,
under reduced pressure. The ensuing light-yellow oil was subjected
˜
max
1144, 772 cm–1. MS (EI, 70 eV): m/z (%) = 303 (17) [M]+·, 256 (19), to flash chromatography (silica, 1:6 v/v pentane/diethyl etherǞdi-
149 (26), 97 (36), 69 (61), 43 (100).
ethyl etherǞ1:1 diethyl ether/ethyl acetate gradient elution) and
concentration of the appropriate fractions (Rf = 0.2 in diethyl
ether) furnished 15[12] (28 mg, 80%) as a white solid, m.p. 192–
194 °C (found [M]+·, 603.2108. C33H33NO10 requires [M]+·,
Compound 11: A magnetically stirred solution of pyrrole 10
(100 mg, 0.33 mmol) in DMF (2.5 mL) was cooled to 0 °C then
treated, in one portion, with NBS (70 mg, 0.396 mmol) and the
ensuing mixture was warmed to 18 °C. After stirring at this tem-
perature for 12 h, another aliquot of NBS (70 mg) was added and
the reaction mixture heated at 50 °C for 4 h. The cooled reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (4ϫ30 mL). The combined organic phases were washed
with water (1ϫ30 mL) and brine (1ϫ30 mL) then dried (Na2SO4),
filtered and concentrated under reduced pressure. The resulting
light-yellow solid was subjected to flash chromatography (silica, 1:1
v/v pentane/diethyl etherǞdiethyl etherǞethyl acetate gradient
elution) and concentration of the appropriate fractions (Rf = 0.5
in diethyl ether) furnished 11 (75 mg, 59%) as a white solid, no
melting point, decomposition above 280 °C (found [M]+·, 380.9848.
C15H12NO679Br requires [M]+·, 380.9848). 1H NMR (400 MHz,
CDCl3): δ = 10.16 (s, 1 H), 8.12 (s, 1 H), 6.95 (s, 1 H), 4.02 (s, 3
H), 4.00 (s, 3 H), 3.95 (s, 3 H) ppm. 13C NMR (125 MHz, 5% [D6]-
DMSO in CDCl3): δ = 159.9 (C), 154.5 (C), 149.6 (C), 146.0 (C),
145.9 (C), 128.1 (C), 126.3 (C), 118.4 (C), 109.2 (C), 104.1 (CH),
100.7 (CH), 96.0 (C), 56.2 (CH3), 56.1 (CH3), 52.3 (CH3) ppm. IR
1
603.2104). H NMR (300 MHz, CDCl3): δ = 6.98 (d, J = 8.1 Hz,
1 H), 6.93–6.88 (complex m, 1 H), 6.89 (s, 1 H), 6.85 (d, J = 3.0 Hz,
1 H), 6.80 (m, 3 H), 6.52 (s, 1 H), 5.11 (t, J = 8.4 Hz, 2 H), 3.94
(s, 3 H), 3.89 (s, 3 H), 3.86 (m, 6 H), 3.85 (s, 3 H), 3.58 (s, 3 H),
3.43 (s, 3 H), 3.11 (t, J = 8.1 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.3 (C), 155.1 (C), 149.2 (C), 148.8 (C), 148.7 (C),
148.6 (C), 147.7 (C), 146.0 (C), 145.7 (C), 130.5 (C), 129.4 (C),
126.9 (C), 126.7 (C), 124.2 (C), 122.6 (CH), 121.1 (CH), 117.5 (C),
113.3 (CH), 112.3 (CH), 111.1 (CH), 110.8 (CH), 109.5 (C), 104.5
(CH), 100.3 (CH), 56.1 (CH3), 56.0 (2ϫCH3), 55.9 (CH3), 55.8
(CH3), 55.5 (CH3), 51.8 (CH3), 48.7 (CH2), 37.9 (CH2) ppm. IR
(KBr): νmax = 2935, 2833, 1729, 1703, 1515, 1444, 1265, 1218, 1155,
˜
1028, 727 cm–1. MS (EI, 70 eV): m/z (%) = 603 (100) [M]+·, 452
(36), 439 (34), 407 (64), 151 (43).
Compound 16: Following the procedure detailed by Steglich et
al.,[7a] a finely ground sample of pyrrole 15 (41 mg, 0.07 mmol) was
suspended in a freshly prepared and degassed solution of KOH
(1.685 g, 0.03 mol) in water (2.6 mL, 0.144 mol). The resulting mix-
ture was heated for 3 h in an oil bath maintained at 150 °C and the
methanol so formed was removed by continuous distillation. The
reaction mixture was then cooled to 0 °C, acidified by the dropwise
addition of HCl (37% w/v aqueous solution) and extracted with
ethyl acetate (3ϫ10 mL). The combined organic layers were
washed with brine (1ϫ10 mL) before being dried (Na2SO4), fil-
tered and concentrated under reduced pressure to afford a deep-
yellow oil. The oil was dissolved in toluene (9 mL) and the resulting
solution treated with pTsOH monohydrate (5 mg) and 4 Å molecu-
lar sieves (73 mg) then heated at reflux for 0.5 h. After cooling,
filtration and evaporation of the solvent, the residue was dissolved
in ethyl acetate (10 mL) and the ensuing solution washed with
aqueous potassium hydrogen sulfate (1ϫ2 mL of a 1.1 m aqueous
solution) and brine (1ϫ5 mL). After drying (Na2SO4) and fil-
tration the solvent was removed under reduced pressure and the
ensuing light-yellow solid subjected to flash chromatography (sil-
ica, CHCl3 Ǟ9:1 v/v CH2Cl2/methanol gradient elution). Concen-
tration of the appropriate fractions (Rf = 0.2 in 9:1 v/v CH2Cl2/
methanol) afforded 16[7b,12] (23 mg, 57%) as a white solid, m.p.
209–211 °C (ref.[12] m.p. 219–220 °C) (found [M]+·, 589.1944.
C32H31NO10 requires [M]+·, 589.1948). 1H NMR (300 MHz, 5%
CD3OD in CDCl3): δ = 6.94–6.68 (complex m, 7 H), 6.43 (s, 1 H),
5.03 (t, J = 7.5 Hz, 2 H), 3.84 (s, 3 H), 3.81 (s, 3 H), 3.78 (4) (s, 3
H), 3.77 (6) (s, 3 H), 3.76 (s, 3 H), 3.34 (s, 3 H), 3.04 (t, J = 7.5 Hz,
2 H) ppm. 13C NMR (100 MHz, 5% CD3OD in CDCl3): δ = 162.5
(C), 155.5 (C), 149.1 (C), 148.7 (0) (C), 148.6 (8) (C), 148.5 (C),
147.6 (C), 145.8 (C), 145.6 (C), 130.8 (C), 130.5 (C), 127.1 (C),
127.0 (C), 124.2 (C), 122.7 (CH), 121.1 (CH), 117.1 (C), 113.6
(CH), 112.3 (CH), 111.3 (CH), 111.0 (CH), 109.6 (C), 104.5 (CH),
100.3 (CH), 56.0 (CH3), 55.9 (CH3), 55.81 (CH3), 55.78 (CH3),
55.60 (CH3), 55.3 (CH3), 48.7 (CH2), 37.8 (CH2) ppm. IR (KBr):
(KBr): ν
= 3412, 3223, 2925, 1705, 1495, 1280, 704 cm–1. MS
˜
max
(EI, 70 eV): m/z (%) = 383 and 381 (both 71) [M]+·, 351 and 349
(100 and 99), 336 and 334 (29 and 30), 308 and 306 (14 and 15),
227 (20).
Compound 13: A solution of pyrrole 11 (75 mg, 0.20 mmol) in THF
(5 mL) was treated with triphenylphosphane (62 mg, 0.24 mmol),
alcohol 12 (43 mg, 0.236 mmol) and DIAD (48 mg, 0.24 mmol).
The ensuing mixture was stirred at 18 °C for 14 h then heated at
50 °C for 1 h. The resulting mixture was cooled then treated with
TLC-grade silica gel (600 mg) before being concentrated under re-
duced pressure. The free-flowing solid thus obtained was subjected
to flash chromatography (silica, dichloromethane elution) and con-
centration of the appropriate fractions (Rf = 0.3) gave 13 (66 mg,
62%) as a white solid, no melting point, decomposition above
190 °C (found [M]+·, 545.0686. C25H24NO879Br requires [M]+·,
1
545.0685). H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H), 6.93 (s,
1 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.73 (s, 1 H), 6.73 (d, J = 5.2 Hz,
1 H), 5.09 (t, J = 7.2 Hz, 2 H), 3.99 (s, 3 H), 3.95 (s, 3 H), 3.92 (s,
3 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.03 (t, J = 8.0 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 160.2 (C), 154.2 (C), 149.9 (C),
148.9 (C), 147.8 (C), 146.1 (C), 145.9 (C), 130.1 (C), 130.0 (C),
126.3 (C), 121.1 (CH), 118.0 (C), 112.2 (CH), 111.2 (CH), 108.9
(C), 104.3 (CH), 100.4 (CH), 95.7 (C), 56.3 (CH3), 56.2 (CH3), 55.9
(CH3), 55.8 (CH3), 52.3 (CH3), 49.4 (CH2), 37.8 (CH2) ppm. IR
(KBr): νmax = 2925, 2850, 1728, 1514, 1462, 1263, 1233, 1158, 1040
˜
cm–1. MS (EI, 70 eV): m/z (%) = 547 and 545 (33 and 32) [M]+·,
383 and 381 (both 20), 351 and 349 (both 25), 164 (100), 151 (64).
Compound 15: A solution of pyrrole 13 (31 mg, 0.06 mmol) in
THF/H2O (1.3 mL of 3:1 v/v mixture) was treated with potassium
carbonate (32 mg, 0.23 mmol), TBAB (4 mg, 20 mol-%) and bor-
onic acid 14 (32 mg, 0.12 mmol). The resulting mixture was flushed
with nitrogen then treated with Pd(PPh3)4 (7 mg, 10 mol-%),
flushed again with nitrogen and the vessel containing the reaction
mixture then sealed and subjected to microwave irradiation (150 W,
90 °C, 1 min ramp time) for 1 h. The cooled reaction mixture was
diluted with H2O (20 mL) and extracted with ethyl acetate
(4ϫ30 mL). The combined organic phases were washed with brine
ν
max = 3436, 2921, 2851, 1716, 1515, 1465, 1260, 1231, 1156, 1027,
˜
769 cm–1. MS (EI, 70 eV): m/z (%) = 589 (28) [M]+·, 545 (100), 425
(14), 407 (19), 394 (52), 381 (87), 334 (11), 164 (33), 151 (56).
Compound 3 (Lamellarin G Trimethyl Ether): Following the pro-
cedure outlined by Iwao et al.,[7b] a magnetically stirred solution
of pyrrole 16 (11 mg, 0.019 mmol) and palladium acetate (5 mg,
0.021 mmol) in acetonitrile (1 mL) was heated to 82 °C for 14 h.
(1ϫ30 mL) before being dried (Na2SO4), filtered and concentrated After cooling the reaction mixture to 18 °C, it was subjected to
94 Eur. J. Org. Chem. 2011, 88–99
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Modular Total Syntheses of Lamellarins
flash chromatography (silica, 19:1 v/v CH2Cl2/ethyl acetateǞ4:1
v/v CH2Cl2/ethyl acetate gradient elution) and concentration of the
appropriate fractions (Rf = 0.5 in 9:1 v/v CH2Cl2/methanol) fur-
150.1 (C), 143.3 (C), 120.3 (CH), 108.2 (CH), 106.7 (CH), 96.9
(CH), 73.1 (CH), 71.3 (CH), 61.8 (CH2), 30.4 (CH2), 25.2 (CH2),
22.2 (2ϫCH ), 22.0 (2ϫCH ), 18.8 (CH ) ppm. IR (NaCl): ν
˜
max
3
3
2
nished 3[7] (5 mg, 48%) as a white solid, m.p. 233–234 °C (ref.[7g] = 2973, 2941, 1605, 1502, 1110, 965 cm–1. MS (EI, 70 eV): m/z (%)
m.p. 238–239 °C) (found [M + Na]+, 566.1789. C32H29NO8 requires = 294 (15) [M]+·, 210 (60), 168 (62), 126 (63), 85 (63), 43 (100).
1
[M + Na]+, 566.1791). H NMR (400 MHz, CDCl3): see Table 1.
Compound 21: Compound 20 (830 mg, 2.82 mmol) and sodium car-
13C NMR (200 MHz, CDCl ): see Table 2. IR (KBr): νmax = 3435,
˜
3
bonate (2.00 g) were dissolved in DMF (10 mL) and the resulting
solution cooled to 0 °C then treated, in portions, with NBS
(702 mg, 3.95 mmol). After 1 h the ice-bath was removed and stir-
ring continued for another 2 h. Ethyl acetate (50 mL) and water
(20 mL) were then added to the reaction mixture and the phases
separated. The aqueous phase was extracted with ethyl acetate
(4ϫ50 mL) and the combined organic phases were then washed
with water (1ϫ50 mL) before being concentrated under reduced
pressure. The residue was taken up in ethyl ether (100 mL) and
the resulting solution washed with water (2ϫ50 mL) then brine
(1ϫ50 mL) before being concentrated under reduced pressure. The
residue was taken up in pentane (200 mL) and the resulting mixture
filtered (to remove residual succinimide) and concentrated under
reduced pressure to give 21 (900 mg, 86%) as a white solid, m.p.
48–50 °C (found [M]+·, 374.0916. C17H25O481Br requires [M]+·,
374.0916). 1H NMR (400 MHz, C6D6): δ = 7.19 (s, 1 H), 6.99 (s, 1
H), 5.17 (t, J = 2.8 Hz, 1 H), 4.26 (sept, J = 6.0 Hz, 1 H), 4.02
(sept, J = 6.4 Hz, 1 H), 3.78 (dt, J = 10.8 and 2.8 Hz, 1 H), 3.31
(td, J = 10.8 and 4.4 Hz, 1 H), 2.01–1.88 (complex m, 1 H), 1.82–
1.72 (complex m, 1 H), 1.56–1.44 (complex m, 1 H), 1.36–1.22
(complex m, 2 H), 1.18–1.15 (complex m, 1 H), 1.09 (d, J = 6.0 Hz,
3 H), 1.08 (d, J = 6.0 Hz, 3 H), 1.04 (d, J = 6.0 Hz, 6 H) ppm. 13C
NMR (75 MHz, C6D6): δ = 149.4 (C), 148.7 (C), 144.5 (C), 122.8
(CH), 107.9 (CH), 103.4 (C), 97.3 (CH), 72.5 (CH), 71.6 (CH), 61.1
(CH2), 30.2 (CH2), 25.2 (CH2), 21.9 (2ϫCH3), 21.8 (2ϫCH3), 18.3
2925, 2851, 1706, 1619, 1580, 1545, 1514, 1486, 1463, 1414, 1338,
1263, 1240, 1213, 1165, 1039 cm–1. MS (ESI): m/z (%) = 567 (39)
[M + Na]+, 545 (100) [M + H]+, 414 (44), 302 (76), 149 (49).
Compound 18: 3,4-Dihydroxybenzaldehyde (8.78 g, 63.6 mmol) was
dissolved in DMF (20 mL) and the resulting solution treated with
finely ground potassium carbonate (27.3 g, 197.5 mmol) and 2-bro-
mopropane (11.1 mL, 118.5 mmol). The ensuing mixture was
heated at 55 °C for 14 h in an apparatus equipped with a reflux
condenser. The cooled reaction mixture was diluted with ethyl acet-
ate (200 mL) then water (300 mL) and the separated aqueous phase
extracted with ethyl acetate (4ϫ150 mL). The combined organic
phases were washed with water (1ϫ200 mL) then concentrated un-
der reduced pressure. The residue thus obtained was dissolved in
diethyl ether (100 mL) and the resulting solution washed with water
(2ϫ100 mL) and brine (1ϫ200 mL) before being dried (Na2SO4),
filtered and concentrated under reduced pressure to give 18[13]
(12.54 g, 89%) as a clear, colorless oil (found [M]+·, 222.1255.
1
C13H18O3 requires [M]+·, 222.1256). H NMR (300 MHz, CDCl3):
δ = 9.82 (s, 1 H), 7.44 (dd, J = 4.8 and 1.8 Hz, 1 H), 7.43 (s, 1 H),
6.98 (d, J = 8.1 Hz, 1 H), 4.96 (quint, J = 6.6 Hz, 1 H), 4.53 (quint,
J = 6.3 Hz, 1 H), 1.39 (d, J = 6.6 Hz, 6 H), 1.36 (d, J = 6.3 Hz, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 190.9 (CH), 154.9 (C),
148.9 (C), 130.0 (C), 126.4 (CH), 116.1 (CH), 114.8 (CH), 72.4
(CH), 71.8 (CH), 22.1 (2ϫCH3), 22.0 (2ϫCH3) ppm. IR (NaCl):
ν
= 2979, 1690, 1594, 1267, 1106, 947 cm–1. MS (EI, 70 eV):
(CH ); ppm. IR (NaCl): ν
= 2974, 2929, 1490, 1196, 1110, 960
˜
2
max
˜
max
cm–1. MS (EI, 70 eV): m/z (%) = 374 and 372 (both 2) [M]+·, 290
and 288 (both 78), 246 and 244 (72 and 70), 206 and 204 (85 and
83), 85 (75), 43 (100).
m/z (%) = 222 (59) [M]+·, 180 (39), 137 (100), 109 (25), 81 (27), 43
(81).
Compound 19: Compound 19 was prepared from benzaldehyde 18
according to the method of Yang et al.[13] and isolated in 98% yield
as a light-brown oil (found [M]+·, 210.1255. C12H18O3 requires [M]
+·, 210.1256). 1H NMR (300 MHz, CDCl3): δ = 6.79 (d, J = 9.0 Hz,
1 H), 6.44 (d, J = 3.0 Hz, 1 H), 6.31 (dd, J = 8.7 and 3.0 Hz, 1 H),
4.75 (s, 1 H), 4.45 (sept, J = 5.7 Hz, 1 H), 4.27 (sept, J = 6.6 Hz,
1 H), 1.32 (d, J = 5.7 Hz, 6 H), 1.28 (d, J = 5.7 Hz, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 152.0 (C), 150.1 (C), 141.0 (C), 121.1
(CH), 107.1 (CH), 104.3 (CH), 74.2 (CH), 71.1 (CH), 22.1
Compound 22: n-Butyllithium (1.0 mL of a 1.6 m solution in hex-
ane, 1.57 mmol) was added, dropwise over 0.25 h, to a magnetically
stirred solution of compound 21 (450 mg, 1.21 mmol) and tri-
isopropyl borate (550 μL, 2.41 mmol) in THF (15 mL) maintained
at –78 °C. Stirring was continued at this temperature for 0.66 h then
the reaction mixture was warmed to 18 °C over 12 h. The reaction
mixture was then treated with HCl (5 mL of a 1 m aqueous solu-
tion) and after a further 0.25 h the phases were separated and the
aqueous one was extracted with THF (3ϫ20 mL). The combined
organic phases were washed with brine (1ϫ50 mL) before being
dried (Na2SO4), filtered, and concentrated under reduced pressure
to give a yellow, mud-like solid. This solid was dissolved in diethyl
(2ϫCH ), 21.9 (2ϫCH ) ppm. IR (NaCl): ν = 3372, 2976,
˜
max
3
3
2932, 1601, 1507, 1110, 995 cm–1. MS (EI, 70 eV): m/z (%) = 210
(53) [M]+·, 168 (69), 127 (78), 97 (71), 43 (100).
Compound 20: DHP (0.8 mL, 8.48 mmol) and PPTS (71 mg, ether (20 mL) and the resulting solution treated with pinacol
0.28 mmol) were added to a magnetically stirred solution of com-
pound 19 (594 mg, 2.83 mmol) in dichloromethane (2 mL) main-
tained at 18 °C. After 2 h the reaction mixture was diluted with
dichloromethane (18 mL) and water (18 mL). The separated aque-
ous phase was extracted with dichloromethane (3ϫ20 mL) and the
combined organic phases were washed with brine (1ϫ50 mL) be-
fore being dried (Na2SO4), filtered and concentrated under reduced
(300 mg, 2.54 mmol). The ensuing slurry was stirred magnetically
for 24 h then concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography (silica, 9:1
v/v pentane/diethyl etherǞ5:1 v/v pentane/diethyl ether gradient
elution) and concentration of the appropriate fractions (Rf = 0.4
in 3:1 v/v pentane/diethyl ether) furnished 22 (221 mg, 55%) as a
clear, colorless oil (found [M]+·, 336.2109. C18H2911BO5 requires
1
pressure to give 20 (830 mg, quant.) as a clear, red oil (found [M]
[M]+·, 336.2108). H NMR (300 MHz, CDCl3): δ = 7.67 (s, 1 H),
+·
,
294.1827. C17H26O4 requires [M]+·, 294.1831). 1H NMR
7.13 (s, 1 H), 6.42 (s, 1 H), 4.54 (quint, J = 6.6 Hz, 1 H), 4.24
(quint, J = 6.6 Hz, 1 H), 1.35 (d, J = 6.6 Hz, 6 H), 1.34 (s, 12 H),
1.27 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
(300 MHz, CDCl3): δ = 6.83 (d, J = 8.7 Hz, 1 H), 6.65 (d, J =
3.0 Hz, 1 H), 6.57 (dd, J = 8.7 and 3.0 Hz, 1 H), 5.30 (t, J = 3.3 Hz,
1 H), 4.48 (quint, J = 6.6 Hz, 1 H), 4.30 (quint, J = 6.3 Hz, 1 H), 160.4 (C), 155.0 (C), 141.4 (C), 126.6 (CH), 102.2 (CH), 84.1 (C),
4.00–3.82 (complex m, 2 H), 3.66–3.54 (complex m, 2 H), 2.08– 74.2 (CH), 70.6 (CH), 24.8 (4ϫCH3), 22.4 (2ϫCH2), 22.0
1.60 (complex m, 4 H), 1.33 (d, J = 6.3 Hz, 6 H), 1.29 (d, J = (2ϫCH3) (signal due to sp2-hybridized carbon bearing B not ob-
6.0 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.5 (C), served) ppm. 11B NMR (96 MHz, CDCl3): δ = 30.0 ppm. IR
Eur. J. Org. Chem. 2011, 88–99
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
95

K. Hasse, A. C. Willis, M. G. Banwell
FULL PAPER
(NaCl): νmax = 3453, 2977, 2933, 1623, 1388, 1140, 1111, 963 cm–1. Pampin et al.[18] and obtained in 82% yield as a light-yellow oil.
˜
MS (EI, 70 eV): m/z (%) = 336 (51) [M]+·, 294 (22), 252 (35), 205 The derived spectroscopic data matched those reported in the lit-
(60), 195 (100), 152 (70).
erature.[18]
Compound 23: A mixture of pyrrole 8 (603 mg, 0.36 mmol), potas-
sium carbonate (1.08 g, 7.81 mmol), TBAB (123 mg, 20 mol-%)
and boronate ester 22 (1.09 g, 3.25 mmol) in THF/H2O (27 mL of
3:1 v/v mixture) was divided into six equal portions each of which
was placed in a microwave reactor vial. The contents of each vial
were flushed with nitrogen then Pd(PPh3)4 (37.3 mg, 10 mol-%) was
added to each and the vials once again flushed with nitrogen before
being sealed. The contents of each vial were subjected to microwave
irradiation (150 W, 60 °C, 1 min ramp time) for 1 h then cooled,
combined and diluted with H2O (200 mL) before being extracted
with ethyl acetate (4ϫ50 mL). The combined organic phases were
washed with brine (1ϫ100 mL) then dried (Na2SO4), filtered and
concentrated under reduced pressure. The resulting light-yellow so-
lid was subjected to flash chromatography (silica, 5:1 v/v pentane/
diethyl etherǞ1:1 v/v pentane/diethyl ether gradient elution) and
concentration of the appropriate fractions (Rf = 0.2 in 1:1 v/v pen-
tane/diethyl ether) furnished 23 (647 mg, 92%) as a white solid,
m.p. 172–173 °C (found [M]+·, 359.1365. C19H21NO6 requires [M]
+·, 359.1369). 1H NMR (400 MHz, CDCl3): δ = 10.41 (s, 1 H), 7.24
(s, 1 H), 7.21 (s, 1 H), 6.95 (s, 1 H), 4.55 (quint, J = 6.4 Hz, 1 H),
4.48 (quint, J = 6.0 Hz, 1 H), 3.98 (s, 3 H), 1.38 (d, J = 6.0 Hz, 6
H), 1.36 (d, J = 6.4 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 160.6 (C), 155.3 (C), 150.4 (C), 147.0 (C), 145.9 (C), 130.6 (C),
129.8 (C), 118.7 (C), 112.4 (CH), 109.9 (C), 107.0 (CH), 105.1
(CH), 73.5 (CH), 72.0 (CH), 52.5 (CH3), 22.2 (2ϫCH3), 21.9
Step iii: 2-(3-Isopropoxy-4-methoxyphenyl)ethanol (25) was pre-
pared from 2-isopropoxy-1-methoxy-4-vinylbenzene according to
the method of Bach et al.[15] and isolated in 58% yield as a clear,
colorless oil. The derived spectroscopic data matched those re-
ported in the literature.[15]
Compound 26: A magnetically stirred solution of pyrrole 24
(583 mg, 1.33 mmol) in THF (20 mL) was treated with tri-
phenylphosphane (698 mg, 2.66 mmol), compound 25 (521 mg,
2.48 mmol) and DIAD (538 mg, 2.66 mmol) and the ensuing mix-
ture stirred at 18 °C for 1 h then treated with TLC-grade silica gel
(2.0 g) and concentrated under reduced pressure. The resulting free-
flowing solid was subjected to flash chromatography (silica, dichlo-
romethane elution) and concentration of the appropriate fractions
(Rf = 0.2) afforded 26 (803 mg, 96%) as a clear, colorless oil (found
[M]+·, 631.1605. C31H3681BrNO8 requires [M]+·, 631.1604). 1H
NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 6.93 (s, 1 H), 6.78 (d,
J = 8.4 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 6.72 (s, 1 H), 5.07 (t,
J = 7.2 Hz, 2 H), 4.56 (quint, J = 5.6 Hz, 1 H), 4.49 (quint, J =
6.4 Hz, 1 H), 4.47 (quint, J = 5.6 Hz, 1 H), 3.92 (s, 3 H), 3.82 (s, 3
H), 3.00 (t, J = 7.6 Hz, 2 H), 1.40 (d, J = 6.4 Hz, 6 H), 1.39 (d, J
= 6.0 Hz, 6 H), 1.33 (d, J = 6.4 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.3 (C), 154.3 (C), 150.3 (C), 149.2 (C),
147.3 (C), 146.7 (C), 145.3 (C), 130.1 (C), 129.9 (C), 126.3 (C),
121.5 (CH), 117.9 (C), 116.5 (CH), 112.1 (CH), 111.9 (CH), 109.3
(C), 104.5 (CH), 95.9 (C), 73.3 (CH), 72.0 (CH), 71.4 (CH), 56.1
(CH3), 52.2 (CH3), 49.3 (CH2), 37.7 (CH2), 22.1 (2ϫCH3), 22.1
(2ϫCH ) ppm. IR (KBr): ν
= 3445, 3261, 2975, 2930, 1737,
˜
3
max
1710, 1278, 1108, 774 cm–1. MS (EI, 70 eV): m/z (%) = 359 (41)
[M]+·, 317 (16), 275 (100), 243 (98), 98 (14), 159 (15), 43 (20).
(2ϫCH ), 21.9 (2ϫCH ) ppm. IR (NaCl): ν = 2976, 2932,
˜
max
3
3
1732, 1507, 1266, 1157, 1109, 1011, 935 cm–1. MS (EI, 70 eV): m/z
(%) = 631 and 629 (100 and 98) [M]+·, 589 and 587 (9 and 8), 547
and 545 (11 and 10), 395 and 393 (21 and 23), 353 and 351 (82),
323 and 321 (both 38).
Compound 24: A magnetically stirred solution of pyrrole 23 (70 mg,
0.20 mmol) in DMF (1.5 mL) was cooled to 0 °C then treated, in
one portion, with NBS (42 mg, 0.24 mmol) and the ensuing mix-
ture warmed to 18 °C, stirred at this temperature for 14 h then di-
luted with water (20 mL) and extracted with ethyl acetate
(4ϫ30 mL). The combined organic phases were washed with water
(1ϫ30 mL) and brine (1ϫ30 mL) before being dried (Na2SO4),
filtered and concentrated under reduced pressure. The ensuing
light-yellow solid was subjected to flash chromatography (silica, 3:1
v/v pentane/diethyl etherǞ1:1 v/v pentane/diethyl ether gradient
elution) and concentration of the appropriate fractions (Rf = 0.2
in 1:1 v/v pentane/diethyl ether) furnished 24 (80 mg, 94%) as a
white solid, no melting point, decomposition above 230 °C (found
[M]+·, 437.0465. C19H2079BrNO6 requires [M]+·, 437.0474). 1H
NMR (300 MHz, CDCl3): δ = 10.00 (s, 1 H), 8.24 (s, 1 H), 6.97 (s,
1 H), 6.95 (s, 1 H), 4.57 (quint, J = 6.3 Hz, 1 H), 4.52 (quint, J =
6.0 Hz, 1 H), 4.01 (s, 3 H), 1.40 (d, J = 6.0 Hz, 12 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.5 (C), 154.7 (C), 150.4 (C), 146.8
(C), 145.6 (C), 127.4 (C), 126.9 (C), 117.9 (C), 111.3 (CH), 109.4
(C), 105.0 (CH), 96.9 (C), 73.3 (CH), 72.1 (CH), 52.7 (CH3), 22.1
Compound 27. Step i: 4-Bromobenzene-1,2-diol was prepared from
4-bromoveratrol according to the method of Hille et al.[19] and ob-
tained in 73% yield as a white, crystalline solid, m.p. 81–84 °C.
Step ii: A magnetically stirred solution of 4-bromobenzene-1,2-diol
(1.42 g, 7.53 mmol) in DMF (8 mL) was treated with finely ground
potassium carbonate (5.21 g, 37.7 mmol) and 2-bromopropane
(2.12 mL, 22.6 mmol). The resulting mixture was heated at 55 °C
for 14 h in an apparatus fitted with a reflux condenser then cooled
and diluted with ethyl acetate (50 mL) and water (50 mL). The sep-
arated aqueous phase was extracted with ethyl acetate (4ϫ30 mL)
and the combined organic phases were washed with water
(1ϫ30 mL) before being concentrated under reduced pressure. The
residue was taken up in diethyl ether (50 mL) and the resulting
solution washed with water (2ϫ40 mL) and brine (1ϫ50 mL) be-
fore being dried (Na2SO4), filtered and concentrated under reduced
pressure to give 4-bromo-1,2-diisopropoxybenzene (1.81 g, 88%) as
a clear, red oil (found [M]+·, 272.0413. C12H1779BrO2 requires [M]
+·, 272.0412). 1H NMR (300 MHz, CDCl3): δ = 7.02 (d, J = 2.4 Hz,
1 H), 7.00 (dd, J = 9.3 and 2.1 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H),
4.43 (sept, J = 6.3 Hz, 2 H), 1.33 (d, J = 6.3 Hz, 6 H), 1.31 (d, J
= 6.6 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.1 (C),
148.3 (C), 124.3 (CH), 120.8 (CH), 119.6 (CH), 113.5 (C), 72.5
(CH), 72.3 (CH), 22.1 (2ϫCH3), 22.1 (2ϫCH3) ppm. IR (NaCl):
(2ϫCH ), 21.9 (2ϫCH ) ppm. IR (KBr): νmax = 3433, 3237, 2974,
˜
3
3
2932, 1709, 1491, 1275, 1111, 771 cm–1. MS (EI, 70 eV): m/z (%) =
439 and 437 (6 and 6) [M]+·, 355 and 353 (17 and 17), 323 and 321
(21 and 21), 277 (90), 149 (62), 69 (75), 57 (100).
Compound 25: Step i: 3-Isopropoxy-4-methoxybenzaldehyde was
prepared from isovanillin according to the method of Pampin et
al.[18] and isolated in quantitative yield as a light-yellow oil. The
derived spectroscopic data matched those reported in the litera-
ture.[18]
ν
= 2976, 2931, 1584, 1488, 1257, 1107, 957 cm–1. MS (EI,
˜
max
70 eV): m/z (%) = 274 and 272 (both 42) [M]+·, 232 and 230 (21
and 22), 189 and 187 (both 100), 161 and 159 (both 12), 109 (14),
79 (19), 44 (57).
Step ii: 2-Isopropoxy-1-methoxy-4-vinylbenzene was prepared from
3-isopropoxy-4-methoxybenzaldehyde according to the method of
96
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 88–99

Modular Total Syntheses of Lamellarins
Step iii: n-Butyllithium (7.0 mL of a 1.6 m solution in hexane,
11.27 mmol) was added, dropwise over 0.25 h, to a magnetically
stirred solution of 4-bromo-1,2-diisopropoxybenzene (1.54 g,
5.634 mmol) and triisopropyl borate (2.6 mL, 11.268 mmol) in
THF (30 mL) maintained at –78 °C and stirring was continued at
this temperature for 0.66 h. The reaction mixture was then warmed
to 18 °C over 12 h and treated with HCl (25 mL of a 1 m aqueous
solution). After a further 0.25 h the separated aqueous phase was
extracted with THF (3ϫ30 mL) and the combined organic phases
were washed with brine (1ϫ100 mL) before being dried (Na2SO4),
filtered, and concentrated under reduced pressure to give a light-
yellow solid. Subjection of this material to flash chromatography
(silica, 3:1 v/v pentane/diethyl etherǞ1:3 v/v pentane/diethyl ether
gradient elution) and concentration of the appropriate fractions (Rf
tion of KOH (8.1 g, 0.144 mol) in water (12.5 mL). The resulting
mixture was heated at 130 °C for 4 h and the methanol so formed
was removed by continuous distillation. The reaction mixture was
cooled to 0 °C, acidified by the dropwise addition of HCl (37%
w/v aqueous solution), and then extracted with ethyl acetate
(3ϫ30 mL). The combined organic phases were washed with brine
(1ϫ50 mL) then dried (Na2SO4), filtered and concentrated under
reduced pressure to afford a deep-yellow oil. The residue thus ob-
tained was dissolved in toluene (43 mL) and the resulting solution
treated with p-toluenesulfonic acid monohydrate (24 mg) and 4 Å
molecular sieves (351 mg) then heated at reflux for 0.5 h. The co-
oled reaction mixture was filtered and the filtrate concentrated un-
der reduced pressure to give a light-yellow oil. Subjection of this
material to flash chromatography (silica, 3:1 v/v pentane/diethyl
ether + 1% acetic acidǞ1:1 pentane/diethyl ether + 1% acetic acid
= 0.3 in 1:3 v/v pentane/diethyl ether) gave 27 (882 mg, 66%) as a
1
white solid, m.p. 44–47 °C. H NMR (300 MHz, CDCl3): δ = 7.82 gradient elution) afforded two fractions, A and B.
(dd, J = 7.5 and 1.2 Hz, 1 H), 7.75 (d, J = 1.2 Hz, 1 H), 7.03 (d, J
Concentration of fraction A (Rf = 0.3 in 1:1 v/v pentane/diethyl
= 8.1 Hz, 1 H), 4.64 (quint, J = 6.0 Hz, 1 H), 4.55 (quint, J =
ether) afforded 29 (34 mg, 16%) as a clear, colorless oil (found [M
6.3 Hz, 1 H), 1.40 (d, J = 6.0 Hz, 6 H), 1.40 (d, J = 6.0 Hz, 6 H)
+ Na]+, 682.3719. C40H53NO723Na requires [M + Na]+, 682.3720).
ppm. 13C NMR (75 MHz, CDCl3): δ = 153.5 (C), 148.1 (C), 130.6
1H NMR (300 MHz, CDCl3): δ = 6.84–6.74 (complex m, 4 H), 6.71
(CH), 125.8 (CH), 115.7 (CH), 72.9 (CH), 71.3 (CH), 22.3
(s, 1 H), 6.67 (s, 1 H), 6.66 (dd, J = 8.4 and 1.5 Hz, 1 H), 6.59 (d,
(2ϫCH3), 22.1 (2ϫCH2) (signal due to sp2-hybridized carbon
J = 1.8 Hz, 1 H), 6.53 (d, J = 2.4 Hz, 1 H), 6.48 (s, 1 H), 5.06 (s,
bearing B not observed) ppm. IR (NaCl): νmax = 3493, 2976, 2932,
˜
1 H), 4.45 (quint, J = 6.0 Hz, 1 H), 4.42 (quint, J = 6.0 Hz, 1 H),
4.37 (quint, J = 5.7 Hz, 1 H), 4.24–4.12 (complex m, 1 H), 4.09 (t,
J = 6.9 Hz, 2 H), 3.84 (s, 3 H), 3.01 (t, J = 6.9 Hz, 2 H), 1.34 (d,
J = 6.0 Hz, 6 H), 1.29 (d, J = 6.0 Hz, 6 H), 1.29 (d, J = 6.3 Hz, 6
H), 1.20 (d, J = 6.3 Hz, 6 H), 1.17 (d, J = 5.7 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 149.8 (C), 149.3 (C), 149.0 (C), 148.7
(C), 147.2 (C), 147.2 (C), 141.8 (C), 145.8 (C), 145.6 (C), 130.6
(CH), 128.9 (CH), 123.5 (C), 122.7 (CH), 121.1 (C), 121.1 (CH),
119.8 (CH), 119.5 (C), 118.7 (CH), 116.5 (C), 116.4 (CH), 115.9
(C), 113.8 (C), 112.0 (CH), 103.8 (CH), 73.5 (CH), 72.4 (CH), 71.6
(CH), 71.4 (CH), 71.4 (CH), 56.0 (CH3), 51.8 (CH2), 37.7 (CH2),
22.3 (2ϫCH3), 22.2 (2ϫCH3), 22.2 (2ϫCH3), 22.1 (2ϫCH3), 22.1
1598, 1412, 1341, 1263, 1109, 948 cm–1. Satisfactory mass spectro-
metric data could not be obtained on this compound.
Compound 28: A magnetically stirred solution of pyrrole 26 (63 mg,
0.100 mmol) in THF/H2O (2.3 mL of 3:1 v/v mixture) was treated
with potassium carbonate (0.055 g, 0.400 mmol), TBAB (6 mg,
20 mol-%) and boronic acid 27 (43 mg, 0.18 mmol). The resulting
mixture was flushed with nitrogen, then Pd(PPh3)4 (12 mg, 10 mol-
%) was added and the reaction vessel again flushed with nitrogen
then sealed. The reaction mixture was subjected to microwave irra-
diation (150 W, 90 °C, 1 min ramp time) for 1.5 h then cooled and
diluted with H2O (20 mL) before being extracted with ethyl acetate
(4ϫ30 mL). The combined organic phases were washed with brine
(1ϫ30 mL) then dried (Na2SO4), filtered and concentrated under
reduced pressure. The ensuing light-yellow oil was subjected to
flash chromatography (silica, 3:1 v/v pentane/diethyl etherǞ1:1
pentane/diethyl ether gradient elution) and concentration of the ap-
propriate fractions (Rf = 0.3 in 1:1 v/v pentane/diethyl ether) fur-
nished 28 (50 mg, 67%) as a white, crystalline solid, m.p. 36–42 °C
(found [M + Na]+, 766.3568. C43H53NO10 requires [M + Na]+,
(2ϫCH ) ppm. IR (NaCl): ν
= 3436, 2974, 2929, 1540, 1499,
˜
3
max
1261, 1109, 957 cm–1. MS (ESI): m/z (%) = 682 (100) [M + Na]+,
660 (76) [M + H]+.
Concentration of fraction B (Rf = 0.1 in 1:1 v/v pentane/diethyl
ether) afforded 30 (118 mg, 49%) as a pale-brown solid, no melting
point, decomposition above 170 °C (found [M]+·, 729.3528.
C42H51NO10 requires [M]+·, 729.3513). 1H NMR (300 MHz,
CDCl3): δ = 8.98 (br. s, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 6.94–6.82
(complex m, 4 H), 6.80–6.70 (complex m, 2 H), 6.55 (s, 1 H), 5.14
(t, J = 8.1 Hz, 2 H), 4.60–4.38 (complex m, 4 H), 3.93 (quint, J =
5.7 Hz, 1 H), 3.79 (s, 3 H), 3.06 (d, J = 6.9 Hz, 2 H), 1.39 (d, J =
6.0 Hz, 3 H), 1.33 (d, J = 6.3 Hz, 3 H), 1.29 (d, J = 6.3 Hz, 3 H),
1.29 (d, J = 6.3 Hz, 3 H), 1.13 (d, J = 5.7 Hz, 3 H), 1.12 (d, J =
6.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.4 (C),
155.2 (C), 149.1 (C), 149.1 (C), 149.0 (C), 148.9 (C), 147.2 (C),
146.1 (C), 145.4 (C), 130.3 (C), 128.0 (C), 127.1 (C), 126.9 (C),
126.0 (C), 123.1 (CH), 121.5 (CH), 119.9 (CH), 118.4 (C), 117.3
(CH), 116.6 (CH), 112.1 (CH), 110.4 (C), 110.1 (CH), 105.1, 72.2
(CH), 72.0 (3ϫCH), 71.3 (CH), 56.0 (CH3), 48.8 (CH2), 37.8
(CH2), 22.4 (CH3), 22.1 (2ϫCH3), 22.1 (3ϫCH3), 21.9 (2ϫCH3),
1
766.3567). H NMR (300 MHz, CDCl3): δ = 6.99 (d, J = 8.1 Hz,
1 H), 6.90 (s, 1 H), 6.88–6.80 (complex m, 3 H), 6.79 (m, 2 H), 6.61
(s, 1 H), 5.10 (t, J = 7.2 Hz, 2 H), 4.60–4.40 (complex m, 4 H),
3.94 (quint, J = 6.0 Hz, 1 H), 3.82 (s, 3 H), 3.54 (s, 3 H), 3.11–3.02
(complex m, 2 H), 1.40 (d, J = 6.0 Hz, 3 H), 1.40 (d, J = 6.6 Hz,
3 H), 1.34 (d, J = 5.7 Hz, 3 H), 1.34 (d, J = 5.7 Hz, 3 H), 1.32 (d,
J = 6.6 Hz, 3 H), 1.13 (d, J = 5.7 Hz, 3 H), 1.12 (d, J = 6.0 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.4 (C), 155.2 (C),
149.1 (C), 149.0 (C), 148.9 (C), 148.7 (C), 147.2 (C), 146.2 (C),
145.4 (C), 130.5 (CH), 129.4 (C), 127.8 (C), 126.9 (C), 124.4 (C),
123.2 (CH), 121.5 (CH), 119.8 (CH), 117.7 (CH), 117.5 (C), 116.5
(C), 111.9 (CH), 110.5 (CH), 110.3 (C), 105.2 (CH), 72.2 (CH),
72.1 (CH), 72.1 (CH), 72.0 (CH), 71.2 (CH), 56.0 (CH3), 51.7
(CH3), 48.6 (CH2), 37.8 (CH2), 22.4 (CH3), 22.2 (CH3), 22.1 (CH3),
22.1 (3ϫCH3), 21.9 (2ϫCH3), 21.9 (2ϫCH3) ppm. IR (NaCl):
21.9 (CH ), 21.8 (CH ) ppm. IR (NaCl): ν = 3292, 2975, 2926,
˜
max
3
3
1729, 1261, 1109, 974 cm–1. MS (EI, 70 eV): m/z (%) = 729 (74)
[M]+·, 685 (100), 369 (72), 325 (87), 151 (66).
ν
= 2976, 2933, 1730, 1264, 1226, 1110, 1017, 936 cm–1. MS
˜
max
(ESI): m/z (%) = 766 (78) [M + Na]+, 744 (100) [M + H]+, 702
Compound 31: Following the procedure detailed by Iwao et al.,[7b]
a magnetically stirred solution of pyrrole 30 (40 mg, 0.06 mmol)
and Pd(OAc)2 (14 mg, 0.006 mmol) in acetonitrile (5 mL) was
heated to 82 °C for 14 h. After cooling the reaction mixture to
18 °C, it was subjected to flash chromatography (silica, 3:1 v/v pent-
(18).
Compounds 29 and 30: Following the procedure detailed by Steglich
et al.,[7a] a finely ground sample of compound 28 (243 mg,
0.327 mmol) was suspended in a freshly prepared, degassed solu-
Eur. J. Org. Chem. 2011, 88–99
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
97

K. Hasse, A. C. Willis, M. G. Banwell
FULL PAPER
ane/diethyl ether + 1% triethylamineǞ1:1 pentane/diethyl ether
+ 1% triethylamine gradient elution) and concentration of the ap-
propriate fractions (Rf = 0.2 in 1:1 v/v pentane/diethyl ether) af-
forded 31 (21 mg, 56%) as a yellow solid, m.p. 169–178 °C (found
[M + Na]+, 706.3362. C41H49NO823Na requires [M + Na]+,
Acknowledgments
We thank the Gottlieb Daimler and Karl Benz Foundation for the
provision of a PhD stipend (to K. H.) and the Australian Research
Council for a grant (DP0771749). Professor Rob Capon and Dr
Fabien Plisson (IMB, University of Queensland) are warmly
thanked for undertaking an HPLC comparison of the synthetically
derived lamellarin S (2) with the natural product.
1
706.3356). H NMR (300 MHz, CDCl3): δ = 7.10 (d, J = 8.4 Hz,
1 H), 7.03 (s, 1 H), 7.01 (d, J = 4.8 Hz, 1 H), 6.92 (s, 1 H), 6.76 (s,
1 H), 6.72 (s, 1 H), 6.71 (s, 1 H), 4.90–4.66 (complex m, 2 H), 4.60–
4.38 (complex m, 4 H), 3.97 (sept, J = 5.7 Hz, 1 H), 3.34 (s, 3 H),
3.08 (t, J = 6.6 Hz, 2 H), 1.39 (d, J = 6.6 Hz, 3 H), 1.39 (d, J =
6.3 Hz, 3 H), 1.37 (d, J = 6.6 Hz, 6 H), 1.34 (d, J = 6.3 Hz, 6 H),
1.31 (d, J = 5.4 Hz, 3 H), 1.29 (d, J = 5.7 Hz, 3 H), 1.14 (d, J =
5.7 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.7 (C),
150.2 (C), 148.8 (C), 148.7 (C), 148.6 (C), 147.2 (C), 146.4 (C),
145.2 (C), 136.0 (C), 129.2 (CH), 128.2 (C), 126.3 (C), 123.8 (CH),
120.2 (C), 119.5 (1ϫCH, 1ϫC), 115.0 (C), 114.6 (C), 113.6 (C),
111.1 (C), 110.8 (CH), 109.1 (CH), 105.3 (CH), 72.8 (CH), 72.2
(CH), 72.1 (CH), 71.9 (CH), 71.3 (CH), 55.1 (CH3), 42.4 (CH2),
28.7 (CH2), 22.2 (2ϫCH3), 22.2 (2ϫCH3), 22.1 (2ϫCH3), 22.0
[1] N. Lindquist, W. Fenical, G. D. Van Duyne, J. Clardy, J. Org.
Chem. 1988, 53, 4570.
[2] S. Urban, R. J. Capon, Aust. J. Chem. 1996, 49, 711.
[3] a) P. Cironi, F. Albericio, M. Álvarez, Prog. Heterocycl. Chem.
2005, 16, 1; b) H. Fan, J. Peng, M. T. Hamann, J.-F. Hu, Chem.
Rev. 2008, 108, 264; c) J. Kluza, P. Marchetti, C. Bailly, in Mod-
ern Alkaloids: Structure, Isolation, Synthesis and Biology (Eds.:
E. Fattorusso, O. Taglialatela-Scafati), Wiley–VCH, Weinheim,
Germany, 2008, pp. 171–187; d) D. Baunbaek, N. Trinkler, Y.
Ferandin, O. Lozach, P. Ploypradith, S. Rucirawat, F. Ishibashi,
M. Iwao, L. Meijer, Mar. Drugs 2008, 6, 514.
(2ϫCH ), 22.0 (2ϫCH ) ppm. IR (NaCl): ν = 2975, 2928,
˜
max
3
3
1710, 1109 cm–1. MS (EI, 70 eV): m/z (%) = 683 (100) [M]+·, 642
[4] a) C. Bailly, Curr. Med. Chem. Anti-Cancer Agents 2004, 4, 363;
b) D. Pla, F. Albericio, M. Alvarez, Anti-Cancer Agents Med.
Chem. 2008, 8, 746; c) M. Chittchang, P. Batsomboon, S. Ru-
chirawat, P. Ploypradith, ChemMedChem 2009, 4, 457.
[5] S. T. Handy, Y. Zhang, Org. Prep. Proced. Int. 2005, 37, 411.
[6] a) M. G. Banwell, B. L. Flynn, E. Hamel, D. C. R. Hockless,
Chem. Commun. 1997, 207; b) M. Banwell, B. Flynn, D. Hock-
less, Chem. Commun. 1997, 2259; c) M. G. Banwell, E. Hamel,
D. C. R. Hockless, P. Verdier-Pinard, A. C. Willis, D. J. Wong,
Bioorg. Med. Chem. 2006, 14, 4627; d) L. C. Axford, K. E.
Holden, K. Hasse, M. G. Banwell, W. Steglich, J. Wagler, A. C.
Willis, Aust. J. Chem. 2008, 61, 80; e) K. Hasse, A. C. Willis,
M. G. Banwell, Aust. J. Chem. 2009, 62, 683.
[7] For previous syntheses of lamellarin G trimethyl ether, see: a)
A. Heim, A. Terpin, W. Steglich, Angew. Chem. Int. Ed. Engl.
1997, 36, 155; b) M. Iwao, T. Takeuchi, N. Fujikawa, T. Fu-
kuda, F. Ishibashi, Tetrahedron Lett. 2003, 44, 4443; c) S. T.
Handy, Y. Zhang, H. Bregman, J. Org. Chem. 2004, 69, 2362;
d) P. Ploypradith, T. Petchmanee, P. Sahakitpichan, N. D. Lit-
vinas, S. Ruchirawat, J. Org. Chem. 2006, 71, 9440; e) J. C. Lier-
mann, T. Opatz, J. Org. Chem. 2008, 73, 4526; f) J. T. Gupton,
B. C. Giglio, J. E. Eaton, E. A. Rieck, K. L. Smith, M. J. Ke-
ough, P. J. Barelli, L. T. Firich, J. E. Hempel, T. M. Smith,
R. P. F. Kanters, Tetrahedron 2009, 65, 4283; g) J. S. Yadav,
K. U. Gayathri, B. V. S. Reddy, A. R. Prasad, Synlett 2009, 43.
[8] a) See ref. [7b]; b) N. Fujikawa, T. Ohta, T. Yamaguchi, T.
Fukuda, F. Ishibashi, M. Iwao, Tetrahedron 2006, 62, 594; c)
T. Ohta, T. Fukuda, F. Ishibashi, M. Iwao, J. Org. Chem. 2009,
74, 8143; d) T. Fukuda, T. Ohta, S. Saeki, M. Iwao, Heterocy-
cles 2010, 80, 841.
(18), 533 (25), 473 (18), 236 (18).
Compound 2 (Lamellarin S): Boron trichloride (175 μL of a 1 m
solution in dichloromethane, 0.175 mmol) was added, dropwise
over 5 min, to a magnetically stirred solution of compound 31
(12 mg, 0.0175 mmol) in dichloromethane (3 mL) maintained at
–78 °C under nitrogen. Stirring was continued at this temperature
for 0.66 h then the cooling bath was removed and the reaction mix-
ture warmed to 18 °C over 0.5 h. Stirring was continued at 18 °C
for 2 h then the reaction mixture was quenched with methanol
(10 mL) and concentrated under reduced pressure. The resulting
yellow solid was subjected to flash chromatography (silica,
CHCl3 Ǟ9:3 v/v CHCl3/ethanol gradient elution) and concentra-
tion of the appropriate fractions (Rf = 0.4 in 9:3 v/v CHCl3/ethan-
ol) afforded lamellarin S (2) (8 mg, 97%) as a pale-brown solid,
m.p. Ͼ 390 °C (found [M + Na]+, 496.1007. C26H19NO823Na re-
quires [M + Na]+, 496.1008). 1H NMR (500 MHz, CD3OD): see
Table 4 and associated text. 13C NMR (125 MHz, CD3OD): see
Table 5. IR (KBr): νmax = 3422, 2924, 2853, 1667, 1279, 1156, 1040
˜
cm–1. MS (ESI): m/z(%)= 496 (78) [M + Na]+, 474 (100) [M +
H]+, 305 (21), 180 (18), 123 (18). HPLC Rt = 8.05 min (Agilent
Zorbax C18 5 μm, 4.6ϫ150 mm column, 1 mL/min gradient
elution from 1:9 v/v H2O/acetonitrileǞacetonitrile over 15 min
with a constant 0.01 v/v TFA/acetonitrile as modifier, monitoring
by DAD at 276 nm).
X-ray Crystallographic Study on Compound 7
[9] A. Fürstner, H. Krause, O. R. Thiel, Tetrahedron 2002, 58,
6373.
[10] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
[11] D. L. Hughes, Org. Prep. Proced. Int. 1996, 28, 127.
[12] D. L. Boger, D. R. Soenen, C. W. Boyce, M. P. Hedrick, Q. Jin,
J. Org. Chem. 2000, 65, 2479.
Crystal Data: C8H7I2NO4, M = 434.96, T = 200 K, monoclinic,
space group C2/c, Z = 8, a = 31.2344(8), b = 4.2399(1), c =
19.1462(5) Å, β = 118.9638(11)°, V = 2218.41(10) Å3, Dx
=
2.604 gcm–3, 2526 unique data (2θmax = 55°), R = 0.019 [for 2107
reflections with I Ͼ 2.0σ (I)]; Rw = 0.053 (all data), S = 0.92.
[13] L.-Y. Yang, C.-F. Chang, Y.-C. Huang, Y.-J. Lee, C.-C. Hu, T.-
H. Tseng, Synthesis 2009, 1175.
Structure Determination: Images were measured on a Nonius
Kappa CCD diffractometer (Mo-Kα, graphite monochromator, λ
= 0.71073 Å) and data extracted using the DENZO package.[20]
Structure solution was by direct methods (SIR92).[21] The structure
of compound 7 was refined using the CRYSTALS program pack-
age.[22]
[14] For closely related building blocks have been prepared by Álva-
rez et al. during the course of their syntheses of lamellarin D
and certain analogs, see: a) D. Pla, A. Marchal, C. A. Olsen,
F. Albericio, M. Álvarez, J. Org. Chem. 2005, 70, 8231; b) D.
Pla, A. Marchal, C. A. Olsen, A. Francesch, C. Cuevas, F. Al-
bericio, M. Álvarez, J. Med. Chem. 2006, 49, 3257.
CCDC-787286 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[15] S. Schröter, T. Bach, Heterocycles 2007, 74, 569.
[16] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.
[17] A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen,
F. J. Timmers, Organometallics 1996, 15, 1518.
98
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 88–99

Modular Total Syntheses of Lamellarins
[18]
lography, part A (Eds.: C. W. Carter Jr., R. M. Sweet), Aca-
demic Press, New York, 1997, pp. 307–326.
[21] For SIR92, see: A. Altomare, G. Cascarano, C. Giacovazzo,
A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli, J. Appl.
Crystallogr. 1994, 27, 435.
[22] P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout, D. J.
Watkin, J. Appl. Crystallogr. 2003, 36, 1487.
M. C. Pampín, J. C. Estévez, R. J. Estévez, R. Suau, L. Cast-
edo, Tetrahedron 2003, 59, 8057.
[19] U. E. Hille, Q. Hu, C. Vock, M. Negri, M. Bartels, U. Müller-
Vieira, T. Lauterbach, R. W. Hartmann, Eur. J. Med. Chem.
2009, 44, 2765.
[20] For DENZO-SMN, see: Z. Otwinowski, W. Minor, Processing
of X-ray Diffraction Data Collected in Oscillation Mode, in:
Methods in Enzymology, vol. 276, Macromolecular Crystal-
Received: August 13, 2010
Published Online: November 9, 2010
Eur. J. Org. Chem. 2011, 88–99
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
99