Chapter 1

Lamellarins" Isolation, activity and synthesis

Pablo Cironi, Fernando Albericio, Mercedes Alvarez

Biomedical Research Institute, Barcelona Scientific Park-University of Barcelona, 08028
Barcelona, Spain
pcironi@[Link], albericio@[Link], malvarez@[Link]

1.1 INTRODUCTION

The lamellarins constitute an important group of natural products isolated from marine
invertebrates such as sponges, molluscs and tunicates with structures without precedents in
natural or synthetic compounds. They are characterized for possessing important biological
activities. The aim of this review is to provide an overview of the work published since the
isolation of the first group of lamellarins <85JA5492> from the marine prosobranch mollusc
Lamellaria sp, until the beginning of 2004.

1.2 I S O L A T I O N AND STRUCTURE

More than thirty lamellarins have been characterized since the isolation of the first group of
lamellarins A-D <85JA5492>. The structure of lamellarin A was established by X-ray
crystallographic analysis <85JA5492>, as was that of lamellarin E <88JOC4570> isolated
together with lamellarins H-G from the marine ascidian Didemnum chartaceum collected in the
Indian Ocean on the atoll of Aldabra. Six new polyaromatic alkaloid lamellarins I-M, the
triacetate of lamellarin N, and four known alkaloids lamellarins A-C were isolated from the
marine ascidian Didemnum sp <93AJC489>. Since molluscs from the family Lamellariidae
had been described as specific predators of colonial ascidians, it was speculated <85JA5492>
that the lamellarins mollusc had most likely sequestered the alkaloids from a colonial ascidian
food source. The re-isolation of lamellarins A-D, which had been previously obtained from the
prosobranch mollusc Lamellaria sp. supported this idea. The presence of lamellarins in
molluscs, tunicates and sponges gives rise to speculations about the role of symbiotic
organisms associated with the invertebrates and represents a target for new investigations
<95AJC1491>.
The first pyrrole non-fused alkaloids of the family were lamellarins O and P isolated from a
marine sponge Dendrilla cactos <94AJC 1919>. Later on, from a specimen of Dendrilla cactos
collected in Australia <95AJC1491> two new pyrrole derivative lamellarins Q and R were
isolated. A new pentacyclic alkaloid, lamellarin S together with the known lamellarin K were
isolated from a tunicate Didemnum sp. <96AJC711 >. Lamellarin S was the first example that
demonstrated atropoisomerism with a positive [Ct]D, which can indicate an enantiomerically
enriched mixture. Repeated optical rotation measurements of lamellarin S over several months
suggested slow racemization with a half-life calculated to be ca. 90 days. The first sulfates of
lamellarins, the 20-sulfate derivatives of lamellarins T-Y, were extracted from an unidentified
2 P. CironL F. Albericio and M. Alvarez

ascidian from the Arabian Sea <97T3457>. From the same organism the non-esterified
lamellarins T-X were also isolated. Later, from the ascidian Didemnum chartaceum, the 20-
sulfated lamellarins B, C, and L, the 8-sulfated lamellarin G plus a non-sulfated compound,
lamellarin Z were identified <99JNP419>. An investigation of the prosobranch mollusc
Corioeella hibyae <99MI39> provided two known compounds; lamellarins C <85JA5492> and
U <97T3457>. A n e w ester, lamellarin c~ 20-sulfate <99JMC1901> was isolated from an
unidentified ascidian collected from the Arabian Sea. From a purple unidentified Didemnum
sp (other than D. chartaceum) lamellarin [3 was identified <02MI 163>.

Structures of pentacyclic lamellarins

Unsaturated Rl R2 R3 R4 R5 R6 R7 R8
A OMe OH OH OMe OMe OMe OMe OH
C OMe OH H OMe OMe OMe OMe OH
E OMe OH H OH OMe OMe OH OMe
F OMe OH H OH OMe OMe OMe OMe
Ra R1 R2 G OH OMe H H OH OMe OH OMe
I OMe OH H OMe OMe OMe OMe OMe
RR 7 ~ I aeet. OMe OAc H OMe OMe OMe OMe OMe
J OMe OH H H OH OMe OMe OMe
K OMe OH H OH OMe OMe OMe OH
R5~R4~-~R30
O K triacet. OMe OAc H OAc OMe OMe OMe OAc
L OMe OH H H OH OMe OH OMe
L triaeet. OMe OAc H H OAc OMe OAc OMe
S OH OH H H OH OMe OH OH
T OMe OH H OMe OMe OMe OH OMe
Tsulf. OMe OSO3Na H OMe OMe OMe OMe OH
U OMe OH H H OMe OMe OH OMe
U sulf. OMe OSO3Na H H OMe OMe OH OMe
V OMe OH OH OMe OMe OMe OH OMe
V sulf. OMe OSO3Na OH OMe OMe OMe OH OMe
Y sulf. OMe OSO3Na H H OMe OH OH OMe
a7 R1 R2 Z OH OMe H H OH OMe OH OH
OH OH H H OH OH OH OMe
RR 6 ~
Saturated

R4~ O B
D
OMe
OMe
OH
OH
OMe
H
OMe
OMe
OMe
OH
OMe
OMe
OH
OH
H OH OH H OH OH OH OH
M OMe OH OH OMe OMe OMe OH
N OMe OH H OMe OMe OH OMe
W OMe OH OMe OMe OMe OH OMe
X OMe OH OH OMe OMe OH OMe
o~ OMe OSO3Na H OMe OMe OH OMe
The structures of the lamellarins, except for A and E, were established by a combination of
1H and 13C N M R analyses using heteronuclear correlation techniques. New procedures for
differentiation of H M B C at two- and three-bond correlation <96TL363> in combination with
ADEQUATE experiments <96JMR282> and with O~l-refocused 1,1-ADEQUATE
< 9 6 J M R 2 9 5 > experiments were developed for a comprehensive identification of 2JcH and 3JcH
 Lamellarins : Isolation, activity and synthesis 3

correlations. The distinction between 2JcH and 3JcHconnectivities facilitates the assignment of
complex structures.
The apparent biogenetic origin of these metabolites is from two, three or more tyrosine and/or
Dopa units and the relationship between them is clear. Looking at the structures, two
important groups of lamellarins can be recognised. The most important group in number
possess a common pentacyclic structure linked to a new phenyl ring. The differences between
the members of this group are in the number and positions of OH/OMe substituents on the
benzene rings and in the oxidation level of ring D. This ring can be saturated or unsaturated
and/or hydroxylated.

Structures of lamellarin pyrrole derivatives

HO/x__ BrBr OH
HO. OH HO HO ,OH Br-~\ //3 ~(
~ ~ ' 7--- Br
HO Br ~ ~ Br

HO OH
O

OH OH
OH @
OH
Lukianol A Ningalin B Polycitone A

Structures of related natural products

HO OH HO. OH HO ~.~OH

Me Me

~R H +
Lamellarin Q
OH
OH Lamellarin R
Lamellarin O R = H
Lameilarin P R = OH

Less numerous is the group of lamellarins in which the pyrrole is not fused to another
aromatic ring, known as pyrrole derivatives. These alkaloids are probably tyrosine derived
metabolites, structurally closer to the lukianols <92HCA1721>, ningalines <97JOC3254>,
polycitones and polycitrines <94JOC999> than to the pentacyclic lamellarins. Chemical
transformations between these groups of natural products have been described. Thus,
dimethoxylamellarin O was transformed into the enol-ether lactam (ring B of pentacyclic
lamellarins) and after cleavage of methoxy groups gave lukianol A <95JOC6637>. The open
diaryl pyrroles were also chemically transformed into the pentacyclic alkaloids, for instance
ningalin B into lamellarin G trimethyl ether <03TL4443>. Again, the ease of chemical
4 P. Cironi, F. Albericio and M./ilvarez

transformation between compounds of these families could indicate their close biogenetic
origin.
Lamellarins O and P displayed a double family of signals corresponding to the aromatic
carbon ortho to the phenolic functions, presumably due to the restricted rotation that generates
chirality in these molecules <94AJC 1919>.

1.3 ACTIVITY

While for the pyrrole derived lamellarins and related compounds no activity has been
described, several pentacyclic lamellarins show important cytotoxic activities. Lamellarin D at
a concentration of 19 ~tg/ml caused a 78% inhibition of cell division in the fertilized sea urchin
egg assay while lamellarin C caused 15% inhibition but lamellarins A and B were inactive
<85JA5492>. Lamellarins I, K and L present significant cytotoxicity against P338 and A549
cultured cell lines and lamellarins K and L also exhibit immunomodulatory activity
<93AJC489>.
The effects of several members of the family of lamellarins on the growth of several tumor
cell lines and on P-glycoprotein (P-gp) mediated multidrug resistance (MDR) was tested
<96MI677>. The use of lamellarins either alone against MDR tumors or in combination with
other anti-tumor drugs as effective treatments against MDR cells has been described
<97WO01336> after testing an important group of natural lamellarins and derivatives. A non-
natural lamellarin derivative proved to have an important potency as a MDR reversal agent
causing hypersensitivity towards vinblastine in the HCT/VM 46 MDR cell line <00JOC2479>.
Lamellarin N tested in the NCI on a cell-line panel showed some selectivity towards the
melanoma cell lines SK-MEL (LCs0 1.87 x 10-7 M) and UACC-62 (LCs0 9.88 x 10-6 M).
Several lamellarins were tested as HIV-1 integrase inhibitors and the a 20-sulfate displayed a
very favorable therapeutic index <99JMC 1901 >.
Lamellarin a 20-sulfate inhibits integrase terminal cleavage activity with an IC50 of 16 ~tM
and strand transfer activity with an IC50 of 16 l,tM and possesses a low toxicity with an LDs0 of
274 ~tM whereas other sulfated lamellarins (lamellarin U 20-sulfate and lamellarin V 20-
sulfate) were toxic in the 100 ~tM range and lamellarins T and N without the sulfate ester were
more toxic. The site of action of lamellarin a 20-sulfate was mapped and it was postulated that
it binds to a site composed of multiple integrase domains.
A molecular modeling analysis suggested that the planar chromophore of lamellarin D can
intercalate between a DNA base pair and that the appended methoxyphenol substituent oriented
at a right angle with respect to the main chromophore may serve as a hook to trap proteins
<03CR7392>. DNA binding measurements by absorbance, fluorescence, and electric linear
dichroism spectroscopy showed that lamellarin D is a weak DNA binder that intercalates
between the double helix. Topoisomerase I was efficiently trapped on DNA by lamellarin D in
P388 and CEM leukemia cells. The results identify lamellarin D as a novel lead candidate for
development of topoisomerase I-targeted antitumor agents. <04BMC 1697, 04WO014917>

1.4. SYNTHETIC STRATEGIES

From a synthetic point of view, lamellarins are rather complex molecules. In the literature,
there are described several approaches, which fall into two main synthetic categories: (i) by
pyrrole formation as the key step of the synthesis and (ii) by transformation of a pre-existent
pyrrole derivative through cross-coupling reactions. Although and due to the structural
 Lamellarins: Isolation, activity and synthesis 5

characteristics of these kinds of molecules, most of the syntheses have been carried out in
solution, recently some synthesis carried out in solid-phase has also been described.

1.4.1 SOLUTION STRATEGY

[Link] Pyrrole ring formation approaches

Fiirstner et al. synthesized lamellarin O dimethyl ether following their previous research on
carbon-carbon double bond formation from carbonyl compounds by catalytic titanium coupling
reactions <94JOC5215, 95JA4468>. A new titanium-mediated approach to pyrrole synthesis,
based on the cyclization of a 3-acylamino-enone, was reported <95JOC6637>.

R1 .-, R1
r" "?r O Iow-valenttitanium
1. = ... R2
v NH
R2.~_~O H

In order to adapt this strategy to the synthesis of lamellarin O dimethyl ether, a 3-

unsubstituted keto-enamine 4 was prepared by hydrogenolysis of precursor isoxazole 3.

O Ar. Ar
H202, NaOH O O 1. BF3.Et20 P; ~~N)~/ H2 (1 atm), Pd (5%)
Ar'~-~Ar 98% ~ Ar r 2. [Link], 94%, (7):(E)- 11
1
Ar = p-MeOC6H4 2 67% (both steps) 3

Ar, Ar Ar. Ar ~OMe Ar, Ar

~O Ti-graphite K2CO3},- ~/OMe
OMe r
NHR 52% 91%
H O O
6
FOrstner intermediate
4R=H
".~/F~O ~ CIOCCOOMe' Py
5 R = 73% (Z):(E) = 2.5:1
lamellarin O dimethyl ether
O OMe

Intermediate 3 was readily prepared from commercially available 4,4'-dimethoxychalcone 1

which by standard oxidation conditions afforded the epoxy ketone 2 in high yield. Compound 2
underwent a clean pinacol/pinacolone-type rearrangement with an excess of BF3"Et20. The
crude 1,3-keto-aldehyde thus formed was trapped by hydroxylamine leading to isoxazole 3 in
good yield. Reductive cleavage of its N-O bond gave the desired keto-enamine 4 (as a ~ 1:1
mixture of the (E)- and (Z)-isomers). Acylation of this mixture with oxalic acid half acid
chloride half methyl ester afforded the coupling precursor 5. The (Z) isomer was used for the
subsequent titanium-induced ring closure. Upon treatment with preformed Ti-graphite (TIC13:
CsK =1:2) <93AG(E)164> in DME, compound 5 bearing three different carbonyl groups
6 P. CironL F. Albericio and M. ,4lvarez

underwent a chemo- and regioselective oxo-amide coupling reaction with formation of pyrrole
6 in good yield without the ester group interfering. N-Alkylation of 6 with 4-methoxyphenacyl
bromide 7 proceeded smoothly affording lamellarin O dimethyl ether in 15% overall yield.
In work aimed at achieving a regiocontrolled preparation of unsymmetrical 2,3,4-
trisubstituted pyrroles, Gupton and Sikorski <98T5075, 99T14515> tested the condensation of
different substrates (9, 10, 11) with glycine methyl ester, glycine ethyl ester and N-
methylglycine ethyl ester under acidic (HOAc), neutral (DMF) and basic conditions (Nail,
DMF). The Firstner intermediate 6 was obtained when glycine methyl ester reacted with
chloropropeniminium salt 10 (basic conditions, 77% yield) or with the [3-chloroenal 11 (neutral
conditions, 82% yield), but no attempt at lamellarin synthesis was published.

MeO OMe MeO OMe MeO OMe MeO OMe

MeO.,,T.. OMe
/N\ POCl3 ~ H20 =
91% THF 1
/ w
/ PF6 Glycine
8 9 10 methyl Nail
ester 77%

A similar approach was described by Kim et al. <01MI 1403> to build the Firstner synthon
from the vinylogous amide 9, previously described, and the commercially available dimethyl
aminomalonate hydrochloride as building block for pyrrole systems. The cyclocondensation
reaction between the vinylogous amide 9 and dimethyl aminomalonate hydrochloride was
performed in acetic acid at room temperature to yield the presumed intermediate 12 via an
acid-catalyzed nucleophilic substitution reaction. The mixture was then diluted with additional
acetic acid and heated under reflux to facilitate the intramolecular ring closure and the loss of
the methoxycarbonyl moiety to produce the desired pyrrole. Formation of lamellarin O
dimethyl ether was achieved as in the Firstner approach <95JOC6637>.

\N HOAc ,. K2003 lamellarin O

/ dimethyl ether
MeO2C 60% 90%
Ar = p-MeOCsH4 CO2Me ]
__J
9 12

Following on from their previous work on the biomimetic synthesis of marine natural products,
Steglich et al. proposed a biomimetic lamellarin synthesis in which an oxidative dimerization
of an arylpyruvic acid and condensation of the resulting 1,4-dicarbonyl compound with a
suitable 2-arylethylamine would be the key steps of the synthesis. Thus, the synthesis of
lamellarin G trimethyl ether was achieved by coupling two molecules of 3-(3,4-
dimethoxyphenyl)pyruvic acid and the appropriate 2-phenylethylamine <95T9941,
97AG(E)155>. The use of a mixture of two different arylpyruvic acids afforded the
unsymmetrical lamellarin L <00MI1147>.
 Lamellarins: Isolation, activity and synthesis 7

The 1,4-dicarbonyl compound 15, a key intermediate for pyrrole ring formation, was
obtained in a one-pot procedure by oxidative coupling, for the symmetrically substituted
pyrroles <97AG(E)155>, or a deprotonation of ethyl ester 13 with sodium hydride and reaction
of the resulting enolate with tx-bromoketone 14 <00MI1147>. The 1,4-dicarbonyl compound
15 thus formed was directly transformed into the pyrrole 17 by adding the amine 16 at room
temperature. Secondary reactions interfered in the coupling between 13 and 14 performed with
the lithium enolate <97AG(E)155> instead of the sodium enolate. A mixture of coupling
products was observed due presumably to bromine exchange between the two coupling
partners with the n-BuLi used for the enolate generation. A selective nucleophilic substitution
on the methyl ester group of 17 on treatment with NaCN in 1,3-dimethyl-3,4,5,6-
tetrahydropyrimidin-2(1H)-one (DMPU) <74HCA987> afforded the monocarboxylic acid 18
leaving the ethyl ester group unchanged. Subsequent oxidative lactonization of the carboxylic
acid 18 with lead tetracetate, <67JCS(C)1639> in refluxing benzene furnished the lactone 19 in
97% yield. As reported before, <97AG(E)155> this reaction forms exclusively the desired
regioisomer by attack of the carboxy radical at the ortho position which carries no adjacent
alkoxy substituent. Hydrolysis of the ethyl ester group was achieved by treatment of 19 with
40% aqueous KOH, and removal of the ethanol by distillation. The Pd(0)-catalyzed Heck
cyclizations of bromide 20 proceeded with concomitant decarboxylation, a reaction type
hitherto not observed in Heck reactions. Treatment of 21 with A1C13 in dichloromethane
removed the isopropyl protecting groups <97CC2259, 98JOC9139> and afforded lamellarin L
in almost quantitative yield.

co2,
0
V o,-Prl"Pr~ OMe

ar
16

1. Nail I i-PrO" ":/ ) \ OMe I NH2 ~-

OMe Oi-Pr 2. B ~ oCo2Me I~ L EtO2C--~O O/~-CO2Me ~ [Link]

A ) 5 3 (4
%

13 1,= ~ "OMe 15
Oi-Pr

MeO' ~ O/-PrOMe Oi-Pr

//~.~" Meu~N /~Ul-I-'r
. ,., Oi-PrMeO ,.,. ,.,

~'\ // \ ~) ~ 1 \ ~ MeO OR1 OMe OR1

0 ~ 2 O ~ O CH3CN'PPh3, ~
Et R Pb(OAc)4R NEt3, Pd(OAc)2
? 97% r ? O 97% M e O ~ ~
Br-.~ Br-~~ R1 0 ~ " '0
"~ "Oi-Pr "~ "Oi-Pr ,
OMe OMe R = Me : lamellarin G trimethyl ether
NaCN,~,. 17 R=Me 40%aq.K O , ~ 19 R=Et AlCl3[_~ 21 RI=i-Pr
DMPU 18 R = H then p-TsOH 20 R = H 96% lamellarinL, R1 = H
98% 80%
Boger et al. developed a common strategy useful for the synthesis of related natural
products and analogues <99JA54>. Their approach employs an aza Diels-Alder reaction
<86CRV781, 89PHC30> using as diene the dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 25 to
8 P. CironL F. Albericio and M. Alvarez

assemble the substituents onto a six-membered 1,2-diazine core followed by a reductive ring
contraction reaction <84JOC4405>. This method provided a tetrasubstituted pyrrole, a five
membered heteroaromatic system, assembled by a [4 + 2] cycloaddition reaction followed by a
ring contraction.

Ar ~ I-Ar
Ar Zn Ar'k~Ar Diels-

A•r
RO2C
H
CO2R
,
reduction
N-N
Alder
~>MeO2C~(~ ~CO2Me ,
N-N
> MeO2C---(
/ \~)~CO2Me
N=N

Pd(0) Ar R3Sn - - SnR3

'~~> + or +
ArOTf 2 ArBr

Significantly, the oxygenation pattern found in the two aryl groups, as in 24, would be
expected to increase the nucleophilic character of the acetylene and improve what is a typically
poor reactivity of alkynes toward 1,2,4,5-tetrazine derivatives <65CB1435> for an inverse
electron demand Diels-Alder cycloaddition.

BnO--~ ~ Pd(PPh3)2CI2, N-N

22 Cul, Et3N Me02C --.~/ \~--C02Me
N TM 25
BnO---~ ~ ~~~--OBn
85%
BnO--@l 75% 24
23
Br

BnO OBn BnO. OBn ~o BnO OBn

K2CO3 ~ ~
~~---~ Zn, HOAc ~ ~ 7 OMe ,,.
72% ~ ' ~ oo% - _ // \\
MeO2C 2Me MeO2Cf\ N~CO2 Me MeO2Cf\N~CO2Me
N-N H
28 L-~ O
26 27
BnO OBn HO OH

OMe
LiOH H2, Pd/C
76% " Me 100% " Me
0 L ~0
TFA~29 R=CO2H 1
30 R = H
97% lamellarin O

OMe OMe

The acetylene 24 was allowed to react with 1,2,4,5-tetrazine 25 to give the desired
pyridazine 26 in excellent yield. Zinc reductive ring contraction followed by N-alkylation of
 Lamellarins: Isolation, activity and synthes• 9

the resulting pyrrole 27 with commercially available 4-methoxyphenacyl bromide 7 gave the
pentasubstituted pyrrole 28. The symmetrical diester 28 was subjected to a selective
hydrolysis with LiOH to provide the monoacid 29 which by decarboxylation afforded the
appropriately substituted and functionalized pyrrole core 3t1 found in lamellarin O. This key
intermediate could be quantitatively converted into lamellarin O by catalytic hydrogenolysis of
O-protecting groups or, more simply, by conducting a TFA treatment of 29 or 30 at more
elevated temperatures.
Later, <00JOC2479> working on the synthesis of the natural product ningalin B, based on a
heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to pyridazine to pyrrole) the same
group synthesized 36 a lamellarin derivative with a 7-membered ring instead of 6. The
synthesis of the product 34 was achieved by N-alkylation with the phenethyl bromide 32 then
subsequent MOM deprotection with concomitant lactonization provided lactone 34. Selective
conversion of the methyl into the carboxylic acid 35 was achieved by reaction witn LiI.
Attempts to promote decarboxylation under acidic conditions resulted in either no reaction
(neat TFA) or Friedel-Crafts acylation (neat Eaton's acid <73JOC4071>) giving 36 in 66%
yield.

Br MeO OMe OMeOMe

M e O ~ OMe MeO~Me ~ OMe ~ ~
K2003
~lOOJOMe 32~ \~_/ HCI-EtOAc '%__/ \
;

_ // ~ OMOM 94% 95% = R-~N

MeO2C~\N~CO2Me MeO2C~\N~CO2Me 0
H
31 33

MeO
MeO OMe
P205,MeSo3HMe~O OMe OMeOMe OMe Lilt---34 R=CO2Me
80%1---35 R CO2H
66% - O ~ N ~ ' O
MeO~ 36 O
MeO
A different methodology was used by Iwao and co-workers to achieve the first total
synthesis of the pentacyclic lamellarins D and H <97T5951>. The strategy was also used to
produce a small library of 10 compounds for cytotoxicity evaluation in an effort to examine
their structure-activity relationships <02JNPS00>. The common pentacyclic lamellarin
skeleton was constructed by N-ylide mediated pyrrole ring formation and subsequent
lactonization. The precursor 40 was obtained by a condensation of the known
benzylisoquinoline 37 and the substituted benzoate 38 followed by N-alkylation with ethyl
bromoacetate. Benzylisoquinoline 37 required for the synthesis of lamellarins was prepared
according to a well known procedure <71JPS1634, 61T46>. The 4-benzyloxy-3-methoxy-6-
methoxymethoxybenzoate 38 was readily obtained by a four-step synthesis from methyl 2,4-
dihydroxybenzoate in 49% overall yield <97T5951>.
Metalation of benzylisoquinoline with LDA was chosen and gave better results than other
tested bases on condensation with 38 to give 39 as a tautomeric mixture. Construction of the
l0 P. CironL F. Albericio and M..~lvarez

lamellarin framework from the mixture of 39a and 39b involves: i) quaternization with
haloacetate, ii) removal of the MOM protecting group, and iii) pyrrole ring formation and
subsequent lactonization. Although the three-step sequence can be operated virtually in a one-
pot procedure, high temperature or prolonged reaction times decreased the yield of 42. The
synthesis of lamellarin D was accomplished by hydrogenolysis of the benzyl groups of 42 over

BnO B n O ~ B n O ~
38
MeO~---~~ N MeO~~~ N == M e O ~ - ~ ' ~ ' t N'H
LDA
>- M e O ~ O M e O ~ O
63%
BnO~ ~/OMOM BnO/X"--~ ~ OMOM
37
39a MeO" "~ 39b MeO" "~
OBn OBn
B n O ~ Q Br RO R10
MeO~.~.~ I ~ / 0 0 2 Et R 1 0 ~ OR
BrCH2CO2Et M e O . . ~ @ O Et3N
" ~ ./J ..1...OR " 3-~o
BnO" ""~ ~ ~ (3steps)
RO~ . ~ 0
MeO" '~
OBn
40 R = MOM
cat. HCI F--
L_~ 41 R=H
H2, r-- 42 R = Bn, R1= Me
BBr3
Pd(OH)2/CI-=- lamellarin D R = H, R1 = Me
68%
82% larnellarinH R=H, RI = H

Pearlman catalyst <67TL1663>. Cleavage of both methyl and benzyl ether linkages in 42
using six molar equivalents of boron tribromide afforded lamellarin H.
In a similar approach, Ruchirawat et al. <01TL 1205> first prepared an o-mesyloxyphenacyl
Br
MeO OMe R R
MeO OMs
R'~'~ ~ K2CO3

MeO" v "1 .. . .. ... . .. . R= (~Me I~ Me Ms DMF, POCI3

63% 80%
MeO" ~ v M e O ~
43 45
e MeO OMe R R
MeO OMeR R MeO OM R R Pd(OAc)2, PPh3' ~

K2CO 3, PhBr
= R1 ~ =_ or = M
=e =e eO ,, N' '
O,'
M e O ~ MeO~ . - ~ . ~ ~ ~ HO 80% MeO~ ~ . . ~- 0

KOH
~
46 R1 = OMs
47 R1 OH
48 49 R = H (from series a)
larnellarin G trirnethyl ether, R = OMe
77% series a (from series b)
81% series b
 Lamellarins: Isolation, activity and synthes& 11

bromide 44a as one of the building blocks, which was further condensed with 3,4-
dihydropapaverine hydrochloride 43 in the presence of potassium carbonate and acetonitrile as
solvent. The expected mesyloxy pyrrolo[2,1-a]isoquinoline 45a was produced presumably due
the intramolecular reaction of the derived enamine from the isoquinolinium salt and the ketone
as found in the Knorr pyrrole synthesis <99T6555>.
The introduction of the formyl group on the pyrrole ring to give 46a was accomplished by
Vilsmeier reaction, using DMF in phosphorus oxychloride at room temperature. The O-mesyl
protecting group in the derived aldehyde intermediate was easily removed by heating with
potassium hydroxide in ethanol to give 47a. Finally, an oxidation of 47a with manganese
dioxide in dichloromethane yielded the lamellarin derivative 49 presumably via the hemiacetal
intermediate 48a.
The same approach was applied again to the synthesis of lamellarin G trimethyl ether as
shown in series b. The first three steps proceeded as expected, however the oxidation of
compound 47b with manganese dioxide gave lamellarin G trimethyl ether in a disappointing
yield (20%). The by-product was found to be the quinone derivative 50 formed by the preferred
oxidation of the electron-rich phenolic ring. For this reason the oxidation was carried out with
bromobenzene, palladium acetate and triphenylphosphine using DMF as the solvent and
potassium carbonate as the base. Lamellarin G trimethyl ether was formed in 80% yield.

50

Later developments from the same group brought some changes <03TL1363> to their
previous routte. One of the drawbacks of the previous sequence was the use of a mesyl
protecting group, which added two synthetic steps. A better approach was found using a
hydroxyl protecting group on the phenacyl bromide synthon that can act as a directing group
for the remote deprotonation at the C-2 position of the pyrrole as well as being the source of
the lactone group in the subsequent lactonization of the resulting anion without the need for a
separate formyl group equivalent. This strategy was pioneered by Snieckus and termed DreM
(for directed remote metalation) <99AG(E)1435>. The directing group is typically a carbonate
or a carbamate group. Alternatively, the intermediates 53 or 54 could be selectively brominated
at the 2-position <02T6373> of the pyrrole to give the bromo compounds 55 or 56 which
could undergo metal-halogen exchange to provide an anion similar to the one from the DreM
strategy after initial remote deprotonation.
Reaction between the benzyl-3,4-dihydroisoquinoline hydrochloride 43 with the carbamates
52a and 52b in the presence of NaHCO3 afforded the pyrrole carbamates 54a and 54b in 91
and 81% yields, respectively. The carbonates 51a and 51b were also coupled with 43 under
similar conditions to give the pyrrole carbonates 53a and 53b in 72 and 60% overall yields.
Lamellarin 49 was synthesized with just 35% yield after some exploratory work on the
DreM methodology. In addition to the low yields, the DreM/cyclizations reactions were not
highly reproducible and partial deprotonation of the starting material was frequently found.
A more direct way to generate the C-2 pyrrole anion would be via metal-halogen exchange and
require the C-2 halo pyrrole. To this end, the pyrroloisoquinolines 53a, 53b, 54a and 54b were
12 P. CironL F. Albericio and M. /ilvarez

selectively brominated with N-bromosuccinimide (NBS) to give the bromo pyrroles 55a, 55b,
56a and 56b in excellent yields (> 95%). Subsequent lithium-halogen exchange of carbamates
using tert-BuLi, gave only the 2-(N,N-diethyl)amido-pyrroles 57a and 57b in virtually
quantitative yield. Other attempts to achieve ring closure of these amido-pyrroles failed
<99AG(E)1435>. However, lithium-halogen exchange of carbonates 55a and 55b with tert-
BuLi, proceeded smoothly to give the desired lamellarins 49 and lamellarin G trimethyl ether
in 72 and 67% yields, respectively.

o MeO OMe R R
MeO.~. Br
O ~ O'Jt"x

MeO'- ~ "] ~--'~'R

MeO. ~ ~ ~ NHQC(
~ a
51 X = OEt, 52 = NEt2 ,Me ~O x
J a R = H or b R = OMe DreM lamellarins
MeO" ~ v NaHCO3 M e O ~
43
53 X = OEt,
54 X = NEt2
M-halogen
bromination [ exchange
MeO OMe R R MeO OMe R R

M-halogen
MeO H ~exchange Me o~X
"~J/~\N/~CONEt2 b

57 56 X = NEt2 55 X = OEt,

Recently, <04AG(E)866> Ruchirawat et al. proposed a more convergent strategy which

envisioned that the lamellarin skeleton could arise from condensation of the
benzyldihydroisoquinoline with a Michael acceptor, such as 61 or 62, which essentially would
install the lactone or the ester group on the 2-position.
Since imines, which exist in equilibrium with their enamines, have been shown to react with 13-
R40 R50 OR6 R40 R50

R30 B R 3 0 ~

' OBn

o
T
58 59
R40 A~, OR5 ~,OR5
/OR6 /OR 6
R30 + 60
R20~ N+
R10~ O2N O2N
O CO2R
60 61 62
 Lamellarins: Isolation, activity and synthes& 13

nitrostyrene to give the corresponding pyrroles <99TL4177>, it seemed that Michael addition
of an enamine derived from a benzyldihydroisoquinoline with a powerful Michael acceptor,
followed by ring closure and aromatisation might provide a more direct route to the lamellarin
alkaloids than previous methods.
Modelling the Michael addition/ring closure reaction, a simple D-nitrostyrene and 3,4-
dihydropapaverine hydrochloride were reacted under basic conditions resulting in complete
consumption of both starting materials but gave no desired product. The ester nitrostyrenes are
more powerful Michael acceptor than the simple nitrostyrenes due to the additional electron-
withdrawing effect provided by the ester group; this allows the ester nitrostyrenes to react
under milder reaction conditions. Consequently, the authors planned to use a coumarin
derivative as the ester nitrostyrene which would offer a significant advantage in that the
structure already contained the lactone moiety. Unfortunately, such a reaction gave the desired
lamellarins in only 5-6% yields. These results prompted the use of an acyclic ester nitrostyrene
like 62. From the structure of compound 59, it was apparent that the desired lactone moiety
could be formed by unmasking the benzyloxy-protected phenol by hydrogenolysis and
subsequently initiating base-mediated lactonization.

X
R10 ~CHO BnO\ ~ / O B n EtO2CCH2NO2 B n O ~ O B n
65; 3 steps= .~ .~I [Link] . ,,. . ,..,II I NO2
R20 / ~ MeO'- -"7-- - - - C H O MeO/~x'~""x~ CO2Et
63 X=OBn, R I = R 2 = M e 66 67
64 X = R2 = H, R 1= Me
65 X = R 1= H, R2 = Me

63-65, 7 steps R40 R50 ~ ,~~ OR6

~ x / ~ OR6 R40 RSo

R30"~'~ NaHCO3,67 M e O . . ~ x f/ \~L OBn Nail M e O ~ N . ~ O

M e O ~ N 70% "~/ / ' ~ \ N / - ' - C O 2 E t 93%
R10~1 ~ R~ O ~ ~ ~ . J RI 0 ~ 0
X X X
68 X = OBn, R1 = R3 = Me, R4 = Bn 70 X = OBn, R1 = R3 = Me, R4 = Bn Lamellarins K
69 X = H , R I = R 3 = B n , R 4=Me ~ - 71 X = H , R I = R 3 = B n , R 4=Me LamellarinsL
H2, Pd/C
72 X = OH, R1 = a 3 = Me, R4 = H
73 X = R1 = R3 = H, R4 = Me

The Michael addition/ring-closure reaction of the imines 68 and 69 with the ester nitrostyrene
67 proceeded smoothly in refluxing anhydrous acetonitrile in the presence of NaHCO3 to give
pyrroles 70 and 71. The syntheses were completed by subjecting pyrroles 70 and 71 to
hydrogenolysis to give compounds 72 and 73 quantitatively, followed by base-mediated
lactonization with sodium hydride in dry THF to produce lamellarin K in 93% and lamellarin L
in 87% yield over two steps. Lamellarins K and L were successfully prepared in three steps in
65% and 61% overall yields, respectively.
14 P. CironL F. Albericio and M. Alvarez

Iwao et aL developed a short and flexible route to 3,4-diarylpyrrole marine alkaloids

applying a new strategy to the synthesis of lamellarin G trimethyl ether and related marine
compounds <03TL4443>. The synthetic strategy involved two key reactions: i) Hinsberg-type
condensation <95S795> of the aminodiacetates 75 with dimethyl oxalate to produce 3,4-
dihydroxypyrrole-2,5-dicarboxylates 76, and ii) palladium-catalyzed Suzuki cross-coupling of
the bis-triflate derivatives 77 with arylboronic acids.
2-Arylethylamines 74a and 74b were alkylated with methyl bromoacetate in acetonitrile in
the presence of NaHCO3 to give the aminodiacetates 75a and 75b. Condensation of 75a and
75b with dimethyl oxalate using NaOMe as a base afforded 3,4-dihydroxypyrrole-2,5-
dicarboxylates 76a and 76b in modest yields. This pyrroles were converted into the bis-triflates
77a and 77b in good yields.

R10 OR 1
NH2 MeO2C~N~CO2Me MeO 78
MeO2C CO2Me MeO. _ ~ B(OH)2
BrCH2CO2Me, (CO2Me)2 L,,
NaHCO3 =~ MeONa ""l Pd(PPh3)4,Na2CO3
=- / =~ 79
R 91% R 49% [ ~ 78%
OMe OMe R
74a R = H 75a OMe
74b R = OMe 75b 76a R = R 1= H
(0F3SO2)20 76b R = OMe, R1= H
86% 77a R = H, R1= Tf
77b R = OMe, R1= Tf

The bistriflate 77b was coupled with 1 equivalent of 3,4-dimethoxyphenylboronic acid 78 to

give the mono-arylated 79 in 78% yield, accompanied by 11% of the di-arylated product. The
second cross-coupling, of 79 with 4,5-dimethoxyphenylboronic acid 80, was found to be
somewhat inefficient due to rapid decomposition of the boronic acid 80 under the coupling
conditions. However when the reaction was carried out using excess (2.0 equiv) of 80 and 8%
of Pd(PPh3)4, the coupling product 81 and its lactone 82 were obtained in 58 and 12% yields,
respectively. Elimination the O-MOM protecting group of 81 by treatment with hydrochloric
acid in methanol caused at the same time lactonization to give 82 with an excellent yield.
Alkaline hydrolysis of 82 methyl ester followed by heating with p-TsOH produced the acid 83
which by Cu20-mediated decarboxylation in hot quinoline afforded permethyl ningalin B 84.
The ring closure of 84 to furnish the lamellarin G trimethyl ether was cleanly effected by
application of Kita's oxidative biaryl coupling conditions <98JOC7698> with good yield.
Examination of a straightforward ring closure of 83 to lamellarin G trimethyl ether through a
Pd(II)-mediated decarboxylative cyclization <97AG(E)155, 00Mill47> also afforded the
same lamellarin G trimethyl ether in 65% yield, accompanied by 12% of 84. The ring closure
was found to be regioselective at C-6 of the pendant aromatic ring. This novel cyclization may
proceed via initial decarboxylative palladation <02JA11250> of the pyrrole ring, followed by
electrophilic palladation of the electron-rich aromatic ring and reductive elimination of Pd(0).
 Lamellarins: Isolation, activity and synthesis 15

MeO , MeO :M' O e

OMOM O
MeO2Cf\ N~CO2Me B(OH)2 MeO2CJ\N~-CO2Me
- - + MeO2C.~ N ~ "
~ T ~OMOM L 0
M~O"'f" .o "1
OMe ~
Pd(PPh3)4,Na2C03
OMe OMe OMe
OMe OMe OMe
79 811 conc. HCI I 82
90%
MeO OMe OMe OMe MeO OMe OMe OMe

0 0
HO2C-~ N~"~~ O ~N~ O MeO ?Me OMeoM e
1. KOH 400/0 L..... O Cu20' quinoline L.~ 0 Phl(OCOCF3)2' ~ ~ /
L _ 2-%
76% - ~J i~L 93% - ~ I~ 86% M e O ~ O
"~\OMe '~ "OMe . ...~\ ~ N \~
OMe OMe MeU " ~
83 I Pd(OAc)2,MeCN 84 l lamellarin G trimethyl ether
65%

A new, convergent and straightforward approach was first developed by Banwell et al.
<97CC2259> in their total synthesis of the parent ring-system lamellarin K. The pivotal step in
their approach to lamellarin ring systems involves construction of the central pyrrole moiety
via an intramolecular [3 + 2] cycloaddition of an isoquinoline-based azomethine ylide to a
suitably tethered bisarylacetylene, a hitherto unknown process. The reaction sequence leading
to the alkyne 85 involved a palladium-mediated cross-coupling reaction between the
appropriate alkynylzinc chloride and the aryl iodide <97CC2259>, or a Sonogashira cross-
coupling between the corresponding arylacetylene and the aryl iodide <02BMC3285,
03OL2959>. The bis-aryl acetylene 85 was subjected to a Baeyer-Villiger reaction using m-
CPBA as oxidant. The resulting formate ester 86 was readily hydrolysed to the phenol 87 with
excellent yield. DCC-mediated condensation of the phenol and ot-iodoacetic acid then provided
ester 88 which was used for the quaternization of 3,4-dihydro-6,7-dimethoxy-5-
isopropoxyisoquinoline 89 to give the salt 90. This last compound was not isolated but
immediately treated with Htinig's base. The resulting mixture was heated at reflux in 1,2-
dichloroethane to bring about the cycloaddition followed by in situ aromatisation to give
lamellarin K triisopropyl ether 91. Treatment of this last compound with A1C13 resulted in the
formation of the target compound lamellarin K. Applying the same methodology they also
synthesized other pentacyclic lamellarins with the isoquinoline core in the dihydro form or in
the oxidized form using," for the oxidation step, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
(DDQ) <98WO50365>.
16 P. CironL F. Albericio and M. Alvarez

Oi-Pr I-- MeO OMe -

MeO~
MeO OMe
M e O ~ N

,_Pro- - /
o,-Pr 89

R "~ l MeO. O./N(~I~=

MeO~,~ O _
m-CPBA I 85 R= CHO
92% two steps
NaHCO3 I --- 86 R = OCHO ' O/-Pr
ICH2COOH, DCC
I s7 R = OH -- I NH3, MeOH 90
DMAP 97% I = 88 R = OCOCH21
Oi-Pr MeO OH MeO
. \ .Oi-Pr X.--, \ , OH

re"ux M e o M e O ,0,96O,
o
O MeO O
OH
O/-Pr 91 lamellarin K

Using a similar strategic procedure Faulkner et aL <02BMC3285> synthesized and

evaluated 20-sulfate analogues of lamellarin ct.

OM e MeO .OiPr OM e MeO .OR

/ - P r O ~ RO
BCI 3
Me
93%

MeO ~ . . ~ . ~ ~ ~ O MeO ~ j ~ ~ O
92 DMF-SO3 r--I_ 9 3 R = H
83% - 94 R = SO3Na

Lamellarins I and K were also synthesized by Guiti~n et aL <01S1164> with a new

approach based on the 1,3-dipolar cycloaddition of a nitrone to an alkyne. The key
cycloaddition step yielded an isoxazoline which rearranged to afford the central
pyrroloisoquinoline core. N-Oxides 96a and 96b were obtained from dihydroisoquinolines 95a
and 95b, which were prepared using standard isoquinoline alkaloid synthetic procedures.
Reduction of the imine double bond 95 with sodium borohydride, followed by a non-optimised
oxidation with sodium tungstate <90JOC1736>, afforded N-oxides 96. The key intermolecular
cycloaddition step was carried out by heating a mixture of nitrone 96 and alkyne 97 at high
temperature in a sealed tube. Under these conditions compounds 99 were obtained in moderate
yields. The cycloaddition appears to produce the expected regiochemistry and form the
isoxazoline 98, which upon heating undergoes rearrangement <96T12049, 70CB3196> to the
corresponding pyrroles 99. Finally, lamellarins I and K were obtained from 99a and 99b
respectively, by removal of the isopropyl protecting groups <98JOC9139> with concomitant
acid-catalyzed lactonization.
 Lamellarins: Isolation, activity and synthesis ]7

OR OR
M e O ~ M e O ~ Oi-Pr .CO2Et

MeO~-~ N 96% MeO ,_PrO~[

~
OM, 120~
"

2. H202,Na2WO4=MeO'~~
45% RO" "~
95a R = Me 96a R = Me
95b R = H 96b R = H

OR
OR MeO OR MeO ....
O-~OMe
MeO----~\ /> ~'/ \~) MeO----~~ ~_
MeO~ ~- "' ~- ~- - % OCO2Et\
,, vMe
MeO/"--~ ~OkPr ~ MeO.
"71
"/ ~"h-'/\N/~'CO2Et I II N \0
98a ~ "OMe
MeO~ ~ / ~ ' y 99a - M e O ~ O
98b OR OR 99b
lamellarin I, R = Me
lamellarin K, R = H

[Link] Approaches starting from the pyrrole core

At about the same time as the Steglich report, Banwell et aL published a convergent
synthesis for the open lamellarin systems: lamellarin O, lamellarin Q, lukianol A and some
more highly oxygenated congeners <97CC207, 99WO67250>. In each case, the key synthetic
step involves Stille <86AG(E)508, 92S803> or Suzuki <94PAC213> or Negishi <87OS67,
93CRV2117> cross-coupling reactions of readily available pyrrole-2-carboxylic ester
derivatives with the appropriate arylstannane, -boronic acid or-iodide. The pivotal
dibromopyrrole 102 required for all the syntheses was prepared from pyrrole itself using
procedures developed by Muchowski and co-workers <90JOC6317>. Thus, the N-
triisopropylsilyl derivative of pyrrole 100 was subjected to reaction with NBS in THF to
prepare the tribromo-derivative 101, which by reaction with PhLi followed by C1CO2Me
afforded the previously unreported compound 102. Stille cross-coupling of pyrrole 102 with
the t-BuMe2Si (TBDMS) protected stannane using Pd(PPh3)2C12 as catalyst gave the expected
product 103. Elimination of N- and O-silyl protecting groups of 103 with Bu4NF afforded
lamellarin Q. The synthesis of lamellarin O followed very similar lines. Thus, compound 102
was desilylated and the resulting pyrrole 104 coupled with the arylstannane. In this manner, the
two-fold coupling product 105 was obtained. Reaction of this with 4-methoxyphencaylbromide
in the presence of base then gave the N-substituted pyrrole which was deprotected with Bu4NF
to afford lamellarin O. Two-fold cross-coupling of pyrrole 104 with p-MeOC6H4B(OH)2 under
standard Suzuki conditions afforded lamellarin Q dimethyl ether. This route was shown to be
more efficient than Ftirstner's route <95JOC6637>.
Stille and Suzuki cross-coupling reactions failed when the authors tried to obtain the mono-
arylated pyrrole under different conditions. As a consequence, these types of coupling reactions
would not seem to be useful in providing access to differentially di-arylated pyrrole systems
 18 P. CironL F. Albericio and M. .4lvarez

that would be required for the synthesis of the more complex lamellarins. This limitation was
overcome by regioselective lithiation of compound 102 followed by transmetallation and
Negishi cross-coupling reaction.

HO OH

R1 R1 ~ Ar Ar Bu4NF(10 mol%),
3x TBDMSO~--~/k--SnMe 3 - ~'' then 0.5 M aq. HCI
R2 Pd(PPh3)2Cl2 (10 mol%)- ~N,,>L---CO2Me 98% Me
9 66% ~ 9
Si~Pr3 Si~Pr3 H
100 R 1 = R2 = H 103 lamellarin Q
NBS ]91% R1 R2
PhLi then I _ _ _ . 101 = = Br
CICO2Me 9 ~ ~ R 1 = Br, 2 = CO2Me
R HO\ _ _ / OH
99% Bu4NF (10 mol%), ~~ (~-~
then 0.5 M aq. HCI
Ar, Ar 1. p-MeOC6H4COCH
BrB ~ ; ,.,r 3x T B D M S O ~ - - S n M e 3 - ~ K2CO3, Bu4NCl _ (~,,N,~CO2Me
CO2MePd(PPh3)2CI2 (10 mol~ - \ N / ~CO2Me 2. Bu4NF (10 mol% ),
66% H then 0.5 M aq. HCI
H 104 105 83%
78% 3x M e O - ~ - B(OH)2
I Pd(PPh3) , sat. aq. Na2CO3
OMe
MeO OMe lamellarin O

Me
H
lamellarin Q dimethyl ether

Thus, reaction of 102 a t - 7 8 ~ with PhLi afforded the mono-lithio-derivative 106 which
was transmetallated with ZnC12 to give the organozinc 107. This last species was, in tum,
cross-coupled with the aryl iodide 108 to give the mono-arylated pyrrole 109. Compound 110
was subjected to a further lithiation-transmetallation sequence and the intermediate 111 then
cross-coupled with aryl iodide 112. This material was desilylated using Bu4NF thereby
affording the target pyrrole 113. A similar reaction sequence where compound 107 was
coupled with aryl iodide 112 and the resulting mono-arylated pyrrole subject to metallation and
coupling with aryl iodide 108 afforded, after deprotection, the isomeric system.
 Lamellarins: Isolation, activity and synthesis 19

OMe
MeO~j/OMe
MeO/ ~ ,
OMe 1, ~OTBDM
OMe S MeO MeO .OMe
, lo8 R2 ~OMe ~ 11l H O ~ O M e
BrR ~ 1 Pd(PPh3)4_ ~ Pd(PPh3)4
CO2Me 69% from 102 ~..NJ~----CO2Me 2. Bu4NF (10 mol%), "-..N/"--CO2Me
ti then 0.5 M aq. HCI H
Si Pr3 ~;iipr3 68% 113
102 R'= Br - - 109 R2= Br
PhLi I ~ 106 R1= Li BuLi L_~ 110 R2= Li
ZnCll = 107 R1= ZnCl ZnCl[ ~_111 R2= ZnCl

A similar approach was used by Liu et aL <00JOC3587> for the synthesis of 2,3,4-
trisubstituted-lH-pyrroles with 1-protected 3,4-bis-(trimethylsilyl)-lH-pyrroles as pivotal
precursors. They introduced the 1-(N,N-dimethylaminosulfonyl) protecting group for
enhancing the acidity of the pyrrole ot proton and also stabilizes an ortho-lithium through
coordination with its nitrogen or oxygen atoms. These factors therefore combine to facilitate
formation of the a-carbon anion. The lithium salt, generated with n-BuLi, reacted with methyl
chloroformate to give the sulfonamide 115. The mono-ipso-iodination of 116 was achieved
with iodine and silver (I) trifluoroacetate. Steric and electronic factors played an important role
in controlling the regioselecvity, C-4 is more nucleophilic as well as less sterically hindered.
Suzuki reaction between 116 and p-methoxyphenylboronic acid gave 117, which was also
allowed to undergo an ipso-iodination followed by another slightly modified Suzuki cross-
coupling reaction with p-methoxyphenylboronic acid to yield the symmetrical compound 119.
Deprotection of 119 with Bu4NF led to 120 but in a low yield. An alternative deprotection
method using Mg in MeOH at room temperature gave a much higher yield of 120. Finally, N-
alkylation of 120 with p-methoxyphenacyl bromide 7 was accomplished to furnish lamellarin
O dimethyl ether. The regioselective methodology would be also suitable for the synthesis of
unsymmetrical open lamellarin derivatives.

Me3Si'., __5/SiMe3 e3Si~ S i M e 3 1 Me3Si~SiMe3

<N ~ n-BuLi \N/--Li / ClCO2Me

58% ~- \N / ~CO2Me 12, CF3CO2Ag
I I 100%
SO2NMe2 SO2NMe2J SO2NMe2

I
114
SiMe3 ArB(OH)2,Pd(PPh3)4 Ar'Nf; /SiMe3
2M Na2CO3 .// \L 12,CF3CO2Ag
115
Ar ,
I
CO2Me 98% = \ N Z -~CO2Me 78% " \N / ~CO2Me
I I
SO2NMe2 SO2NMe2 SO2NMe2
116 117 Ar = C6H4-p-OMe 118
BF Ar~Ar

ArB(OH)2, Pd(PPh3)4 Ar \ / Ar Ar, Ar \N / ~'CO2Me

2M Na2CO3 ~ Mg~ OMe
K2003
95% " <"N">L''CO2Me 85% = \N / ~'CO2Me 90%
I
SO2NMe2 H
119 120
OMe
lamellarin 0 dimethyl ether
20 P. CironL F. Albericio and M. Alvarez

A cross-coupling methodology was also used by Banwell et al. to build the lamellarin
framework around the pyrrole core 122 using Negishi and double-barrelled Heck-type
reactions to establish key carbon-carbon bonds from 121 <99AJC755>.

oub,e-barre,,ed
Heck cyclization O
' ' :> ( O

Br
122 121

Following the procedure described by Bailey et al. <71OS100, 72JOC3618> the authors
synthesized 124, then treated with iodine in the presence of silver trifluoracetate and the 4-
iodinated product 125 <97AG(E)1442> thereby obtained was hydrolyzed with potassium
carbonate in aqueous dimethyl sulfoxide to give the previously unreported acid which was later
transformed into the acid chloride 126 by standard methods and reacted with o-bromophenol
127 to give the ester 128. Treatment of this last compound with tosylate 129 resulted in N-
alkylation and the formation of the trisubstituted pyrrole 130 which contains two tethered
arylbromide units required for the projected double-barrelled Heck cyclizations studies. Prior
to conducting such studies, compound 130 was subjected to a Negishi cross-coupling reaction
<87OS67, 93CRV2117> with phenylzinc chloride 131. No complications associated with
coupling between organometallic 131 and the brominated carbon centers within compound 130
was reported in that coupling. This result is testimony to the chemoselectivity usually found
with the Negishi cross-coupling reaction which is useful for selective coupling reactions with
iodides in the presence of bromides.

I 1. K2003, I
'2'Ag+ ~ Me2SO'H2O~ " IOH 127
R1 82%- COCCI32. (COCl)2, COCI 92% =
H H DMF,92% H H O
123 R 1= H 125 126 128

I~-~r/~L"~
80%~124 RI= COCI3 ~ ~znc1131 ~ B r ~
K2CO3, DMF Pd(PPh3)2CI2
LOZ,
.. 89% DMF,95% N
Br..~ 129 O O
LJ
Br Br

130 121

Based on the application of three iterative halogenation/cross-coupling reaction sequences

Handy et aL developed a modular synthesis of the lamellarin G trimethyl ether <04JOC0000>.
 Lamellarins: Isolation, activity and synthesis 21

Bromopyrrole ester 132 (prepared in three steps from pyrrole) was protected with t-butyl
carbamate to afford 133 prior to the first coupling to avoid extensive dehalogenation. Coupling
with boronic acid 78 proceeded cleanly to afford monoaryl compound 134 in good yield. It is
worth nothing that a modest excess (2-3 equiv) of the boronic acid was required. The use of
only 1.2 equivalents of the boronic acid afforded lower yields of compound 134, along with
some homocoupling of bromide 133. Treatment of 134 with an equimolar amount of N-
bromosuccinimide led cleanly to selective halogenation at the C5 position. The second
coupling with boronic acid 136 was then carried out under standard Suzuki coupling conditions
to afford 137. Dihydroisoquinoline ring was closed in a two step procedure: formation of the
tosylate followed by intramolecular alkylation of the pyrrole nitrogen. As their expected, on the
basis of the previous halogenation, the final halogenation also proceeded cleanly at C3 to
afford bromide 139. Several attempts to achieve the lamellarin G trimethyl ether failed due a
the thermal sensitivity of the boronic acid 140. Finally, an excess of the boronic acid added
slowly increased the yield of the final step producing lamellarin G trimethyl ether in 46% yield
(overall yield after 11 steps: 9%).

BOC
I
BOC BOC
I

~ (BOC)20
CO2Et DMAP . s:r co et
Br/ 93% ;r 7o% oo% /
132

MeO OMe MeO OMe

OH
MeO" ~ f B OC MeO.~~'J~ IT"~ 1 ~ OH
. . ~ B~o.,2

13sHOv~l~-~
JL ~..LOMe MeO~ ' ~ ~ C O 2 E t
(HO)2B" ~ "OMe
MeO~L'~ ~ CO2Et MeOe ~UM 140
pd(PPh3)4,Na2CO3 ~ 1. TsCI, Pyr ,. ~ , ,/ \"X Pd(PPh3)4.
' .Na2CO3,~
54% "~ 6/ ~1 % \ \ / / ~ 2. Nail, D M S O ~ 46%
MeO OMe MeO OMe
137

jOMe NBS ~ 138X=H

139 X = Br
O N
.~ Me

leO OMe ()Me "OMe

lamellarin G trimethyl ether
22 P. Cironi, F. Albericio and M. Alvarez

1.4.2 S O L I D - P H A S E SYNTHESIS

The solid-phase mode offers several attractive features over and in comparison to classical
solution synthesis: molecules are synthesized while covalently linked to the solid support, thus
facilitating the removal of excess of reagents, soluble side products and solvents. Furthermore,
solid-supported reactions can be driven to completion through the use of excess of reagents.
Finally, physical manipulations are easy, rapid and amenable to automation facilitating the
preparation of libraries of compounds. Although this strategy has been applied widely for the
preparation of biomolecules, such as peptides and oligonucleotides, and more recently for the
preparation of simple organic molecules, only very few total syntheses of complex organic
molecules have been attempted. The following syntheses of lamellarins carried out in solid-
phase mode illustrate very well the suitability of this approach for the preparation of complex
natural products.
The first solid-phase strategy was developed in order to improve and optimise conditions for
application to a combinatorial chemistry process <03OL2959>. A hydroxy polystyrene resin,
Merrifield-OH or Wang-OH, was used as the starting solid support. The key steps in this
synthesis were the Baeyer-Villiger reaction on the solid phase <02TL9437>, which converted
the aldehyde group of 143 into a formate and the intramolecular cycloaddition of the
dihydroisoquinolinium salt 146 to give the anchored pentacyclic system. Hydrolysis of the
formate group gave phenol 144. The anchored lamellarin was achieved in a process similar to
Banwell's work. Cleavage of 147 with AIC13 in dry dichloromethane gave lamellarins U and L
in 10 and 4% overall yield, respectively.
It is possible to obtain diversity in the solid phase synthesis of lamellarins by modifying the
conditions of cleavage <04T0000>. The selection of different Lewis acids as a
cleavage/deprotection method in the solid-phase synthesis of 147 can produce several
analogues, which, after purification, can be submitted for biological evaluation.
 Lamellarins: Isolation, activity and synthesis 23

Using another approach, starting from the pyrrole core <04TL0000> syntheses of
lamellarins Q and O were also achieved. In this work, the methyl N-(triisopropylsilyl)-3,4-
dibromopyrrole-2-carboxylate 102 was used as the initial scaffold. Banwell et al. <97CC207>
used the dibromopyrrole 102 in an elegant convergent synthesis of several compounds from
this family of marine alkaloids (shown above).
After several attempts, the strategy showed below was the most convenient one. In this case,
4-iodophenol was attached to the resin under basic conditions through the phenoxy anion,
which displaces the chlorine of the resin <99TL9085>. Treatment with NaOMe was also
carried out in order to cap any residual reactive chloromethyl groups. The organometallic
compound 107 was employed in a Pd(0)-catalysed Negishi cross-coupling reaction with the
resin-bound iodophenol 148 to achieve 149 in quantitative yield. The second aromatic ring was
introduced by a Suzuki cross-coupling reaction between 149 and the corresponding arylboronic
acids. It was found that the best conditions establish with Pd(PPh3)4, Na2CO3 solution as the
base in dimethoxyethane or in dioxane as solvent. Preparation of lamellarins Q and O required
the use of p-hydroxyphenylboronic acid with a suitable hydroxy protecting group for the
introduction of the second aryl substituent. After the Suzuki cross-coupling, it was possible to
achieve the N-deprotection, the O-deprotection and the cleavage in one step giving the desired
lamellarin Q. For the preparation of lamellarin O, the triisopropylsilyl group was removed from
150b with NH4F at reflux for 6 h. N-Alkylation of 152a with 7 was investigated under
different experimental conditions <02OL2633>. The use of excess Nail or LDA as a base in
dry THF under reflux gave, after cleavage with A1C13, moderate yields of the N-alkyl
derivative 154a. Similar N-alkylation results were obtained starting with the O-isopropoxy-
protected derivative. Cleavage of 153b also with A1C13 afforded mixtures of lamellarin Q and
O. Using for the second cross-coupling reaction arylboronic acids with different substituents
several lamellarin derivatives were prepared. At the same time different alkylation agents
afforded lamellarin O derivatives.
24 P. CironL F. Albericio and M..4lvarez

These precedent syntheses have shown that is possible to circumvent one of the main
drawbacks usually attributed to the solid-phase mode, which is the lack of control of the
reactions taking place on the supl~ort. Thus, the "in situ" monitoring of all reactions in real
time, using FT-IR (KBr pellets), C gel-phase NMR and 13C MAS-NMR, made possible a full
and an accurate control of the progress in these syntheses <04QSAR61 >.

1.5 CONCLUSIONS
Lamellarins are a family of sea natural products with a broad therapeutic profile. Thus,
currently several of them are in advanced pre-clinical phase testing for the treatment of
different tumors. Syntheses of this family of molecules have been possible only by the use of
the most modem synthetic protocols, mainly cross-coupling reagents and cycloadditions.
Furthermore, the application of solid-phase methodology for the synthesis of lamellarins is
essential for the preparation of libraries of analogues, for speeding up the process of
discovering good drug candidates.
 Lamellarins: Isolation, activity and synthesis 25

1.5 REFERENCES

61T46 A.R. Battersby, D.J. Le Count, S. Garratt, R.I. Thrift, Tetrahedron 1961, 14, 46.
65CB1435 J. Sauer, A. Mielert, D. Lang, D. Peter, Chem. Ber. 1965, 98, 1435.
67JCS(C)1639 D.I. Davies, C. Waring, J. Chem. Soc. C. 1967, 1639.
67TL1663 W.M. Pearlman, Tetrahedron Lett. 1967, 1663.
70CB3196 G. Schmidt, H. U. Strake, E. Winterfeldt, Chem. Ber. 1970, 103, 3196.
71JPS1634 C.H. Chen, T.O. Soine, K.H. Lee, J. Pharm. Sci. 1971, 60, 1634.
71OS100 D.M. Bailey, R.E. Johnson, N.F. Albertson, Org. Synth. 1971, 51, 100.
72JOC3618 J.W. Harbuck, H. Rapoport, J. Org. Chem. 1972, 37, 3618.
73JOC4071 P.E Eaton, G.R. Carlson, J.T. Lee, J. Org. Chem. 1973, 38, 4071.
74HCA987 P. Mtiller, B. Siegfried, Helv. Chim. Acta 1974, 57, 987.
84JOC4405 D.L. Boger, R.S. Coleman, J.S. Panek, D. Yohannes, J. Org. Chem. 1984, 49, 4405.
85JA5492 R.J. Andersen, D.J. Faulkner, H. Cun-heng, G.D. Van Duyne, J. Clardy, J. Am. Chem. Soc.
1985, 107, 5492.
86AG(E)508 J.K. Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508.
86CRV781 D.L. Boger, Chem. Rev. 1986, 86, 781.
87OS67 E. Negishi, T. Takahashi, A.O. King, Org. Synth. 1987, 66, 67.
88JOC4570 N. Lindquist, W. Fenical, G.D. Van Duyne, J. Clardy, J. Org. Chem. 1988, 53, 4570.
89PHC30 D.L. Boger, M. Patel, Prog. Heterocycl. Chem. 1989, 30.
90JOC1736 S. Murahashi, H. Mitsui, T. Shiota, T. Tsuda, S. Watanabe, J. Org. Chem. 1990, 55, 1736.
90JOC6317 B.L. Bray, P.H. Mathies, R, Naef, D.R. Solas, T.T. Tidwell, D.R. Artis, J.M. Muchowski, J.
Org. Chem. 1990, 55, 6317.
91JA9585 V. Farinas, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585.
92HCA1721 W.Y. Yoshida, K.K. Lee, A.R. Carroll, P.J. Schemer, Helv. Chim. Acta 1992, 75, 1721.
92S803 T.N. Mitchell, Synthesis 1992, 803.
93AG(E)164 A. Fttrstner, Angew. Chem. Int. Ed. Engl. 1993, 32, 164.
93AJC489 A.R. Carroll, B.F. Bowden, J.C. Coll, Aust. J. Chem. 1993, 46, 489.
93 CRV2117 P. Knochel, R.D. Singer, Chem. Rev. 1993, 93, 2117.
94AJC1919 S. Urban, M.S. Butler, R.J. Capon, Aust. J. Chem. 1994, 47, 1919.
94JOC5215 A. Ftirstner, A. Hupperts, A. Ptock, E. Janssen, J. Org. Chem. 1994, 59, 5215.
94JOC999 A. Rudi, I. Golberg, Z. Stein, F. Frolow, Y. Benayahu, M. Schleyer, Y. Kashman, J. Org. Chem.
1994, 59, 999.
94PAC213 A. Zuzuki, Pure Appl. Chem. 1994, 66, 213.
94SL 189 K. Voigt, U. Schick, F.E. Meyer, A. de Meijere, Synlett 1994, 189.
95AJC1491 S. Urban, L. Hobbs, J.N.A. Hooper, R.J. Capon, Aust. J. Chem. 1995, 48, 1491.
95JA4468 A. Ftirstner, A. Hupperts, J. Am. Chem. Soc. 1995, 117, 4468.
95JOC6637 A. Fiarstner, H. Weintritt, A. Hupperts, J. Org. Chem. 1995, 60, 6637.
95S795 A. Merz, R. Schropp, E. D6tterl, Synthesis 1995, 795.
95T9941 A. Terpin, K. Polborn, W. Steglich, Tetrahedron 1995, 51, 9941.
96AJC711 S. Urban, R.J. Capon, Aust. J. Chem. 1996, 49, 711.
96JA2087 S. Hillers, S. Sartori, O. Reiser, J. Am. Chem. Soc. 1996, 118, 2087.
96JMR(A)282 B. Reif, M. K6ck, R. Kerssebaum, H. Kang, W. Fenical, C. Griesinger, J. Magn. Reson. Series A
1996, 118, 282.
96JMR(B)295 B. Reif, M. KOck, R. Kerssebaum, J. Schleucher, C. Griesinger, J. Magn. Reson. Series B 1996,
112,295.
96MI677 A. Rodriguez, M.D. Garcia Gr~valos, J.L. Fernandez Puentes, Br. J. Cancer 1996, 74, 677.
96T10113 T. Jeffrey, Tetrahedron 1996, 52, 10113.
96T12049 B.-X. Zao, Y. Yu, S. Eguchi, Tetrahedron 1996, 52, 12049.
96TL363 M. K6ck, B. Reif, W. Fenical, C. Griesinger, Tetrahedron Lett. 1996, 37, 363.
97AG(E)1442 H. Volz, M. Holzbecher, Angew. Chem. Int. Ed. 1997, 36, 1442.
97AG(E)155 A. Heim, A. Terpin, W. Steglich, Angew. Chem. Int. Ed. 1997, 36, 155.
97CC207 M.G. Banwell. B.L. Flvnn. E. Hamel. D.C.R. Hockle.~s. ('hem CornrnTm 1007 907
26 P. Cironi, F. Albericio and M. Alvarez

97T5951 F. Ishibashi, Y. Miyazaki, M. Iwao, Tetrahedron 1997, 53, 5951.

97WO01336 J.L. Fern~indez Puentes, D. Garcia Gr~ivalos, A. Rodriguez Quesada, PCT. Int. Appl.
WO97/01336.
98JOC7698 T. Takada, M. Arisawa, M. Gyoten, R. Hamada, H. Tohma, Y. Kita, J. Org. Chem. 1998, 63,
7698.
98JOC9139 M.G. Banwell, B.L. Flynn, S.G. Stewart, J. Org. Chem. 1998, 63, 9139.
98JOM165 D.S. McGuinness, M.J. Green, K.J. Cavell, B.W. Skelton, A.H. White, J. Organomet. Chem.
1998, 565, 165.
98T5075 J.T. Gupton, K.E. Krumpe, B.S. Burnham, K.A. Dwornik, S.A. Petrich, K.X. Du, M.A. Bruce,
P. Vu, M. Vargas, K.M. Keertikar, K.N. Hosein, C.R. Jones, J.A. Sikorski, Tetrahedron 1998,
54, 5075.
98WO50365 M.G. Banwell, B.L. Flynn, PCT. Int. Appl. WO 98/50365.
99AG(E)1435 B.A. Chauder, A.V. Kalinin, N.J. Taylor, V. Snieckus, Angew. Chem. Int. Ed. 1999, 38, 1435.
99AJC755 M.G. Banwell, [Link], D.C.R. Hockless, R.W. Longmore, A.D. Rae, Aust. J. Chem. 1999,
52, 755.
99JA54 D.L. Boger, C.W. Boyce, M.A. Labroli, C.A. Sehon, Q. Jin, J. Am. Chem. Soc. 1999, 121, 54.
99JMC 1901 M.V.R. Reddy, M.R. Rao, D. Rhodes, M.S.T. Hansen, K. Rubins, F.D. Bushman, Y.
Venkateswarlu, D.J. Faulkner, J. Med. Chem. 1999, 42, 1901.
99JNP419 R.A. Davis, A.R. Carroll, G.K. Pierens, R.J. Quinn, J. Nat. Prod. 1999, 62, 419.
99T14515 J.T. Gupton, K.E. Krumpe, B.S. Burnham, T.M. Webb, J.S. Shuford, J.A. Sikorski, Tetrahedron
1999, 55, 14515.
99T6555 A. Alberola, A.G. Ortega, M.L. Sadaba, C. Sanudo, Tetrahedron, 1999, 55, 6555.
99TL4177 S. Lim, I, Jabin, G. Revial, Tetrahedron Lett. 1999, 40, 4177.
99TL9085 W-R. Li, Y-C. Yo, Tetrahedron Lett., 1999, 40, 9085.
99WO67250 M.G. Banwell, B.L. Flynn, PCT Int. Appl. WO 99/67250.
00JOC2479 D.L. Boger, D.R. Soenen, C.W. Boyce, M.P. Hedrick, Q. Jin, J. Org. Chem. 2000, 65, 2479.
00JOC3587 J-H. Liu, Q-C. Yang, T.C.W. Mak, H.N.C. Wong, J. Org. Chem. 2000, 65, 3587.
00MI1147 C. Pescko, C. Winklofer, W. Steglich, Chem. Eur. J. 2000, 6, 1147.
01MI1403 S. Kim, S. Son, H. Kang, Bull, Korean Chem. Soc. 2001, 22, 1403.
01S1164 M. Diaz, E. Guiti~in, L. Castedo, Synlett 2001, 1164.
01TL1205 S. Ruchirawat, T. Mutarapat, Tetrahedron Lett. 2001, 42, 1205.
02BMC3285 C.P. Ridley, M. Venkata Rami Reddy, G. Rocha, F.D. Bushman, D.J. Faulkner, Bioorg. Med.
Chem. 2002, 10, 3285.
02JA11250 A.G. Myers, D. Tanaka, M.R. Mannion, J. Am. Chem. Soc. 2002, 124, 11250.
02JNP500 F. Ishibashi, S. Tanabe, T. Oda, M. lwao, J. Nat. Prod. 2002, 65, 500.
02MI163 J. Ham, H. Kang, Bull Korean. Chem. Soc. 2002, 23, 163.
02OL2633 A. Namsaaid, S. Ruchirawat, Org. Lett. 2002, 4, 2633.
02T6373 A. Ftirstner, H. Krause, O.R. Thiel, Tetrahedron 2002, 58, 6373.
02TL9437 P. Iyer, S.K. Ghosh, Tetrahedron Lett. 2002, 43, 9437.
03CR7392 M. Facompr6, C. Tardy, C. Bal-Mahieu, P. Colson, C. P6rez, I. Manzanares, C. Cuevas, C.
Bailly, Cancer Res. 2003, 63, 7392.
03OL2959 P. Cironi, I. Manzanares, F. Albericio, M./~,lvarez, Org. Lett. 2003, 5, 2959.
03PHC140 T. Janosik, J. Bergman, Prog. Heterocycl. Chem. 2003, 140.
03TL1363 P. Ploypradith, W. Jinaglueng, C. Pavaro, S. Ruchirawat, Tetrahedron Lett. 2003, 44, 1363.
03TL4443 M. Iwao, T. Takeuchi, N. Fujikawa, T. Fukuda, F. Ishibashi, Tetrahedron Lett. 2003, 44, 4443.
04AG(E)866 P. Ploypradith, C. Mahidol, P. Sahakitpichan, S. Wongbundit, S. Ruchirawat, Angew. Chem. Int.
Ed. 2004, 43, 866.
04BMC1697 C. Tardy, M. Facompre, W. Laine, B. Baldeyrou, D. Garcia-Gr~valos, A. Francesch, C. Mateo,
A. Pastor, J.A. Jim6nez, I. Manzanares, C. Cuevas, C. Bailly, Biorg. Med. Chem. 2004, 12,
1697.
04JOC0000 S. T. Handy, Y. Zhang, H. Bregman, J. Org. Chem. 2004,
04QSAR61 P. Cironi, M. ,/~lvarez, F. Albericio, QSAR & Comb. Sci. 2004, 23, 61.
04T0000 M. Marfil, F. Albericio, M./klvarez, Tetrahedron 2004, 60, 0000.
04T0000 P. Cironi, C. Cuevas, F. Albericio, M. ,/dvarez, Tetrahedron 2004, 60, 0000
04WO014917 C. Bailly, A. Francesch, M.C. Mateo, J.A. Jim6nez, A. Pastor, C. Cuevas, PCT Int. Appl. WO
04/014917.