A high-yielding modular access to the lamellarins: Synthesis of lamellarin G trimethyl ether, lamellarin η and dihydrolamellarin η

Article abstract of DOI:10.1002/chem.201303563

A deprotonated α-aminonitrile serves as a key intermediate in a highly efficient (95 % per step on average; see scheme) modular synthetic approach to the lamellarin alkaloids. Its reaction with an α,β- unsaturated aldehyde forms the central pyrrole ring in a one-pot procedure. The construction of the fused pentacyclic skeleton is completed by a microwave-assisted Ullmann-type lactone formation.

Full text of DOI:10.1002/chem.201303563

DOI: 10.1002/chem.201303563
A High-Yielding Modular Access to the Lamellarins: Synthesis of
Lamellarin G Trimethyl Ether, Lamellarin h and Dihydrolamellarin h
Dennis Imbri, Johannes Tauber, and Till Opatz*[a]
Dedicated to Professor Wolfgang Steglich on the occasion of his 80th birthday
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Figure 1. Structure of lamellarins of type 1a, 1b and 2.
Lamellarins are polyaromatic marine alkaloids sharing
a common condensed pentacyclic skeleton with a saturated
(Figure 1, type 1a) or unsaturated (type 1b) isoquinoline
moiety. In rarer cases, the scaffold is limited to an unfused
3,4-diarylpyrrole core (type 2).
The structural diversity within the lamellarin family large-
ly originates from their varying oxygenation and O-substitu-
tion pattern.[1] Since their discovery by Faulkner et al. in
1985,[2] more than 50 lamellarins were isolated and charac-
terized, many of which were found to exhibit significant bio-
logical activities, such as cytotoxicity, antiproliferative and
multidrug resistance reversal activity.[1,3] In the last decade,
efforts were undertaken to employ lamellarins and their de-
rivatives as anticancer agents[4] and lately their application
in combination treatments for various neoplastic diseases
and autoimmune disorders was reported.[5] Due to their at-
tractive molecular architecture, the limited supply of lamel-
larins from natural sources, and the increasing demand for
sufficient quantities for biomedical evaluations, various syn-
thetic strategies have been developed for the construction of
the lamellarin skeleton,[3f,6] beginning with the pioneering
work of Steglich and co-workers in 1997.[7a] In particular, la-
mellarin G trimethyl ether 1a (R1,R2,R3,R4,R6,R7 =OMe,
R5 =H, Scheme 1) though not found in nature, has become
a benchmark target for the development of new synthetic
routes as it obviates the necessity of any protecting-group
manipulations.[7]
Herein, we report on a highly efficient modular synthesis
based on the 1,4-addition of a deprotonated a-aminonitrile
to construct the central pyrrole ring of the type 1 lamellar-
ins. In a first retrosynthetic consideration, the lactone ring D
is constructed at a late stage from ortho-haloarene 2 in a car-
boxylation/halogen-oxygen exchange sequence. The re-
quired precursor could in turn be obtained from a-aminoni-
trile building block 4 and stilbene carbaldehyde 3 in a one-
pot 1,4-addition/cycloaromatization procedure (path A)[7e,8]
or by Hantzsch-type reaction of a suitably substituted
phenacyl bromide (5) with dihydroisoquinoline 7, which can
be readily prepared from the same aminonitrile by C-benzy-
lation and spontaneous dehydrocyanation (path B,
Scheme 1. Retrosynthetic analysis of the lamellarins.
Scheme 1).[9] The latter method for the construction of the
pyrrole ring has been employed by Ruchirawat and co-
workers for the synthesis of numerous lamellarins.[7b,10]
The synthesis of pyrroles from deprotonated a-aminoni-
triles and a,b-unsaturated carbonyls requires an N-mono- or
N-unsubstituted pronucleophile and was first reported by
von Miller and Plçchl in 1898.[8a] While this method is re-
stricted to a,N-diaryl-substituted substrates,[11] we found the
use of quantitatively deprotonated a-aminonitriles to toler-
ate a much broader substrate scope and to permit the syn-
thesis of N-alkylpyrroles as well.[8b] Although an earlier ap-
proach to the lamellarin core by using benzylidenepyruvates
has met with little success,[7e] very satisfactory results were
obtained for path A described here.
The a,b-unsaturated aldehyde required for the C3-annula-
tion was prepared from commercial 3,4-dimethoxyphenyl-
AHCTUNGTREGaNNUN cetonitrile (8a) or from 4-benzyloxy-3-methoxyphenylace-
tonitrile (8b, obtained by benzylation of commercial 4-hy-
droxy-3-methoxyphenylacetonitrile in 95% yield). Bromina-
tion with N-bromosuccinimide (NBS) to intermediates 9a
and 9b proceeded quantitatively, and subsequent Knoevena-
gel condensation with veratraldehyde furnished cyanostil-
benes 10a and 10b in 93 and 84% yields, respectively
(Scheme 2).
Both condensation products were obtained as E/Z-isomer-
ic mixtures (1:4 and 1:2.2, respectively, as judged by
1H NMR spectroscopy and gated decoupling 13C NMR spec-
troscopy), which is in contrast to the literature.[12] Reduction
of the nitrile function with diisobutylaluminium hydride
(DIBAL-H) in dichloromethane at ꢀ788C afforded alde-
hydes 3a and 3b in 99 and 97% yields. Remarkably, the
pure E isomers were isolated, presumably due to an equili-
bration during the acidic workup. The second building
block, a-aminonitrile 4a, can be prepared from homovera-
trylamine (11) by using an improved version of our earlier
protocol in 84% yield over three steps (Scheme 3).[9a]
Quantitative deprotonation of a-aminonitrile 4a with po-
tassium bis(trimethylsilyl)amide (KHMDS) in THF at
[a] D. Imbri, J. Tauber, Prof. Dr. T. Opatz
Institut fꢁr Organische Chemie, Universitꢂt Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
Fax : (+49)6131/39-22338
E-mail: opatz@uni-mainz.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303563.
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T. Opatz et al.
Scheme 2. Preparation of a,b-unsaturated aldehydes 3a and 3b: a) NBS,
MeCN, TFA, 258C, 16 h; b) veratraldehyde, NaOEt, EtOH, reflux, 5 h
(9a) or veratraldehyde, NaOMe, EtOH, reflux, 24 h (9b); c) DIBAL-H,
CH2Cl2, ꢀ78!258C, 3 h, then 10% HCl, 258C, 30 min. TFA=trifluoro-
acetic acid
Scheme 3. Preparation of a-aminonitrile 4a: a) HCO2Et, reflux, 16 h;
b) PCl5, CH2Cl2, 258C, 2 h; c) KCN, HCl, MeOH/H2O, 25 8C, 16 h.
ꢀ788C and subsequent addition of the a,b-unsaturated alde-
hydes 3a/b furnished 5-hydroxypyrrolidine-2-carbonitriles,
which afforded pyrroles 2a and 2b upon dehydration/dehy-
drocyanation in excellent yields of 93% in both cases
(Scheme 4). Intermediates 2a/b were converted into the cor-
responding carbaldehydes 12a/b in a Vilsmeier formylation.
Further transformation into the carboxylic acids 13a/b was
accomplished by Pinnick oxidation with sodium chlorite and
monosodium phosphate in a mixture of tBuOH/THF/H2O
(3:3:1) with the scavenger 2,3-dimethyl-2-butene as recently
published for the synthesis of similar compounds.[6k]
However, intermediates 13 are unstable and readily decom-
pose even upon acidification of the crude reaction mixture
or upon dissolving in CDCl3 stored over basic alumina.[6a,k]
Furthermore, reaction control by HPLC-ESI-MS revealed
the formation of undesired by-products under the aforemen-
tioned reaction conditions. A solvent screening taught us
that the Pinnick oxidation needs to be performed in 1,4-di-
oxane/water (7:1) to almost exclusively furnish the carboxyl-
ic acids 13a/b as judged by HPLC analysis.
DMF was added to the organic layer and the lower boil-
ing solvents were stripped off in vacuo to afford crude 13a/
b in DMF solution, which were treated with copper(I)-thio-
phene-2-carboxylate (CuTC) under microwave irradiation to
obtain lamellarin G trimethyl ether 1a and intermediate 1b
in yields of 85 and 84% over 2 steps, respectively. This ring
closure has already been employed by Ruchirawat et al. for
the preparation of isolamellarins, lamellarin isomers with an
inverted ester group, in which spontaneous decarboxylation
does not constitute a problem.[10] Debenzylation of inter-
mediate 1b with boron trichloride at ꢀ788C[3f] quantitatively
afforded dihydrolamellarin h (1c). Introduction of the 5,6-
double bond was achieved by treatment of 1b with 2,3-di-
Scheme 4. Synthetic route to lamellarin G trimethyl ether, dihydro-lamel-
larin h, and lamellarin h by path A: a) KHMDS, THF, ꢀ788C, 3 min.,
then 3a/3b, THF, ꢀ78!258C, 30 min, then AcOH/EtOH, reflux, 30 min;
b) DMF, POCl3, CH2Cl2, 0!708C, 7.5 h; c) NaClO2, NaH2PO4, 1,4-diox-
ane/H2O, 2,3-dimethyl-2-butene, 258C, 18 h; d) CuTC, DMF, microwave,
1508C, 30 min; e) BCl3, CH2Cl2, ꢀ78!08C, 3.5 h; f) DDQ, CH2Cl2,
reflux, 30 h.
chloro-5,6-dicyano-1,4-benzoquinone (DDQ)[3f] to furnish
intermediate 1d. Debenzylation of the latter compound with
BCl3 under identical conditions as for 1b quantitatively fur-
nished lamellarin h (1e).
To test whether the alternative synthesis of key intermedi-
ate 2a by path B offers a competitive overall efficiency,
phenacyl bromide 5a was prepared from veratraldehyde by
a
bromination–methylation–oxidation–bromination
se-
quence in 67% overall yield as the double bromination of
acetoveratrone turned out to be cumbersome. Cycloconden-
sation of 5a with 3,4-dihydropapaverine 7a afforded the de-
sired pyrrole intermediate 2a in a yield of only 47%
(Scheme 5). Thus, the vinylogous addition route (path A) is
superior in terms of brevity and yield.
In summary, a very high-yielding modular total synthesis
of lamellarin alkaloids has been devised. Its key steps are an
extended von Miller–Plçchl-type reaction of a quantitatively
deprotonated a-aminonitrile and an Ullmann-like lactone
formation. By starting from commercially available homo-
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A High-Yielding Modular Access to the Lamellarins
COMMUNICATION
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Scheme 5. Synthesis of pyrrole intermediate 2a by path B: a) Br2, AcOH,
NaOAc, 258C, 2 d; b) MeMgBr, THF, 258C, 2 h; c) PCC/SiO2, CH2Cl2,
258C, 6 h; d) Br2, CHCl3, 08C, 3 h; e) K2CO3, MeCN, reflux, 3 d. PCC=
pyridinium chlorochromate.
veratrylamine and 3,4-dimethoxyphenylacetonitrile, the
benchmark compound lamellarin G trimethyl ether (1a)
could be prepared in 69% yield over seven linear steps, cor-
responding to an average per step efficiency of 95%. More-
over, only two chromatographic purifications are required.
This approach compares most favourably with all other syn-
theses of this compound reported to date and surpasses the
hitherto most efficient general and restricted protocols
(Yadav et al., 2009:[7g] 44% overall, uses molecular symme-
try and has not been extended to other lamellarins; Ruchir-
awat et al., 2001:[6a,7b] 27% overall, general applicability
demonstrated).[13] An updated comparison[7h] of syntheses of
1a can be found in the Supporting Information. Our scala-
ble procedure could be extended without any difficulties to
the total synthesis of the 5,6-unsaturated lamellarin h (1e)
as well as its dihydro analogue 1c in overall yields of 54
(10 steps) and 59% (9 steps), respectively, and does not in-
volve any expensive reagents or catalysts.
Experimental Section
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For experimental details, see the Supporting Information.
Acknowledgements
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopic analyses
and Dr. N. Hanold (Mainz) for mass spectrometry. J.T. is grateful for
a PhD scholarship of the “Fonds der Chemischen Industrie”.
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Keywords: alkaloids · heterocycles · microwave chemistry ·
natural products · total synthesis
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Received: July 31, 2013
Published online: October 7, 2013
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