Diversity-oriented synthesis of bicyclic and tricyclic alkaloids

Article abstract of DOI:10.1039/b917965h

A diversity-oriented synthesis involving a cascade sequence, taking linear aminoalkenes to polycyclic scaffolds reminiscent of natural alkaloids, is presented.

Full text of DOI:10.1039/b917965h

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Diversity-oriented synthesis of bicyclic and tricyclic alkaloidsw
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Monica Dıaz-Gavilan,z Warren R. J. D. Galloway, Kieron M. G. O’Connell,
James T. Hodkingson and David R. Spring*
Received (in Cambridge, UK) 2nd September 2009, Accepted 25th November 2009
First published as an Advance Article on the web 14th December 2009
DOI: 10.1039/b917965h
A diversity-oriented synthesis involving a cascade sequence,
taking linear aminoalkenes to polycyclic scaffolds reminiscent
of natural alkaloids, is presented.
Diversity-oriented synthesis (DOS) aims to efficiently prepare
structurally diverse compounds, particularly involving variation
of molecular scaffolds and stereochemistry.1 An effective
strategy for DOS is to fold linear starting materials into
complex polycyclic frameworks,2 and this has been elaborated
elegantly in the preparation of natural products3 and
compounds for screening.4 We envisaged combining the folding
pathway approach (to give different polycyclic scaffolds) with
reagent diversity (to vary the stereochemistry of products).5
Inspiration came from naturally occurring bicyclic and tricyclic
alkaloids.6 For example, the tricyclic diastereoisomeric family
of Coccinellidae defensive alkaloids (Fig. 1), which are secreted
by ladybirds as a repellent for predators.7 Three diastereo-
isomers have been isolated and synthesized,8 namely pre-
coccinelline, hippodamine9 and myrrhine.10 The N-oxides of
precoccinelline and hippodamine are natural products;
however, the N-oxide of myrrhine has not been isolated from
nature to date. Herein, we report a diversity-oriented synthesis
of bicyclic and tricyclic scaffolds reminiscent of natural
alkaloids. The new methodology developed was applied to
the total synthesis of previously unknown myrrhine N-oxide.
In order to discover novel biological functions of small
molecules the diversity-oriented synthesis was designed to
include populating new areas of chemical space. Nature
illuminates the constitution and three dimensional shapes
required for evolved biological activity. Therefore, we
designed a diversity-oriented synthesis around bicyclic and
Scheme 1 Synthesis of N-Boc-aminodialkenes (1).
tricyclic alkaloid scaffolds. Inspired by the elegant two-
directional approach towards such scaffolds pioneered by
Stockman et al., our synthetic strategy was based around the
folding of suitably designed linear substrates.11 Towards this
end linear aminoalkenes (1) were prepared via Mitsunobu
substitution,12 tosyl deprotection,13 and cross-metathesis with
ethyl acrylate14 (Scheme 1).
We envisaged that the N-Boc group could be deprotected by
various Lewis acids, which could also catalyze a double
conjugate addition15 and Dieckmann condensation cascade,
thereby converting 1 into cyclic frameworks. Heating 1a with
aluminium chloride or scandium triflate led to the synthesis of
bicyclic trans-2a (Scheme 2).16 Whereas, heating 1a with tin(II)
triflate (0.5 equiv.) resulted in the synthesis of tricyclic 3a
(along with cis-2a [9%] and trans-2a [2%]).
Interestingly, use of higher amounts of tin(II) triflate led to
the formation of trans-2a, with no trace of cis-2a or 3a.17 Since
the stereochemistry of 3a is expected from a Dieckmann
condensation on cis-2a, this suggested that a different mecha-
nism is in operation depending on the amount of Sn(OTf)2
present. To test this, the following experiments and observa-
tions were made: (1) when trans-2a was treated with catalytic
18
or excess Sn(OTf)2 starting material was recovered; (2)
treatment of the cis-2,6-disubstituted monocyclic intermediate
with catalytic Sn(OTf)2 led to a mixture of trans-2a and 3a;
(3) treatment of 3a with catalytic Sn(OTf)2 gave cis-2a. These
data could indicate that when Sn(OTf)2 is used in catalytic
amounts the enolate formed after the first conjugate addition
undergoes a Dieckmann condensation before the second
conjugate addition. Therefore, cis-2a would originate from
3a by a retro-Dieckmann reaction.19
Fig. 1 Ladybird alkaloids.
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: spring@ch.cam.ac.uk
w Electronic supplementary information (ESI) available: Full experi-
mental procedures and spectroscopic and crystallographic data.
CCDC 746888. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b917965h
z Present address: Departamento de Quı
Organica, Facultad de Farmacia, Campus de Cartuja, s.n., 18071
Granada, Spain. E-mail: monicadg@ugr.es
mica Farmaceutica y
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Scheme 2 Preparation of 6–6-fused bicycles and 6–6–6-fused tricycles
from 1a. Inset: X-ray crystal structure of tricycle 3a.29
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excess TFA to give mainly trans-2b with some cis-2b
(Scheme 4).22 1H-NMR and 13C-NMR data for cis-2b
are consistent with the expected values for cis-fused
pyrrolizidines23 (unshielded H-7 at 3.5–4.0 ppm, and shielded
C-7 at 60–67 ppm) with NOESY interactions between H-7,
H-4 and H-10 suggesting a cis disposition of all the CH
protons in the ring system. Transformation of 1b into 5–5–6
tricycles in one step was not possible despite exploration of a
wide range of reaction conditions (temperature, solvent,
equivalents of Lewis acid). Nevertheless, the tricyclic products
could be obtained over two steps involving a base-catalyzed
Dieckmann condensation on 2b isomers.
Indolizidine scaffolds trans-2c and trans-2c0 could be
obtained selectively dependent on the amount and identity
of the Lewis acid utilized (Scheme 5). Intense bands in the IR
spectra (2850 cmꢁ1) and 1H-NMR chemical shifts (H-7 at
2.4 ppm) suggested the trans-fused ring junctions.24 Transfor-
mation of 1c into 5–6–6 tricycles in one step could be achieved
with stoichiometric Sn(OTf)2 yielding an inseparable mixture
of the isomers 3c and 3c0 (along with cis-2c in 13% isolated
yield). In contrast to the formation of 6–6–6 tricycles, use of
catalytic Lewis acid gave only 4% of 3c and 3c0.
Scheme 3 Total synthesis of myrrhine N-oxide.
Tricycle 3a was used as a precursor for the total synthesis of
the unknown or unnatural alkaloids epi-myrrhine and
myrrhine N-oxide for inclusion in the DOS. Ester hydrolysis,
decarboxylation and Wittig olefination gave the exocyclic
alkene 4 (Scheme 3). Diastereoselective reduction of the
exocyclic double bond was achieved by protonating the
nitrogen lone pair and thereby forcing the hydrogenation to
occur on the desired face with the bridge-head hydrogen
atoms. Using p-toluenesulfonic acid20 and RANEYs nickel
under hydrogen gas we obtained a 10 : 1 ratio of myrrhine:
epi-myrrhine. As a reference, myrrhine was made in 8 steps
with an overall yield of 7% (unoptimized), which compares
favourably to former syntheses.10 The total synthesis of
myrrhine N-oxide was completed by treatment of myrrhine
with m-CPBA (dried, titrated, 1 equiv.), which gave the
N-oxide with complete stereoselectivity.21
We have visually assessed the skeletal diversity of the DOS
through the use of ‘‘Scaffold Hunter’’, a computer-based tool
developed by Waldmann et al.,25 which extracts the molecular
scaffolds present in a compound collection and correlates
the relationship between them in a hierarchical tree-like
arrangement.26 According to this analysis, out of the 14 final
compounds synthesized, 7 distinct molecular scaffolds were
prepared,27 in a total of 23 synthetic steps, and contained
natural and unnatural products. Although the number of
compounds for a library is relatively small compared to typical
combinatorial chemistry libraries, we believe that the ‘steps per
scaffold efficiency’ is highly attractive (23 C 7 = 3.3 steps per
scaffold), along with the complexity of the final products.
In summary, we have reported a DOS involving the first
diastereoselective one-pot reaction cascade for the total
folding of linear aminoalkenes to tricyclic systems, including
naturally occurring all-trans-perhydro-9b-azaphenalene. The
reaction sequence includes N-Boc deprotection, two conjugate
additions and a Dieckmann condensation. The reaction was
used for the diversity-oriented synthesis of unknown or
unnatural alkaloids epi-myrrhine and myrrhine N-oxide, along
with myrrhine that has been isolated from nature before.
Moreover, the new methodology was exploited to make
5–6–6- and 5–5–6-fused tricycles, as well as quinolizidine,
indolizidine and pyrrolizidine scaffolds, present in natural
alkaloids.28 In total 7 different scaffolds were generated
(3.3 steps per scaffold) that populated new and biologically
active areas of chemical space. The synthetic strategy outlined
in this report should offer substantial scope for the intro-
duction of additional diversity in the library; for example,
variation in ring sizes and substituents could be achieved
through alterations in the structure of the linear aminoalkenes
and it may prove possible to generate heteroatom-containing
scaffolds. Furthermore, we anticipate that this new methodo-
logy will prove valuable in a wider synthetic context, with
potentially broad applications in the synthesis of a variety of
natural product-like alkaloid frameworks.
The DOS included different sized fused tricycles as well as
quinolizidine, indolizidine and pyrrolizidine rings, present in
and reminiscent of several natural products. These bicyclic and
tricyclic products were prepared by the same folding sequences
starting from different length aminoalkenes 1b (n = m = 2)
(Scheme 4) and 1c (n = 2, m = 3) (Scheme 5).
Modified conditions were required for the cascade reactions,
depending on the length of the chain. The conversion of 1b
into pyrrolizidine bicycles occurred at room temperature with
Scheme 4 Synthesis of pyrrolizidine bicycles and 5–5–6 tricycles.
Scheme 5 Synthesis of indolizidine bicycles and 5–6–6 tricycles.
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The authors thank the EU for a Marie-Curie Intra-
European Fellowship (MDG) and the EPSRC, BBSRC,
MRC, and Newman Trust for funding.
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29 Crystal data for 3a: M = 265.34, triclinic, a = 8.6717(2) A, b =
8.8865(2) A, c = 9.6551(2) A, a = 86.555(1)1, b = 72.478(1)1,
3
ꢀ
g = 80.643(1)1, V = 700.02(3) A , T = 180(2) K, space group P1,
10 First characterization of myrrhine: B. Tursch, D. Daloze,
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Z = 2, 12 361 reflections measured, 4060 independent reflections
(Rint = 0.0271). The final R1 values were 0.0412 (I > 2s(I)). The
final wR(F2) values were 0.1107 (I > 2s(I)). The final R1 values
were 0.0514 (all data). The final wR(F2) values were 0.1185
(all data). CCDC number 746888.
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This journal is The Royal Society of Chemistry 2010
778 | Chem. Commun., 2010, 46, 776–778