Communications
doi.org/10.1002/ejoc.202100453
Stereodivergent Total Syntheses of (+)-Monomorine I and
(+)-Indolizidine 195B
A simple and efficient stereoselective total syntheses of two
natural products (+)-monomorine I and (+)-indolizidine 195B in
high yields starting from a readily available alcohol is described.
The key step in this synthetic route exploits the judicious use of
solvent to enable a closed or open transition state in a
nucleophilic addition of Grignard reagent to sulfinimine, giving
selective access to two distinct diastereomers required for the
formation of the two target natural products.
Figure 1. Structures of (+)-monomorine I (1) and (+)-indolizidine 195B (2).
(+)-Monomorine I (1) is a trail pheromone, isolated for the
first time in 1973 by Ritter et al. from pharaoh’s ants (Mono-
morium pharaonis L); a small transparent ant (2 mm) with yellow
or light brown colour.[20] This ant, which is of tropical origin, is
now established in North America and Western Europe. A
diastereomer, (+)-indolizidine 195B (2), was isolated by Daly
and co-workers in 1986 from the skin secretions of Colombian
neotropical poison frogs belonging to the Dendrobates family (a
genus of poison dart frogs).[12,13,21–24] Their interesting structures
and stereochemistries have made these common test-beds for
synthetic methodologies.[24] Herein we report a facile and
efficient diastereodivergent synthetic strategy for these two
different indolizidines (+)-monomorine I (1) and (+)-indolizidine
195B (2). The stereodivergent route pivots on the key stereo-
controlled nucleophilic addition of Grignard reagent to chiral
The indolizidine framework contains a 5,6-fused ring system,
with a nitrogen atom at the ring fusion, and is present in a wide
range of medicinally and biologically active natural products.[1–3]
Because of their often potent biological activities, many
approaches have been developed for their synthesis.[4–6]
Indolizidine alkaloids isolated from amphibians and ants have
been identified as toxic and noxious molecules, and are
believed to play a significant role in the self-defense system of
these animals toward microorganisms and predators. Their
biological activity is likely to arise from interference with ion
channels in nerve and muscles cells.[7] In amphibians, indolizi-
dine alkaloids are part of many classes of alkaloids which are
accumulated in skin glands, which can be released onto the
skin surface of the animal when needed. Structurally identical
alkaloids have recently been isolated from ants and after
feeding experiments, and it was suggested that the ants could
be the amphibian’s source of these alkaloids.[8–11] The indolizi-
dine alkaloids isolated from ants and amphibians are disubsti-
tuted by alkyl chains at the 3,5-positions in most cases. These
compounds have proved attractive targets for synthesiss,[12,13]
with a variety of different synthetic strategies towards their
synthesis including racemic, diastereoselective and enantiose-
lective approaches.[14–19]
sulfinimine
4 in the presence of two different solvents
(coordinating and non-coordinating) to give two different
stereochemistry outcomes at the CÀ N bond formed (Figure 2).
To access (+)-monomorine I (1), our synthetic route began
with the preparation of sulfinimine 4 over two steps, which
included oxidation of cis-4-hexen-1-ol 3 with PCC to give the
aldehyde analogue of 3. This was then condensed with (S)-tert-
butanesulfinamide as
a
chiral auxiliary using Ellman’s
protocol,[25,26] which afforded the corresponding (SS)-sulfinimine
4 in good yield (84%) (Scheme 1). The product 4 was reacted
(+)-Monomorine I (1) and (+)-indolizidine 195B (2) are two
examples of indolizidine natural products isolated from ant and
amphibian sources. They have three stereogenic centres at C-3,
C-5 and C-9, with cis- and trans relationships at C-3 and C-5
substituents, respectively (Figure 1).
[a] Dr. R. S. Dawood, Prof. R. A. Stockman
School of Chemistry
University of Nottingham
Nottingham. NG7 2RD, UK
E-mail: Robert.stockman@nottingham.ac.uk
[b] Dr. R. S. Dawood
Department of Chemistry
College of Sciences, University of Bagdad
Baghdad, 10071, Iraq
Figure 2. Use of non-coordinating solvent (toluene) favours closed transition
state, and coordinating solvent (THF) favours an open transition state in
Grignard addition to sulfinimines.[25,26]
Supporting information for this article is available on the WWW under
Eur. J. Org. Chem. 2021, 3850–3853
3850
© 2021 Wiley-VCH GmbH