COMMUNICATION
Total synthesis of cis-reticulatacin-10-ones A and B: absolute stereochemical
assignment†
Sherif B. Abdel Ghani,a Lynda J. Brown,b Bruno Figade`rec and Richard C. D. Brown*b
Received 15th June 2010, Accepted 14th July 2010
DOI: 10.1039/c0ob00259c
cis-Reticulatacin-10-ones A and B were synthesised as a
predefined mixture of diastereoisomers (dr ~ 1 : 9) in nine
steps from the acid chloride 8, and without the use of
hydroxyl protecting groups. Comparison of the chiral HPLC
chromatogram of the synthetic sample with that of the natural
product isolated from the roots of the tropical fruit tree
Annona muricata L. showed the natural product to be a
mixture of A and B diastereoisomers (dr ~ 1 : 1).
Acetogenins isolated from Annonaceae (custard apple family)
exhibit a wide range of significant bioactivities including pes-
ticidal, antiparasitic, and potent in vitro cytotoxic antitumour
activities.1 Investigation of the roots of the tropical fruit tree
Annona muricata L. (soursop) led Cave´ and co-workers to
isolate seven mono-THF acetogenins including the previously
known trans-mono-THF solamin.2 Among the six new mono-
THF compounds, possessing the less common threo/cis/threo
configuration in their 2,5-bis-hydroxyalkyl THF (THF-diol) cores,
were cis-solamin (1), cis-uvariamicin I (2), cis-reticulatacin (3),
Fig. 1 Structures of threo/cis/threo configured mono-THF acetogenins
isolated from Annona muricata L.
and cis-reticulatacin-10-one (4). On the basis of the physical data
available for the natural products or their derivatives, it was not
possible to identify the absolute stereochemistry within the cis-
THF-diol region. For example the structure of cis-solamin was
possesses a ketone functionality at C10 of its carbon backbone.
It also has localised symmetry in the THF-diol core, but only
extending out through six methylene groups. We suspected that
cis-reticulatacin-10-one, isolated from the same plant source, was
also a mixture of A and B diastereoisomers. Therefore, we set out
to establish this proposal by total synthesis of a predefined mixture
thought to be either (15R,16R,19S,20S,34S)-cis-solamin (1A) or
(15S,16S,19R,20R,34S)-cis-solamin (1B).3 For convenience, these
diastereoisomers will be referred to as cis-solamin A and cis-
solamin B, respectively.
Subsequently, we discovered that the THF containing com-
of cis-reticulatacin-10-one A/B (4A/B), and comparison by chiral
pounds cis-solamin, cis-uvariamicin I and cis-reticulatacin iso-
lated from Annona muricata L. are all present as mixtures of
threo/cis/threo diastereoisomers A and B in approximately equal
amounts (Fig. 1).4 The specific rotations, proton and carbon
NMR spectra of these pairs of diastereoisomers are “substantially
identical” due to the local “meso” symmetry of the THF-diol core,5
which extends out by ten methylene units on either side. However,
the A and B diastereoisomers 1A/B–3A/B could be distinguished
using chiral HPLC or chiral HPLC-MS.3f,4
HPLC with the natural isolate.6,7
Rather than preparing the individual threo/cis/threo di-
astereoisomers 4A and 4B, we elected to prepare cis-reticulatacin-
10-one as an approximately 1 : 9 mixture of the A and B
diastereoisomers, respectively (Fig. 2). This was to be achieved
from the enantiomeric epoxides (5B/A, er ~ 9 : 1) previously
synthesised in our laboratory in eight steps from 2-(but-3-yn-
1-yn)-1,3-dioxolane, using a permanganate-mediated oxidative
cyclisation of a 1,5-dienoyl sultam.4a
cis-Reticulatacin-10-one differs most obviously from the other
cis mono-THFs isolated from Annona muricata L. in that it
The synthesis of the C3–C15 chain began from commercially
available acid chloride 8, which was converted to its Weinreb
amide and homologated using heptenyl magnesium bromide
affording a mixture of haloketones 9 (Scheme 1). During the first
of these transformations, some halogen exchange occurred giving
aPlant Protection Department, Faculty of Agriculture, Ain Shams University,
Hadayek Shoubra 11241, Cairo, Egypt
bSchool of Chemistry, University of Southampton, Highfield, Southampton,
UK, SO17 1BJ. E-mail: rcb1@soton.ac.uk; Fax: +44-(0)23-8058-6805;
Tel: +44-(0)23-8059-4108
1
a mixture of primary alkyl halides (Br : Cl ~ 4 : 1 by H NMR).
Use of this mixture was ultimately of little consequence as both
compounds converged on the sulfone 6, following borohydride
reduction and halide displacement. At this point we chose to carry
the alcohol through the remaining synthetic steps unprotected.
However, for this approach to succeed would later require a
selective oxidation of the C10 carbinol in the presence of the
cLaboratoire de Pharmacognosie, associe´ au CNRS (BioCIS), Universite´
Paris-Sud, Faculte´ de Pharmacie, Rue J-B Cle´ment, Chatenay-Malabry,
92296, France
† Electronic supplementary information (ESI) available: Preparation of
all novel compounds and copies of 1H and 13C NMR spectra and
chromatograms. See DOI: 10.1039/c0ob00259c
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4543–4545 | 4543
©
Abdel Ghani, Sherif B.
