confirms the proposed structure of the olive oil irritant but
also permits assignment of the absolute stereochemistry.
Importantly, the syntheses provided ready access to an ample
supply of totally synthetic material for further biological/
sensory evaluation. The latter studies, reported elsewhere,
demonstrate that the enantiomers of oleocanthal are both
potent non-steroidal anti-inflammatory agents and strong anti-
oxidants and that the levorotary enantiomer of 1 is the agent
responsible for the back of the throat irritant properties often
experienced upon ingestion of extra virgin olive oils (vide
infra).3
In 1993, Montedoro and co-workers reported5 the isolation
of a new class of phenolic compounds (1-4), including the
aglycons of ligstroside (5) and oleuropein (6) from virgin
olive oils (Figure 1).6 These phenolic compounds comprise
important minor constituents that have been implicated in
the organoleptic characteristics of olive oils, including
bitterness, pungency, and astringency.7 In addition, these
agents have been suggested to contribute to the oxidative
stability of virgin olive oils, and as such are often associated
with the health benefits of olive oils, particularly their anti-
oxidant/anti-cancer activities8 and more recently their pos-
sible role in preventing cognitive decline due to neurode-
generative disorders such as Alzheimer’s disease.9
configuration of 1, however, remained unknown. That 1 was
responsible for the strong irritant (burning) sensation was
based on extensive HPLC fraction analysis, omission analysis/
correlation, and hydrolysis studies, in conjunction with
human sensory studies. Busch and co-workers, however,
acknowledged that “a co-elution compound causing the
burning sensation could not be eliminated without completing
a synthesis of 1”, which they stated to be “extremely
challenging”.
We envisioned both enantiomers of 1 to derive from the
enantiomeric forms of cyclopentanediols 7 via oxidative
cleavage of the diol moiety (Scheme 1). The requisite
Scheme 1
Oleocanthal (1), the principle contributor to the potent back
of the throat irritant (burning) sensation often associated with
the consumption of high quality extra virgin olive oils, was
subsequently identified by Busch and co-workers at Unilever
Research and Development, Vlaardingen (The Netherlands).7
Concurrent collaborative studies at the Monell Chemical
Senses Center and at Firmenich, Inc., had reached the same
conclusion.3 The structure of 1 was assigned by both groups,
employing a series of 1D and 2D NMR experiments,3,7 in
conjunction with comparison to literature data.5 The absolute
cyclopentanediols (7) in turn would be prepared from
cyclopentanones (+)- and (-)-10 via alkylation to introduce
stereoselectively the side chain from the convex face,
followed by stereoselective Wittig ethylenation, esterification,
and removal of the acetonide moiety.
Toward this end, we initially prepared (+)- and (-)-
cyclopentanones 10 either via the sulfoximine and/or via
enzymatic protocols, the former introduced and developed
by Johnson.10 Although effective on modest scale (10-100
mg), the requirement for gram quantities of the oleocanthals
demanded that we secure more scalable routes to the
enantiomers of 10. We therefore optimized a hybrid of known
synthetic sequences11 as outlined in Scheme 2. Importantly,
both enantiomers of 10 could be prepared in multigram
quantities in six steps, with an overall efficiency of 40% from
inexpensive D-(-)-ribose. Key elements of both sequences
entailed vinyl Grignard addition to the enantiomers of
aldehyde 12, followed in turn by ring closing metathesis
(RCM), PCC oxidation, and hydrogenation (Scheme 2).
Alkylation of (+)- and (-)-cyclopentanone 10 with methyl
bromoacetate was then anticipated to proceed from the less
hindered convex face of the bicyclic skeleton to install the
side chain in a stereoselective fashion. Initial attempts to
alkylate (-)-10 with methyl bromoacetate, employing LDA
in the presence of HMPA, however, furnished only a
(3) Beauchamp, G.; Keast, R.; Morel, D.; Liu, J.; Pika, J.; Han, Q.; Lee,
C.; Smith, A. B., III; Breslin, P. Nature 2005, 437, 45-46.
(4) Unpublished results.
(5) Montedoro, G.; Servili, M.; Baldioli, M.; Selvaggini, R.; Miniati,
E.; Macchioni, A. J. Agric. Food Chem. 1993, 41, 2228-2234.
(6) Similar structural features have also been reported in the constituents
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U.; George, V.; Pushpandadan, P.; Rajasekharan, S.; Duus, J.; Nyman, U.;
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Takenaka, Y.; Okazaki, N.; Tanahashi, T.; Nagakura, N.; Nishi, T.
Phytochemistry 2002, 59, 779-787 and references therein.
(7) Andrewes, P.; Busch, J.; de Joode, T.; Groenewegen, A.; Alexandre,
H. J. Agric. Food Chem. 2003, 51, 1415-1420 and references therein.
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B.; Bartsch, H. Food Chem. Toxicol. 2000, 38, 647-659. (b) Owen, R.
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