A chiron approach to the cyclopropyl lactone oxylipins

Article abstract of DOI:10.1016/S0957-4166(98)00413-3

Enantiomerically pure key intermediates for the synthesis of constanolactones A and B and solandelactones A, B, E and F, the hydroxy- protected (3S,5Z)-undec-1-yn-5-en-3-ol and (3S,1E,5Z)-1-iodoundec-1,5-dien- 3-ol, have been obtained in nine steps starting from (S)-malic acid.

Full text of DOI:10.1016/S0957-4166(98)00413-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3951–3954
A chiron approach to the cyclopropyl lactone oxylipins
C. Barloy-Da Silva and P. Pale ∗
Laboratoire de Synthèse et Réactivité Organique, Université L. Pasteur, 4 rue B. Pascal, 67000 Strasbourg, France
Received 29 September 1998; accepted 12 October 1998
Abstract
Enantiomerically pure key intermediates for the synthesis of constanolactones A and B and solandelactones A,
B, E and F, the hydroxy-protected (3S,5Z)-undec-1-yn-5-en-3-ol and (3S,1E,5Z)-1-iodoundec-1,5-dien-3-ol, have
been obtained in nine steps starting from (S)-malic acid. © 1998 Elsevier Science Ltd. All rights reserved.
The metabolism of fatty acids by marine organisms provides a unique source of novel and di-
verse compounds, the so-called oxylipins.1–3 Cyclopropyl lactone seems to be an often encountered
motif among them, as judged from the isolation of hydridalactone,4 constanolactones,5 halicho- and
neohalicholactone,6 and more recently solandelactones.7 Although still unknown, the biological activities
of these cyclopropyl compounds might be important and useful in physiology and medicine owing
to their structural and biogenetic similarities with the bioactive mammalian eicosanoids.1,8 With the
goal of providing enough materials and analogs, we have developed a general approach towards these
cyclopropyl oxylipins.9,10 In this communication, we present two routes starting from (S)-malic acid
toward two key intermediates for the synthesis of constanolactones A–B (CL A–B) and solandelactones
A–B and E–F (SL A–B and E–F).
CL A–B and SL A–B and E–F are diastereoisomeric at the carbinol position adjacent to the cyclopropyl
lactone motif, and they both exhibit a common end chain with a Z and an E double bond and an
allylic alcohol having the S absolute configuration. Therefore, they should both be obtainable in a
convergent way by addition of a (3S,1E,5Z)-3-hydroxyundeca-1,5-dienyl organometallic to a formyl
cyclopropyl lactone (west and east fragments respectively in Scheme 1).11 Such an organometallic would
be conveniently obtained by hydrometallation of the corresponding acetylenic derivative, (3S,5Z)-undec-
5-en-1-yn-3-ol 6, or by halogen–metal exchange of the corresponding (3S,1E,5Z)-1-haloundec-1,5-dien-
3-ol 512 (Scheme 2). Both compounds could be obtained from the same aldehyde 4 by homologation
to either an acetylenic group or a 1-haloalkene. This aldehyde (2S,4Z)-2-hydroxydec-4-enal 413 could
in turn be obtained from the natural (S)-malic acid through a reduction–oxidation sequence and a
stereoselective Wittig reaction (Scheme 2).
∗
Corresponding author. E-mail: ppale@chimie.u-strasbg.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00413-3

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C. Barloy-Da Silva, P. Pale / Tetrahedron: Asymmetry 9 (1998) 3951–3954
Scheme 1.
Scheme 2.
The sequences toward the aldehyde 4 are described in Scheme 3. (S)-Malic acid was first totally
reduced to the corresponding triol 1.14 The 1,2-diol unit in this compound was then protected as an
acetonide and the third alcohol oxidized through a Swern reaction.15 Due to the instability of the so-
obtained aldehyde, the oxidation and the subsequent stereoselective Wittig reaction were performed
in a one-pot procedure which led to the alkene 2a with a good overall yield.16 The conditions of
the Wittig step ensured the exclusive formation of the required Z double bond.17 We then planned to
use the Rychnovsky procedure18 which should have achieved a selective deprotection of the enediol
acetonide 2a, liberating the free primary alcohol while maintaining the secondary protected. This
methodology, however, proved to be inefficient in our hands. Therefore, we turned to more conventional
methods. Complete deprotection, reprotection of the diol as a para-methoxyphenyl methylene ketal19 and
subsequent ketal reduction20 provided the required enediol 3 monoprotected at the secondary alcohol. To
avoid such protection–deprotection steps, we experimented an alternative route to the corresponding
alcohol 3. Starting from the dimethylester of (S)-malic acid, the Moriwake’s procedure21 provided the
monoreduced ester. Protection of the so-obtained 1,2-diol as a para-methoxyphenyl methylene ketal was
achieved.19a The remaining ester was then reduced and the corresponding alcohol 1b oxidized. A Wittig
reaction in the conditions mentioned above afforded the Z alkene 2b. Regioselective opening20 of the
para-methoxybenzylidene ketal provided the alcohol 3. Oxidation of the free primary alcohol in 3 then
led to the required aldehyde intermediate 4 which was directly used without purification in the next step.
This key aldehyde 4 must then be homologated either to a terminal acetylene or a 1-haloalkene
(Scheme 4). Different procedures have been described to achieve such transformations.22 Since a
(E)-1-haloalkene was required, the Takai reaction23 known to be highly E stereoselective was used.
Condensation of the aldehyde 4 with iodoform in the presence of chromium dichloride yielded the
expected (3S,1E,5Z)-3-para-methoxyphenylmethoxy-1-iodoundec-1,5-diene 5 as the major isomer in
good yield when the Evans modification was used.24 The terminal acetylene can be obtained either

C. Barloy-Da Silva, P. Pale / Tetrahedron: Asymmetry 9 (1998) 3951–3954
3953
Scheme 3.
directly from the aldehyde25 or in a two-step procedure.26 Although the two-step procedure also
provides an alternative to the Takai reaction for the formation of a 1-haloalkene,27 we chose the
direct homologation of the aldehyde to the terminal acetylene. Addition of dimethyl diazophosphonate,
generated in situ using the Hohira conditions,25 to the aldehyde 4 gave the expected acetylene 6 in good
yields.
Scheme 4. (a) Yields over two steps starting from 3
The enantiomeric excess of both 5 and 6 was secured after deprotection of the para-methoxybenzyl
group28 and comparison of their specific rotations with literature values.29 Two key enantiomerically
pure intermediates for the synthesis of constanolactones A–B and solandelactones A–B and E–F as well
as other eicosanoids12 have thus been obtained in nine steps from (S)-malic acid with good overall yield
(22 or 28%, 6 or 5 respectively).
Acknowledgements
The authors thank the University L. Pasteur and the Institut Universitaire de France for financial
support.

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