SCHEME 1. Retrosynthetic Analysis of
(+)-(1R,2S)-1 and (+)-(1R,2S)-3
SCHEME 2 a
a Key: (a) (PhS)2, n-Bu3P, THF, 0 °C, 92%; (b) DIBAL-H, DCM,
-78 °C, followed by MeOH, PTSA, -20 °C, 94%; (c) (NH4)2MoO4,
H2O2, MeOH, rt, 98%; (d) nBuLi, THF, -78 °C, followed by
ClC(O)OMe, -50 °C; (e) Mg, MeOH, rt, 85% overall; (f) H2, 5% Rh
on Al2O3, MeOH, rt, 99.5%; (g) (i) 0.3 N HCl, THF/H2O, rt, 87%,
(ii) propyltriphenylphosphonium bromide, KHMDS, PhMe, rt, 95%;
(h) (i) H2, 5% Rh on Al2O3, EtOAc, 99%, (ii) 2N KOH, MeOH/H2O,
rt, followed by 1 N HCl to pH ) 7, 100%.
nor diastereoselective.10 The obtained magnolione exhib-
ited, however, a soft, delicate magnolia fragrance, with
an increased odor strength, a better stability, and a more
floral note than methyl dihydrojasmonate.4c
The so-called garlicky-free magnolione is now a pre-
cious ingredient in several perfumes and odorant
compositions.4c The first synthesis of both enantiomers
of trans-magnolione 4 was achieved by Rosini and col-
laborators very recently, allowing the authors to establish
the absolute configuration of these two stereoisomers;11
the highest enantiomeric excess was, however, only 76%,
impairing the odor tests.
We decided to embark upon the stereoselective syn-
thesis of cis-(1R,2S)-3, which, notwithstanding lack of
experimental evidence, we presumed to exhibit superior
olfactory properties than the other stereoisomers due to
the close structural analogy with methyl dihydro-
jasmonate (1R,2S)-1.
A recurrent synthetic challenge in the construction of
1,2-disubstituted cyclopentanone derivatives of this kind
is the installation of the two cis-oriented side chains,
which are prone to undergo a ready acid- and base-
catalyzed epimerization to the thermodynamically more
stable trans-configuration. According to our strategy
(Scheme 1), which significantly differs from previous
syntheses, we envisaged to deliver both compounds 1 and
3 from the same advanced intermediate 5. A likely
starting material for the hydroxy acid 5 was the enan-
tioenriched hydroxymethyl δ-lactone (-)-(3aS,4S,6aR)-
6, which was available on a multigram scale12 and
already contained two differently functionalized 1,2-cis-
oriented alkyl substituents; furthermore, to minimize
epimerization, we considered it advantageous to delay
unveiling of the stereochemically fragile cyclopentanone
moiety until the final step.
Conversion of lactone 6 into acid 5 seemed to be
feasible through homologation of the homoallylic alcohol,
followed by a standard Wittig reaction13 to install the side
chain at C-2. On the other hand, 5 appeared to be the
immediate precursor of methyl dihydrojasmonate 1, while
the same acid was envisaged to afford the acetyl group
of (1R,2S)-3 by alkylation with methyllithium.
At first, one-carbon homologation of the hydroxymethyl
group of 6 was tried by nucleophilic substitution of the
corresponding iodide either with a cyanide or an 1,3-
dithiane anion; however, we met with no success, owing
to a considerable formation of elimination products. We
then decided to reverse the reactivity of 6 by preparing
the corresponding protected sulfone 7 which was expected
to open the way to the carbomethoxy derivative 8, an
advanced precursor of acid 5 (Scheme 1).
According to this plan, protected sulfide 10, the direct
precursor of sulfone 7, was readily prepared by a three-
step sequence following the reaction conditions depicted
in Scheme 2. Thus, lactone 6 was first treated with
diphenyl disulfide in the presence of tributylphosphine
to give the corresponding sulfide 9 in 92% yield.14
Reduction of the lactone moiety with DIBAL-H afforded
the corresponding lactol in 99% yield, which was im-
mediately protected as methyl acetal 10 (MeOH, PTSA,
-20 °C, 95%). The synthesis proceeded with the chemo-
selective oxidation of sulfide 10 to sulfone 7, which was
carried out with hydrogen peroxide in the presence of a
catalytic amount of (NH4)2MoO4 in methanol (Scheme
(10) Celli, C. (Givaudan Roure) FR 71-31578, Prior. September 1,
1971; Chem. Abstr. 1973, 78, 147433n; AN 1973, 147433; US 4308179,
1981; Chem. Abstr. 1982, 96, 148996g; AN 1982, 148996.
(11) Donnoli, M. I.; Scafato, P.; Nardiello, M.; Casarini, D.; Giorgio,
E.; Rosini, C. Tetrahedron 2004, 60, 4975.
(12) (a) Zanoni, G.; Agnelli, F.; Meriggi, A.; Vidari, G. Tetrahedron:
Asymmetry 2001, 12, 1779. (b) Zanoni, G.; Porta, A.; Meriggi, A.;
Franzini, M.; Vidari, G. J. Org. Chem. 2002, 67, 6064.
(13) (a) Sarkar, T. K.; Ghorai, B. K. J. Indian Chem. Soc. 1999, 76,
693. (b) Ernst, M.; Helmchen G. Angew. Chem., Int. Ed. 2002, 41, 4054.
(14) Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.; Fukumoto,
K. Tetrahedron 1995, 51, 9873.
J. Org. Chem, Vol. 70, No. 12, 2005 4877