A simple and efficient highly enantioselective synthesis of α-ionone and α-damascone

Article abstract of DOI:10.1021/jo049012j

An efficient highly enantioselective (ee ≥99%) synthesis of α-ionone and α-damascone is described. Both enantiomers of title compounds were synthesized through two straightforward pathways diverging from enantiopure (R)- or (S)-α-cyclogeraniol. These versatile building blocks were obtained by regioselective ZrCl₄-promoted biomimetic cyclization of (6S)- or (6E)-(Z)-6,7-epoxygeraniol, respectively, followed by deoxygenation of the so formed secondary alcohol. The chiral information was encoded by a highly regioselecive Sharpless asymmetric dihydroxylation of inexpensive geranyl acetate.

Full text of DOI:10.1021/jo049012j

the notes and the odor thresholds even of the two
enantiomers. Furthermore, the endocyclic double bond
confers particularly characteristic nuances to the fra-
grance that can favorably complement the use of other
widely used compounds from the same family.
A Simple and Efficient Highly
Enantioselective Synthesis of r-Ionone and
r-Damascone
Marcella Bovolenta, Francesca Castronovo,
Alessandro Vadala`, Giuseppe Zanoni, and
Giovanni Vidari*
For example, whereas â-damascone is floral-woody,
somewhat tobacco-like, R-damascone smells floral-fruity,
green, apple-like with a harsh camphoraceous cork-note.
This cork-stopper off-note is due to (R)-(+)-R-damascone
1, whereas the (S)-(-)-isomer 2 is linear, clean, and more
intense, besides possessing a pleasant wine-like nuance.3
As to R-ionone, relative sensitivities for the enantiomers
were found to diverge widely for different flavorists;5-8
however, according to recent results collected by Fuganti
et al. on almost enantiopure samples, both stereoisomers
show similar odor description, (S)-(-)-R-ionone 3 being
slightly more powerful than the (R)-antipode 4.9 The odor
of (S)-(-)-R-ionone is described as floral, woody, with an
additional honey aspect.9 Early enantioselective ap-
proaches to R-damascone by Yamada10 and Ohloff11
delivered the (R)-(+)-enantiomer 1 in poor to modest ee’s
of 17.5% and 66%, respectively. Later, thanks to an
efficient method for the enantioselective protonation of
enolates,12 coupled with a fractional crystallization, Fehr
and Galindo achieved both R-damascone enantiomers in
a very high ee (>98%).12-15 Despite its elegance, this
approach requires, however, very demanding reaction
conditions and is therefore of difficult industrial ap-
plicability. From (R)- and (S)-R-damascone, Fehr then
developed a four-step entry to the corresponding R-ionone
enantiomers (ee >98%) through an ingenious enone
transposition.8 Highly enantioselective enzyme-based
synthesis of useful precursors of damascones and ionones
have been published recently. They are exemplified by
the preparation of (S)-R-damascone 2 (ee ca. 100%) by
Mori,16 as well as of (R)-R-ionone 4 (85% ee) by Pfander17
Dipartimento di Chimica Organica, Universita` di Pavia,
Via Taramelli 10, 27100 Pavia, Italy
vidari@unipv.it
Received June 11, 2004
Abstract: An efficient highly enantioselective (ee g99%)
synthesis of R-ionone and R-damascone is described. Both
enantiomers of title compounds were synthesized through
two straightforward pathways diverging from enantiopure
(R)- or (S)-R-cyclogeraniol. These versatile building blocks
were obtained by regioselective ZrCl4-promoted biomimetic
cyclization of (6S)- or (6R)-(Z)-6,7-epoxygeraniol, respec-
tively, followed by deoxygenation of the so formed secondary
alcohol. The chiral information was encoded by a highly
regioselecive Sharpless asymmetric dihydroxylation of in-
expensive geranyl acetate.
Ionones and damascones are established among the
most highly valued fragrance constituents as a result of
their distinctive fine violet and rose scents.1,2 Besides
their use in the perfumery industry, ionones and dam-
ascones are also appreciated synthetic building blocks.3,4
Both of these C13 norterpenoids exist in nature as three
distinct regioisomers, which differ in the position of the
double bond, and are called the R-, â-, and γ-isomers.
(3) Fra´ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54,
7633-7703.
(4) (a) Buchecker, R.; Egli, R.; Regel-Wild, H.; Tscharner, C.;
Eugster, C. H.; Uhde, G.; Ohloff, G. Helv. Chim. Acta 1973, 56, 2548-
2563. (b) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Polo, E.;
Simoni, D. J. Chem. Soc., Chem. Commun. 1986, 757-758. (c)
U¨ belhart, P.; Baumeler, A.; Haag, A.; Prewo, R.; Bieri, J. H.; Eugster,
C. H. Helv. Chim. Acta 1986, 69, 816-834. (d) Colombo, M. I.; Zinczuk,
J.; Ruveda, E. A. Tetrahedron 1992, 48, 963-1037.
(5) Polak, E. H.; Fombon, A. M.; Tilquin, C.; Punter, P. H. Behav.
Brain Res. 1989, 31, 199-206.
(6) Werkhoff, P.; Bretschneider, W.; Gu¨ntert, M.; Hopp, R.; Surburg,
H. Z. Lebensm.-Unters. Forsch. 1991, 192, 111-115.
(7) Bransdorf, R.; Hener, U.; Lehmann, D.; Mosandl, A. Dtsch.
Lebensm.-Rundsch. 1991, 87, 277-280.
(8) Fehr, C.; Guntern, O. Helv. Chim. Acta 1992, 75, 1023-1028.
(9) Fuganti, C.; Serra, S.; Zenoni, A. Helv. Chim. Acta 2000, 83,
2761-2768.
(10) Shibasaki, M.; Terashima, S.; Yamada, S. Chem. Pharm. Bull.
1975, 23, 279-284.
Olfactory evaluation shows that the regioisomeric
purity and the absolute stereochemistry of these isomers
dramatically determines the fragrance properties, some-
times with amazingly pronounced differences between
(11) Ohloff, G.; Uhde, G. Helv. Chim. Acta 1970, 53, 531-541.
(12) Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1998, 110, 6909-6911.
(13) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566-2587.
(14) Fehr, C. Enantioselective Protonation in Fragrance Synthesis.
In Chirality in Industry II; Collins, A. N., Sheldrake, G. N., Crosby,
J., Eds; Wiley: Chichester, 1997; pp 335-351.
* Towhomcorrespondenceshouldbeaddressed.Tel: +390382507322.
Fax: +39 0382507323.
(1) Ohloff, G. Scent and Fragrances: The Fascination of Fragrances
and their Chemical Perspectives; Springer-Verlag: Berlin, 1994.
(2) Pybus, D. H.; Sell, C. S. The Chemistry of Fragrances; The Royal
Society of Chemistry: London, 1999.
(15) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. Engl. 1994, 33,
1888-1890.
(16) (a) Mayer, H.; Ruttimann, A. Helv. Chim. Acta 1980, 63, 1451-
1455. (b) Mori, K.; Amalke, M.; Itou, M. Tetrahedron 1993, 49, 1871-
1878.
(17) Pfander, H.; Semadeni, P. A. Aust. J. Chem. 1995, 48, 145-151.
10.1021/jo049012j CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/11/2004
J. Org. Chem. 2004, 69, 8959-8962
8959

SCHEME 1. Retrosynthetic Analysis of
Damascones 1, 2 and Ionones 3, 4
SCHEME 2 a
and of 4 (98% ee) and (S)-R-ionone 3 (97% ee) by Fuganti
et al.18,19 These achievements, though still quite laborious,
compare favorably with the original preparation of R-ion-
one enantiomers based on a classical resolution through
multiple tedious fractional crystallization of (-)-menthyl
hydrazone derivatives.20
As shown in Scheme 1, our original access to com-
pounds 1, 4 and 2, 3 is through the use of diols 5 and 11,
respectively, which we envisaged to obtain in high optical
purities by biomimetic cyclization of the corresponding
epoxygeraniol antipodes 6 and 10, respectively. Actually,
each of these valuable chiral oxirane intermediates is
readily available by selective mesylation of diols 7 and
9, respectively, followed by exposure to a base (Scheme
2).21,22 On the other hand, the two diols are smoothly
derived from inexpensive (E)-geranyl acetate 8 simply by
switching the chiral auxiliary used in two separate
Sharpless asymmetric dihydroxylation (AD) reactions.22
The same cheap monoterpene ester 8 would thus fur-
nish 10 of the 13 carbons of the final products 1-4.
The synthesis of each enantiomeric pair 1, 4 and 2, 3
would then proceed from the same intermediates 5
and 11, respectively, on the basis of a diverging strategy
conceived to install the two isomeric enone append-
ages. For the sake of conciseness, herein we describe only
the synthesis of the enantiomers (S)-(-)-R-damascone 2
and (S)-(-)-R-ionone 3, by using diol 921,22 as chiral
building block. The opposite series of antipodes was
obtained starting from diol 722 via the same synthetic
pathway.
a Reagents and conditions: (a) (1) MsCl, Py, CH2Cl2, 22 °C; (2)
K2CO3, MeOH, 0 °C, 80% overall; (b) ZrCl4, CH2Cl2, 22 °C, 53%
(48% after two recrystallizations to constant mp); (c) p-BrC6H4COCl,
Et3N, CH2Cl2, -40 °C, 84%; (d) (1) MsCl, Et3N, CH2Cl2, 0 °C; (2)
DBU, toluene, reflux, 72% overall; (e) (1) H2, Rh/Al2O3, EtOAc, 22
°C; (2) NaOH, MeOH, 22 °C, 78% overall; (f) Dess-Martin
periodinane,31 CH2Cl2, 22 °C, 82%; (g) allylBu3Sn, BF3‚Et2O,
CH2Cl2, -78 °C, 73%; (h) as (f), 88%; (i) DBU, CH2Cl2, 22 °C, 86%;
(l) (EtO)2P(O)CH2COCH3, Ba(OH)2‚8H2O, THF/H2O 40:1, 22 °C,
57% at 13% conversion; (m) (1) PhSSPh, nBu3P, THF, 0 f 22 °C;
(2) 30% H2O2, cat. (NH4)2MoO4, MeOH, 0 f 22 °C, 71% overall;
(n) nBuLi, THF, -78 °C, then add (S)-2-tert-butyldiphenylsilyloxy-
propanal,37 THF, -78 °C; (o) 10% Na(Hg), MeOH, Na2HPO4, -40
f -20 °C; (p) Bu4NF, THF, 0 f 22 °C, 71% from 18; (q) as (f),
89%.
ture and stereochemistry of cis-diol 11, resulting from a
chairlike conformation of the cyclization transition state,
were confirmed by comparison with literature data.25 As
to the ee of diol 11, it could not be determined directly
either by enantioselective HPLC or GC; we assumed it
to be identical to that of diol 9, namely, in the range of
88-94%,26 since both the preparation of epoxide 10 and
the subsequent highly concerted cyclization should occur
with complete stereospecificity. The ee of diol 11 could,
however, be increased by two successive recrystallizations
to constant melting point from hexanes-Et2O, and the
so obtained excellent optical purity was proved by the ee
observed for the subsequently produced alcohol 14 (vide
Scheme 2 summarizes our synthesis of 2 and 3. The
strategic common intermediate 11 was readily obtained
by ZrCl4-promoted cyclization of (S)-(-)-geraniol epoxide
10. As already proven with racemic 10, the reaction was
remarkable as to positional control of the double bond in
the product, yielding the monocyclic endo-olefin 11 in
reproducible reasonable yields (50-55%).23,24 The struc-
(18) Brenna, E.; Fuganti, C.; Grasselli, P.; Redaelli, M.; Serra, S. J.
Chem. Soc., Perkin Trans. 1 1998, 4129-4134.
(19) Aleu, J.; Brenna, E.; Fuganti, C.; Serra, S. J. Chem. Soc., Perkin
Trans. 1 1999, 271-278.
(24) In addition to diol 11, the product mixture contained 3-5% of
the internal ether, 10-15% of chlorohydrins, and an intractable
mixture of unidentified nonpolar compounds. Interestingly, the NMR
spectra of chromatographically purified 11 revealed no regioisomeric
olefins.
(20) Eschenmoser, W.; U¨ belhart, P.; Eugster, C. H. Helv. Chim. Acta
1979, 62, 2534-2538.
(21) Corey, E. J.; Noe, M. C.; Shieh, W.-C. Tetrahedron Lett. 1993,
34, 5995-5998.
(25) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Le Gall, T.; Shin,
D.-S.; Falck, J. R. J. Org. Chem. 1995, 60, 7209-7214 and references
therein.
(22) Vidari, G.; Dapiaggi, A.; Zanoni, G.; Garlaschelli, L. Tetrahedron
Lett. 1993, 34, 6485-6488.
(23) Vidari, G.; Beszant, S.; El Merabet, J.; Bovolenta, M., Zanoni,
G. Tetrahedron Lett. 2002, 43, 2687-2690.
(26) Enantiomeric excesses of diol 10 varied, depending on the
reaction scale and AD-mix-â batches used in the asymmetric step.22
8960 J. Org. Chem., Vol. 69, No. 25, 2004

infra). The latter was envisaged to be the immediate
precursor of aldehyde 15, which was the starting point
from where we initially planned to reach the isomeric
enones 2 and 3 by two separate routes. Conversion of 11
into 14 required selective deoxygenation of the secondary
alcohol. This was readily executed in three uneventful
steps. Selective protection of the primary alcohol of 11
as p-bromobenzoate 12 was followed by smooth dehydra-
tion of the secondary hydroxyl group to yield diene 13,
whose less substituted double bond was readily hydro-
genated with complete regioselectivity.27 Removal of the
applied to aldehyde 15 furnished (S)-(-)-R-ionone 3 very
sluggishly, resulting in only 13% conversion after 17 h.
Moreover, the optical purity of the product (95% ee)
indicated a slight racemization due to the prolonged
exposure to basic condition. Therefore, an unprecedented
methodology for the construction of the enone moiety of
R-ionone was investigated. Indeed, we anticipated that
a highly stereoselective approach might be based upon a
Julia-Lythgoe olefination,35,36 in which the configura-
tionally stable sulfone 18 and (S)-2-tert-butyldiphenyl-
silyloxypropanal37 were the suitable starting compounds.
Actually, the unique stereochemical features of the
Julia-Lythgoe reaction not only would allow the absolute
configuration of sulfone 18 to be preserved but also would
give rise to the required stereodefined E double bond.38
In the event, (S)-R-cyclogeraniol 14 was converted into
the corresponding sulfide under Mitsunobu condition,39
and the sulfide chemoselectively oxidized to sulfone
18 with H2O2 in the presence of a catalytic amount of
(NH4)2MoO4 in MeOH.40 Under these conditions, the
double bond was not affected by the oxidant and the
expected product 18 was obtained in 71% yield. Subse-
quent condensation of sulfone 18 with the cited 2-hy-
droxypropanal derivative was carried out under our
recently reported protocol,41 which requires no Lewis acid
activation, contrary to the original procedure developed
by Wicha for the coupling of lithiated sulfones with
protected hydroxy-aldehydes.42 Thus, reaction of the
lithium salt of 18 with the required aldehyde afforded
the desired hydroxysulfone 19 as a mixture of stereoiso-
mers, which were immediately exposed to 10% sodium
amalgam to deliver the desired TBDPS protected
(6S,9S)-(-)-R-ionol 20 in about 80% yield. Synthesis of
enantiomerically pure (ee g99% by GC analysis)
protective group afforded (S)-R-cyclogeraniol 14,16 [R]20
D
-109 (c 0.9, EtOH), g99% ee (GC). We preferred this
lengthy but very clean procedure to different variants of
the Barton-like radical deoxygenation reaction, which is
the common protocol employed for the excision of hin-
dered secondary alcohols structurally related to com-
pound 11.28-30 Indeed, when the O-phenyl thionocarbon-
ate or the imidazolyl thionoformate derivative of compound
12 was exposed to Bu3SnH and catalytic AIBN, deoxy-
genation promptly occurred; however, the resulting prod-
uct was contaminated by inseparable tin residues. Oxi-
dation of (S)-R-cyclogeraniol 14 with the Dess-Martin
periodinane reagent.31 readily furnished the stereochemi-
cally labile aldehyde (S)-R-cyclocitral 15, identical with
the literature.16b
The syntheses of (S)-R-damascone 2 and (S)-(-)-R-
ionone 3 were completed by using aldehyde 15 as a
common intermediate. Thus, BF3‚Et2O-promoted addi-
tion30,32 of allyltributyltin to 15 smoothly afforded
(S)-iso-R-damascol 16 in 73% yield, as a diastereomeric
mixture (undetermined stereochemistry at the carbinol
center) in a ratio of 9:1 (GC). Subsequent oxidation of
alcohol 16 with the Dess-Martin periodinane reagent31
gave ketone 17 in 88% yield, which on exposure to a
hindered base (DBU) at room temperature underwent
complete double bond isomerization, affording the crys-
talline conjugated ketone (S)-R-damascone 2, [R]20D -482.6
(c 2.2, CH2Cl2), in 86% yield. The ee of synthetic (S)-2
was estimated to be g99% by enantioselective HPLC
analysis, confirming that no appreciable racemization
occurred during the elongation of aldehyde 15.
(S)-(-)-R-ionone 3, [R]20 -414.7 (c 0.7, CH2Cl2), was
D
completed uneventfully by hydroxyl group deprotection,
followed by oxidation with the Dess-Martin periodinane
reagent.31
In conclusion, the extremely valuable aroma constitu-
ents (S)-(-)-R-damascone 2 and (S)-(-)-R-ionone 3 have
been obtained enantiomerically pure by following two
simple synthetic pathways diverging from (S)-R-cycloge-
raniol 14, which was readily prepared from inexpensive
geranyl acetate 8. Of general interest in our approach
are the ZrCl4-promoted stereospecific and regioselective
biomimetic cyclization of (S)-(-)-geraniol epoxide 10 to
diol 11 and the installation of the enone moiety of
compound 3 through a stereoselective Julia-Lythgoe
olefination.
In the synthesis of our second target, (S)-(-)-R-ionone
3, at first aldehyde 15 was submitted to the barium
hydroxide promoted modification of the Horner-Wad-
sworth-Emmons (HWE) olefination reaction, according
to the procedure previously reported by Monti.33 Indeed,
this has been suggested to be the method of choice for
epimerizable, base-sensitive aldehydes.34 The procedure
(27) When the primary hydroxyl group of diol 11 was protected as
a nonaromatic ester, i.e., as a pivalate, hydrogenation of the diene
moiety proceeded less cleanly and regioselectively, affording a mixture
of dihydro- and tetrahydroderivatives. Presumably, the trisubstituted
double bond of 13 was deactivated by π-stacking interaction with the
benzoate group.
(35) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833-4836.
(36) Kocienski, P. J.; Lythgoe, B.; Waterhouse, I. J. Chem. Soc.,
Perkin Trans. I 1980, 1045-1050.
(37) Prepared from (S)-2-hydroxypropionic acid ethyl ester (ee g99%)
by hydroxyl group protection (tBuPh2SiCl, imidazole), followed by
DIBAL reduction of the ester group; overall yield ) 82%, ee g 99%
(GC).
(28) Fish, P. V.; Johnson, W. S. J. Org. Chem. 1994, 59, 2324-2335.
(29) Corey, E. J.; Luo, G.; Lin, L. S. Angew. Chem., Int. Ed. 1998,
37, 1126-1128.
(38) Kocienski, P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin
Trans. 1 1978, 829-834.
(30) Beszant, S.; Giannini, E.; Zanoni, G.; Vidari, G. Tetrahedron:
Asymmetry 2002, 13, 1245-1255.
(39) Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.; Fukumoto,
K. Tetrahedron 1995, 51, 9873-9890.
(31) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(40) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem.
1963, 28, 1140-1142.
(32) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207-2293.
(33) Laval, G.; Audran, G.; Galano, J.-M.; Monti, H. J. Org. Chem.
2000, 65, 3551-3554.
(41) Zanoni, G.; Porta, A.; Vidari, G. J. Org. Chem. 2002, 67, 4346-
4351.
(34) Paterson, J.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774-776
and references therein.
(42) Achmatowicz, B.; Baranowska, E.; Daniewski, A. R.; Pankowski,
J.; Wicha, J. Tetrahedron 1988, 44, 4989-4998.
J. Org. Chem, Vol. 69, No. 25, 2004 8961

Supporting Information Available: Experimental de-
tails for general procedures and for the preparation and spec-
tral data of compounds 2, 3, 11-18, and 21. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Italian MURST
(funds COFIN), and the University of Pavia (funds
FAR) for financial support, and Prof. Mariella Mella and
Prof. Giorgio Mellerio for NMR and MS spectra, respec-
tively.
JO049012J
8962 J. Org. Chem., Vol. 69, No. 25, 2004