Syntheses of Woody Odorants Georgyone and Arborone
A R T I C L E S
adduct (from an exo [2+4] pathway).10 The assignment of
stereochemistry to 6 follows from previous work.9 The adduct
6 was transformed efficiently into (-)-1, the (1R,2S)-enantiomer
of Georgywood, in three straightforward steps. The dextroro-
tatory (1S,2R)-enantiomer of 1 was synthesized by the corre-
sponding pathway using the (R)-enantiomer of catalyst 5 (ent-
5) for the Diels-Alder step. Whereas 1 possesses an intense
clean woody odor, the (+)-enantiomer was found to possess a
relatively weak odor which is best described as distinctly
unpleasant-acrid-musty.11 It is fortunate that the pleasant odor
of 1 masks the disagreeable odor of ent-1 in the commercial
scent. After our assignment of absolute configuration to the
active odorant enantiomer of Georgywood was transmitted to
the Givaudan group (July 16, 2004), it was accepted by them
as consistent with rotation data obtained with a sample of 1
that had been prepared by resolution of a racemic intermediate.12
They also reported that the threshold for odor detection of ent-1
is 103 times greater than that for 1. We believe that the synthesis
of 1 outlined in Scheme 1 provides an excellent route for the
production of this desirable component of Georgywood.
We turn next to the enantioselective synthesis of the chiral
enone 2 and its antipode ent-2. This synthetic problem was
considerably more challenging than the synthesis of Georgy-
wood, and a number of approaches that seemed feasible failed.
It should be mentioned that there is no published synthesis of
2 or ent-2.5b,12 An effective enantioselective synthesis of 2 is
summarized in Scheme 2. The key enantioselective step again
was the (S)-oxazaborolidinium cation (5)-catalyzed Diels-Alder
reaction, in this instance using 1,3-butadiene and (E)-2-methyl-
2-butenal as components.9 The required product, aldehyde 8,
was formed with 16:1 enantioselectivity and in 84% yield.
Oxidation of 8 to the corresponding carboxylic acid (H2Cr2O7,
acetone-H2O) and an iodolactonization-â-elimination sequence
provided in good yield the unsaturated γ-lactone 9, which was
further converted to the methyl ester-enone 10 by sequential
methanolysis and oxidation with pyridinium chlorochromate
(PCC) in CH2Cl2 at 23 °C. Reaction of 10 with the cyanocuprate
reagent prepared from 5-chloro-5-methyl-1-hexene13 (11), lithium
4,4′-di-tert-butylbiphenylide, and cuprous cyanide in THF at
-78 °C in the presence of Me3SiCl14 afforded diastereoselec-
tively a conjugate adduct which, upon aqueous workup and
simultaneous silyl ether cleavage, resulted in a single unsaturated
keto ester in 76% yield. Ozonolysis of this product gave the
required keto aldehyde 12 (91%). Acid-catalyzed aldol cycliza-
tion of 12 led to the bicyclic R,â-enone 13. This enone was
converted to the olefinic ester 14 (68% overall) by the sequence
(1) p-toluenesulfonylhydrazone formation and (2) reduction-
Scheme 1
To address such questions, we started with the odorant
substance known commercially as “Georgywood”, a racemic
mixture of 1 and its enantiomer.5b Georgywood possesses a
characteristic pleasant woody odor, different from those of
cedar-wood and sandalwood, which exhibit distinctive and
characteristic odor notes in addition to a “woody” scent.5-7 An
even more widely acclaimed woody odorant than Georgywood
is the product “Iso E Super”, which is a mixture of several
isomeric racemic compounds containing <5% of 2 and its
enantiomer and 60% of 3 and its enantiomer.5b Remarkably,
the highly desirable rich warm-woody odor of Iso E Super is
due to the minor racemic component (()-2, since (()-3 has a
threshold odorant concentration 105 times greater.5b,8 Our
research started with the development of enantioselective
syntheses of chiral 1 and 2 and their enantiomers. The
enantiomeric forms of 1 and 2 had not previously been
synthesized. One of the first objectives of this work was to
identify the exact stereostructure of the effective odorants of
Georgywood7 and Iso E Super.8
The enantioselective total synthesis of 1 was accomplished
by the sequence that is outlined in Scheme 1. The key step in
this process is the enantioselective Diels-Alder reaction of diene
4 with 2-methylacrolein, catalyzed by the (S)-oxazaborolidinium
salt 5.9 As expected from previous studies, this reaction was
highly enantioselective and produced the adduct 6 in 96% ee
and 76% yield, together with 12% of the diastereomeric (1S,2S)-
(9) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808-3809. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
2002, 124, 9992-9993. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
2003, 125, 6388-6390. (d) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett.
2003, 5, 3979-3982. (e) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem.
Soc. 2004, 126, 4800-4802. (f) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J.
Am. Chem. Soc. 2004, 126, 5984-5986. (g) Hu, Q.-Y.; Zhou, G.; Corey,
E. J. J. Am. Chem. Soc. 2004, 126, 13708-13713.
(10) Although synthetic 1 was contaminated by about 10% of the (1S,2S)-
diastereomer, there is no contribution of this impurity to odor since it is
essentially odorless, as shown in a later section of this paper.
(11) Odor testing was carried out with several members of our research group,
including the authors, with good agreement on the consensus evaluation
of odor.
(6) We are indebted to Dr. G. Fra´ter of Givaudan Du¨bendorf AG for a gift of
racemic Georgywood.
(7) Fra´ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633-7703.
(8) Nussbaumer, C.; Fra´ter, G.; Kraft, P. HelV. Chim. Acta 1999, 82, 1016-
1024.
(12) See: Fra´ter, G.; Mu¨ller, U.; Schro¨der, F. Tetrahedron: Asymmetry 2004,
15, 3967-3972.
(13) Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,
10127-10128.
(14) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019-6022.
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