U.S. patent application number 11/106338 was filed with the patent office on 2006-10-19 for efficient and economic asymmetric synthesis of nootkatone, tetrahydronootkatone, their precursors and derivatives.
Invention is credited to William E. Crowe, Gregg Henderson, Roger A. Laine, Anne M. Sauer.
Application Number | 20060235247 11/106338 |
Document ID | / |
Family ID | 37018882 |
Filed Date | 2006-10-19 |
United States Patent
Application |
20060235247 |
Kind Code |
A1 |
Sauer; Anne M. ; et
al. |
October 19, 2006 |
EFFICIENT AND ECONOMIC ASYMMETRIC SYNTHESIS OF NOOTKATONE,
TETRAHYDRONOOTKATONE, THEIR PRECURSORS AND DERIVATIVES
Abstract
An inexpensive, stereoselective synthesis for nootkatone,
tetrahydronootkatone, and their derivatives is disclosed. The
starting materials used in the synthesis are inexpensive. The
principal starting material, (-)-.beta.-Pinene, is on the GRAS list
(generally recognized as safe).
Inventors: |
Sauer; Anne M.; (Baton
Rouge, LA) ; Crowe; William E.; (Baton Rouge, LA)
; Laine; Roger A.; (Baton Rouge, LA) ; Henderson;
Gregg; (St. Gabriel, LA) |
Correspondence
Address: |
PATENT DEPARTMENT;TAYLOR, PORTER, BROOKS & PHILLIPS, L.L.P
P.O. BOX 2471
BATON ROUGE
LA
70821-2471
US
|
Family ID: |
37018882 |
Appl. No.: |
11/106338 |
Filed: |
April 14, 2005 |
Current U.S.
Class: |
568/817 ;
260/665G |
Current CPC
Class: |
C07C 45/66 20130101;
C07C 45/66 20130101; C07B 2200/07 20130101; C07C 49/653 20130101;
C07C 49/693 20130101; C07C 49/433 20130101; C07C 35/28 20130101;
C07C 49/653 20130101; C07C 49/653 20130101; C07C 45/74 20130101;
C07C 45/28 20130101; C07C 45/65 20130101; C07C 29/44 20130101; C07C
49/693 20130101; C07C 45/28 20130101; C07C 2602/42 20170501; C07C
49/433 20130101; C07C 45/74 20130101; C07C 29/44 20130101; C07C
45/65 20130101 |
Class at
Publication: |
568/817 ;
260/665.00G |
International
Class: |
C07C 35/22 20060101
C07C035/22; C07F 3/02 20060101 C07F003/02 |
Goverment Interests
[0001] The development of this invention was funded in part by the
Government under grant number 58-6435-8-084 awarded by the
Department of Agriculture, Agricultural Research Service. The
Government has certain rights in this invention.
Claims
1. A process comprising reacting ##STR2## and a metal to produce
##STR3## wherein X is a halogen atom; and wherein R is a hydrogen
atom or methyl.
2. A process as recited in claim 1; wherein the metal is Mg; and X
is Cl.
3. A process as recited in claim 1, additionally comprising the
step of subjecting ##STR4## to Oxy-Cope rearrangement to produce
##STR5##
4. A process as recited in claim 3; wherein the metal is Mg; and X
is Cl.
5. A process as recited in claim 3; wherein said Oxy-Cope
rearrangement is promoted by heating; or by the presence of base
and a metal chelating agent; or by the presence of a transition
metal catalyst.
6. A process as recited in claim 3; wherein said Oxy-Cope
rearrangement is promoted by the presence of potassium hydride and
18-crown-6.
7. A process as recited in claim 3; wherein said Oxy-Cope
rearrangement is promoted by the presence of a platinum or
palladium catalyst.
8. A process as recited in claim 1, additionally comprising the
steps of oxidizing .beta.-pinene to produce nopinone; and reacting
the nopinone with acetaldehyde and a base to produce ##STR6##
9. A process as recited in claim 3, additionally comprising the
steps of reacting ##STR7## with a methyl halide and a base to
produce ##STR8## oxidizing the ##STR9## to produce ##STR10##
reacting the ##STR11## with hydrochloric acid to produce ##STR12##
dehydrohalogenating the ##STR13## to produce nootkatone.
10. (canceled)
11. A process as recited in claim 9, additionally comprising the
steps of oxidizing .beta.-pinene to produce nopinone; and reacting
the nopinone with acetaldehyde and a base to produce ##STR14##
12. (canceled)
13. A process as recited in claim 11, wherein the metal is Mg; and
X is Cl.
14. A process comprising reacting ##STR15## with an alkali metal in
the presence of a proton source, whereby tetrahydronootkatone is
produced.
15. A process as recited in claim 14, wherein the alkali metal
comprises sodium or lithium, and wherein the proton source
comprises liquid ammonia.
16-17. (canceled)
Description
[0002] This invention pertains to the synthesis of nootkatone and
its derivatives.
[0003] Nootkatone, whose IUPAC nomenclature is
4,4a,5,6,7,8-hexahydro-6-isopropenyl-4,4a-dimethyl-2(3H)-naphthalone,
and whose structure is depicted as Compound 9 in FIG. 1, occurs
naturally in certain plant sources including cedar, vetiver grass,
and citrus oils. Nootkatone has a fragrance reminiscent of
grapefruit, and is used commercially as a flavor or fragrance
ingredient. Nootkatone is nontoxic to humans and other mammals.
[0004] Nootkatone has activity, however, as a repellant or toxicant
against various arthropods, including termites, ants, flies, ticks,
mole crickets, and cockroaches; as well as against certain other
invertebrates including nematodes. Nootkatone also acts as an
environmentally-friendly wood preservative. See, e.g., published
international patent application WO 01/28343; and published United
States patent application US-2003-0073748-A1.
[0005] Nootkatone is expensive, however, which impedes its broader
use for these and other purposes. There is an unfilled need for an
efficient and economical synthesis of nootkatone,
tetrahydronootkatone, and other nootkatone derivatives; preferably
a synthesis that is stereoselective, so that the products have the
desired biological activity; and preferably a synthesis that is
based on starting materials that are on the GRAS (generally
recognized as safe) list, to reduce the burdens of regulatory
approval. No prior synthesis of nootkatone has satisfied all of
these criteria. Most of the nootkatone sold commercially to date
has been produced by the semi-synthetic oxidation of the orange oil
component valencene. Valencene is an expensive starting
material.
[0006] J. Marshall et al., "The Total Synthesis of Racemic
Isonootkatone (.alpha.-Vetivone)," Chem. Commun., pp. 753-754
(1967) suggested that the compound .alpha.-vetivone should be
considered an isomer of nootkatone, and that it should be renamed
isonootkatone. A multi-step synthesis of racemic .alpha.-vetivone
(or isonootkatone) from diethyl isopropylidene malonate was
described.
[0007] A. van der Gen et al., "Stereoselective synthesis of
eremophilane sesquiterpenoids from .beta.-pinene," Recueil Trav.
Chim. Pays-Bas, vol. 90, pp. 1034-1044 (1971) disclosed a multistep
synthesis of 2-methyl-4-isopropylidenecyclohexanone from
.beta.-pinene. Robinson annulation of
2-methyl-4-isopropylidenecyclohexanone with trans-3-penten-2-one
stereoselectively produced .alpha.-vetivone, which could then be
converted to nootkatone.
[0008] S. Torii et al., "Functionalization of trans-decalin. V. A
synthesis of (.+-.)-nootkatone and (.+-.)-valencene from
4.beta.,4a.beta.-dimethyl-.DELTA..sup.6,7-octalin-1-one ethylene
acetal," Bull. Chem. Soc. Jpn., vol. 55, pp. 887-890 (1982)
disclosed a multi-step synthesis of racemic nootkatone and racemic
valencene from
4.beta.,4a.beta.-dimethyl-.DELTA..sup.6,7-octalin-1-one ethylene
acetal.
[0009] G. Revial et al., "Enantioselective synthesis of
(+)-.alpha.-vetivone through the Michael reaction of chiral
amines," Tetrahedron: Asymmetry, vol. 11, pp. 4975-4983 (2000)
disclosed a multi-step synthesis of (+)-.alpha.-vetivone, involving
the stereoselective Michael addition of a chiral imine of
4-isopropylidene-2-methylcyclohexanone to phenyl crotonate.
[0010] T. Yanami et al., "Synthetic Study of (+)-Nootkatone from
(-)-.beta.-Pinene," J. Organic Chem., vol. 45, pp. 607-612 (1980)
disclosed a multi-step synthesis of (+)-nootkatone from
(+)-nopinone, the latter of which could be prepared by the
oxidation of .beta.-Pinene. The authors described their key step as
the conjugate addition of methallyltrimethylsilane to
trans-3-ethylidenenopinone, which was obtained from nopinone by
cross-condensation with acetaldehyde followed by acid treatment.
The dione that was obtained from the resulting adduct was
methylated, followed by ozonization, to produce nootkatone
hydrochloride upon treatment with hydrogen chloride. Regioselective
dehydrochlorination of the hydrochloride produced nootkatone. An
alternative route using allyltrimethylsilane was also
described.
[0011] Prior methods for synthesizing nootkatone have one or more
of the following disadvantages: the synthesis is lengthy; the
synthesis requires relatively expensive starting materials; the
yield is low; the synthesis produces a racemic mixture; or one or
more starting materials are not on GRAS list (generally recognized
as safe).
[0012] There is an unfilled need for a less expensive method for
the stereoselective synthesis of nootkatone. While the current high
price of nootkatone may be tolerable in certain fields of use, such
as flavorings and fragrances, it would still be desirable to have a
less expensive source of nootkatone even for such purposes.
However, the high cost of nootkatone precludes commercial use in
other areas, for example as a repellant or toxicant against
termites or other pests. If nootkatone could be produced far more
inexpensively than is currently the case, it would become
commercially feasible to use it and its derivatives as a repellant
or toxicant against various arthropods, including termites, ants,
flies, ticks, mole crickets, and cockroaches; as well as against
certain other invertebrates such as nematodes. It could also become
commercially feasible to use it as a wood preservative for
protection against wood-destroying insects.
[0013] We have discovered a novel, inexpensive, stereoselective
synthesis for nootkatone, tetrahydronootkatone, and their
derivatives. The starting materials used in the synthesis are
inexpensive. The principal starting material, (-)-.beta.-Pinene, is
a natural compound on the GRAS list (generally recognized as safe).
The synthesis is shorter, less expensive, and of significantly
higher yield than prior synthetic schemes for nootkatone.
[0014] Ourexperimental data have shown that the synthetic scheme
outlined in FIG. 1 stereoselectively yields nootkatone as the
exclusive product. The starting material was converted to this
single product.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 depicts an embodiment of a synthetic scheme in
accordance with the present invention.
[0016] FIG. 2 depicts alternative embodiments of a synthetic scheme
in accordance with the present invention.
[0017] FIG. 3 depicts an alternative synthetic route to
tetrahydronootkatone from Compound 8.
EXAMPLE 1
[0018] 6,6-dimethyl-bicyclo[3.3.1]heptan-2-one, Nopinone (Compound
2): Finely ground KMnO.sub.4 (2.8 g, 17.8 mmol), acidic alumina
(Brockmann Activity 1, 11.2 g, 0.1098 mol), and water (2.79 g,
0.1552 mol) were mixed for five minutes to produce a homogeneous
mixture. Commercially-obtained (-)-.beta.-Pinene (0.5 g, 0.582 mL,
3.67 mmol) was dissolved in dichloromethane (DCM) (100 mL), and the
solution was placed in a round bottom flask. The moistened
permanganate/alumina mixture was added in small portions to this
solution over a 10 minute period with continual stirring. The
reaction was allowed to proceed at room temperature, and the
progress of the reaction was monitored by TLC (90:10/hexane:EtOAc).
After essentially all starting material had reacted, the crude
mixture was filtered through a fritted glass funnel, and the
residue was washed with DCM (2.times.50 mL). Excess solvent was
removed via rotary evaporator to leave a yellow oil, which was
further purified by column chromatography (90:10/hexane:EtOAc) to
give colorless Compound 2 (0.48 g, 95% yield). .sup.1H NMR: (250
MHz, CDCl.sub.3), .delta. 2.7-2.5 (m, 3H), 2.42-2.29 (m, 1H),
2.27-2.2 (m, 1H), 2.13-1.87 (m, 2H), 1.61-1.57 (d, J=9.46, 1H),
1.33 (s, 3H), 0.86 (s, 3H). .sup.13C NMR: (62.5 MHz, CDCl.sub.3),
.delta. 214.77, 57.94, 41.10, 40.30, 32.57, 25.88, 25.17, 22.10,
21.31.
EXAMPLE 2
[0019]
(1R,5R)-6,6-dimethyl-3-(E)-ethylidenebicyclo[3.3.1]heptan-2-one
(Compound 3): A magnetic stir bar was placed in a clean, dry,
3-neck, jacketed, round bottom flask fitted with a constant
addition funnel and two inlet valves. The flask was then purged
with argon. Compound 2 (1 g, 1.0194 mL, 7.24 mmol) and KOH (0.4872
g, 8.7 mmol) were dissolved in ethanol (17.2 mL) in the flask,
under argon. The resulting solution was cooled to 5.degree. C. A
solution of acetaldehyde (0.609 mL, 0.4781 g, 10.9 mmol) in EtOH
(4.3 mL) was added to the flask over 30 minutes, still under Ar.
The mixture was allowed to react at 5.degree. C. for 15 hours. At
15 hour intervals, four additional portions of acetaldehyde (0.609
mL) in EtOH (4.3 mL) were added to the reaction mixture, which was
held at 5.degree. C. After the final portion of acetaldehyde and
EtOH was added, stirring was continued an additional 6 hours. Then
p-toluenesulfonic acid monohydrate (1.927 g, 10.1 mmol) in EtOH (5
mL) was added to the mixture, and the resulting solution was
stirred for 3 hours at room temperature. The solvent was removed
via rotary evaporator, and the remaining crude brown residue was
then dissolved in ether. The ether solution was passed through a
series of dry columns (with a 90:10/Hexane:EtOAc solvent), and the
eluted solution was then distilled in a Kugelrohr apparatus
(85-95.degree. C., 3 mmHg) to give Compound 3 (1 g, 84% yield) as a
colorless liquid. .sup.1H NMR: (250 MHz, CDCl.sub.3), .delta.
6.89-6.86 (m, 1H), 2.59-2.56 (m, 4H), 2.21 (m,1H), 1.81-1.77 (m,
3H), 1.46 (m,1H), 1.35 (s, 3H), 0.86 (s, 3H). .sup.13C NMR: (62.5
MHz, CDCl.sub.3), .delta. 202.48, 134.76, 134.00, 55.5, 40.5,
38.98, 27.9, 27.8, 26.2, 21.6, 13.7.
[0020] As an alternative, NaOH may be used as the base in this
synthesis, in lieu of KOH.
EXAMPLE 3
[0021]
3-ethylidene-6,6-dimethyl-2-(2-methyl-allyl)-bicyclo[3.1.1]heptan--
2-ol (Compound 4a): A solution of methallylchloride (0.692 g, 7.64
mmol) in freshly distilled tetrahydrofuran (THF) (2.5 mL) was added
to a suspension of flame-dried Mg metal turnings (0.28 g, 11.5
mmol) in THF (2.5 mL) over 30 minutes at 60.degree. C. The
resulting Grignard solution darkened during heating at reflux for
an additional 20 minutes. The mixture was then cooled to
-42.degree. C. (dry ice/chlorobenzene bath), and a solution of the
enone Compound 3 (0.4182 g, 2.6 mmol) in THF (2.5 mL) was added
dropwise. After 5 minutes, the cooling bath was removed, and the
reaction was stirred for 1.5 hours as it warmed to room
temperature. The mixture was then decanted into ice-cold 0.1 N HCl
(50 mL) and extracted with ether. The combined organic fractions
were washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Column chromatography (with
90:10/Hexane:EtOAc) provided Compound 4a (0.52 g, 92% yield) as a
colorless liquid. .sup.1H NMR: (250 MHz, CDCl.sub.3), .delta. 0.973
(s 3H), 1.05-1.01 (d 1H), 1.21 (s 3H), 1.60-1.57 (d of t, 3H), 1.61
(s 3H), 1.92 (s 3H), 2.63-2.18 (m 5H), 4.82-4.65 (m 2H), 5.79-5.77
(m 1H); .sup.13C NMR (62.5 MHz, CDCl.sub.3) .delta. 13.1, 22.4,
24.7, 27.3, 30.1, 31.6, 37.9, 38.7, 48.9, 49.8, 78.7, 114.4, 122.0,
143.2, 143.4.
EXAMPLE 4
[0022] 2-allyl-3-ethylidene-6,6-dimethyl-bicyclo[3.1.1]heptan-2-ol
(Compound 4b): Mg metal turnings (0.33 g, 13.7 mmol) were placed in
a clean, dry round bottom flask and flame-dried under vacuum.
Freshly-distilled THF (2.5 mL) was added to the flask, and the
contents were heated to reflux. The mixture was cooled to
40.degree. C., and a solution of allyl chloride (0.75 mL, 0.70 g,
9.1 mmol) in THF (2.5 mL) was added dropwise over a 30 minute
period. The resulting Grignard solution was held at 40.degree. C.
for an additional 20 minutes. The mixture was then cooled to
-42.degree. C. (dry ice/chlorobenzene bath), and a solution of the
enone Compound 3 (0.5 g, 3 mmol) in THF (2.5 mL) was added
dropwise. After 5 minutes, the cooling bath was removed, and the
reaction was stirred for 1.5 hours as it warmed to room
temperature. The mixture was then decanted into ice-cold 0.1 N HCl
(50 mL) and extracted with ether. The combined organic fractions
were washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Column chromatography (with
90:10/Hexane:EtOAc) provided Compound 4b (0.62 g, 98% yield) as a
colorless liquid. .sup.1H NMR: (250 MHz, CDCl.sub.3), .delta. 0.976
(s 3H), 1.03 (s 1H), 1.19 (s 3H), 1.58-1.61 (d of t, 3H), 1.82 (s
1H), 1.92 (s 1H), 1.95 (s 1H), 2.27-2.67 (m 5H), 4.97-5.07 (m 2H),
5.79-5.83 (m 2H); .sup.13C NMR (62.5 MHz, CDCl.sub.3) .delta. 13.1,
22.4, 27.2, 29.3, 31.5, 38.1, 38.8, 46.7, 49.1, 78.3, 117.7, 122,1,
134.8, 142.9.
EXAMPLES 5 AND 6
[0023] General Procedure for Oxy-Cope Rearrangement (Conversion of
Compound 4a to Compound 5a, or of Compound 4b to Compound 5b):
Under an argon atmosphere, oil-free potassium hydride, KH (4.1
mmol) was placed in a round bottom flask. Freshly distilled THF (35
mL) was cannulated into the flask, and the contents were stirred at
0.degree. C. Alcohol 4a or 4b (2.4 mmol) was added to the flask,
followed immediately by a solution of 18-crown-6 in THF (2.4 mmol)
via cannulation. The mixture was allowed to react at 0.degree. C.
for .about.6 hours. The reaction was then quenched with a phosphate
buffer solution (pH=7), and the contents were extracted with ether.
The combined organic layers were washed with water and brine, and
dried over Na.sub.2SO.sub.4. After filtration, excess solvent was
removed under vacuum to provide crude product 5a or 5b,
respectively.
[0024]
3-(1,3-dimethyl-but-3-enyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-on-
e (Compound 5a): Purified Compound 5a (0.49 g, 71%) was obtained by
column chromatography (with a 90:10/Hexane:EtOAc solvent). .sup.1H
NMR: (250 MHz, CDCl.sub.3), .delta. 0.79 (s 3H), 0.93-0.90 (d 3H),
1.32 (s 3H), 1.73-1.68 (s and q overlapping, 5H), 2.12-1.95 (m 3H),
2.42-2.25 (m 1H), 2.47-2.43 (m 1H), 2.57-2.50 (m 2H), 2.65-2.60 (m,
--OH, 1H), 4.76-4.71 (d 2H); .sup.13C NMR (62.5 MHz, CDCl.sub.3)
.delta. 15.3, 21.2, 21.8, 25.8, 26.8, 27.6, 40.6, 43.2, 43.5, 44.9,
57.9, 111.9, 144.0, 215.9.
[0025]
6,6-dimethyl-3-(1-methyl-but-3-enyl)-bicyclo[3.1.1]heptan-2-one
(Compound 5b): Purified Compound 5b (0.4 g, 81%) was obtained by
column chromatography (90:10/Hexane:EtOAc). .sup.1H NMR: (250 MHz,
CDCl.sub.3), .delta. 0.70 (s 3H), 0.87-0.84 (d 3H), 1.22 (s 3H),
1.65-1.61 (d 2H), 2.09-1.96 (m 3H), 2.38-2.19 (m 3H), 2.49-2.44 (t
1H), 2.73-2.61 (m, --OH, 1H), 4.99-4.90 (m 2H), 5.71-5.60 (m 1H);
.sup.13C NMR (62.5 MHz, CDCl.sub.3) .delta. 15.4, 21.3, 22.3, 25.7,
26.7, 30.2, 39.2, 40.5, 43.4, 45.0, 57.8, 116.1, 137.2, 215.8.
EXAMPLES 7 AND 8
[0026] General Procedure for Methylation (Conversion of Compound 5a
to Compound 6a, or of Compound 5b to Compound 6b): Sodium amide
(3.64 mmol, assay 90%) was placed in a round bottom flask that was
fitted with a reflux condenser, evacuated, and then purged with
nitrogen. Freshly distilled benzene (dried over Na/benzophenone)
was cannulated into the apparatus, and the mixture was warmed with
a heating mantle. The ketone Compound 5a or 5b (1.2 mmol) was then
injected, and the reaction mixture was refluxed with continual
stirring for 5 hours. The reaction was then cooled to 45.degree. C.
(via a hot water bath), and iodomethane (2.9 mmol) (freshly
distilled and dried over Drierite) was injected as a single
portion. An additional portion of iodomethane (1.57 eq.) was
injected 2.5 hours later, and the solution was allowed to react at
45.degree. C. for an additional 15 hours. Saturated aqueous
NH.sub.4Cl was then added to the cooled solution, and the product
was extracted with ethyl ether. The organic layer was then washed
with water and brine, and dried over Na.sub.2SO.sub.4. Removal of
excess solvent under vacuum provided crude product 6a or 6b,
respectively.
[0027] As an alternative, toluene may be used as solvent in this
synthesis, in lieu of benzene.
[0028]
3-(1,3-dimethyl-but-3-enyl)-3,6,6-trimethyl-bicyclo[3.1.1]heptan-2-
-one (Compound 6a): Purified Compound 6a (0.25 g, 78%) was obtained
by column chromatography (with a 90:10/Hexane:EtOAc solvent).
.sup.1H NMR: (250 MHz, CDCl.sub.3), .delta. 0.89-0.87 (s and d
overlapping, 6H), 1.31 (s 3H), 1.33 (s 3H), 1.70 (s 3H), 1.80-1.73
(m 2H), 2.13-1.89 (m 3H), 2.30-2.22 (q 1H), 2.49-2.36 (m 1H),
2.60-2.56 (t 1H), 3.12-3.01 (brd, 1H), 4.72-4.67 (d 2H); .sup.13C
NMR (62.5 MHz, CDCl.sub.3) .delta. 14.7, 21.8, 22.3, 25.8, 26.6,
35.2, 38.1, 40.7, 41.7, 43.1, 45.9, 59.5, 111.3, 145.1, 219.2.
[0029]
3,6,6-trimethyl-3-(1-methyl-but-3-enyl)bicycle[3.1.1]heptan-2-one
(Compound 6b): Purified Compound 6b (0.19 g, 73%) was obtained by
column chromatography (with a 90:10/Hexane:EtOAc solvent). .sup.1H
NMR: (250 MHz, CDCl.sub.3), .delta. 0.79 (s 3H), 0.87-0.84 (d 3H),
1.26-1.23 (d 6H), 1.72-1.58 (m 2H), 1.95-1.79 (m 3H), 2.23-2.19 (m
1H), 2.39-2.31 (m 1H), 2.54-2.49 (t 1H), 3.18-3.04 (m 1H),
4.99-4.87 (m 2H), 5.82-5.62 (m 1H); .sup.13C NMR (62.5 MHz,
CDCl.sub.3) .delta. 14.7, 22.6, 25.8, 26.1, 26.5, 35.4, 36.9, 40.4,
41.6, 43.0, 45.9, 59.5, 115.1, 138.7, 219.3.
EXAMPLES 9 AND 10
[0030] (1R, 3S,
5R)-3-[(1R)-1-Methyl-3-oxobutyl]-3,6,6-trimethylbicyclo[3.1.1]heptan-2-on-
e (Compound 7). We developed two syntheses for Compound 7, one
starting with Compound 6a, and the other starting with Compound
6b.
[0031] (a) Starting from Compound 6a: Finely ground KMnO.sub.4 (400
mg, 2.5 mmol) and acidic alumina (Brockmann Activity 1, 1.56 g,
15.3 mmol) were mixed in water (0.4 g, 22 mmol) for five minutes to
obtain a homogeneous mixture. The terminal olefin Compound 6a (120
mg, 0.512 mmol) was dissolved in DCM (20 mL) in a round bottom
flask. The moistened permanganate/alumina mixture was added to the
flask in small portions over 10 minutes with continual stirring.
The mixture was allowed to react at room temperature, and the
progress of reaction was monitored by TLC (with a
90:10/Hexane:EtOAc solvent). After essentially all starting
material had reacted, the crude mixture was filtered through a
fritted glass funnel, and the residue was washed with DCM
(2.times.50 mL). Excess solvent was removed via rotary evaporator
to leave a yellow oil, which was further purified by column
chromatography (90:10/hexane:EtOAc) to give colorless Compound 7
(0.11 g, 89% yield). .sup.1H NMR: (250 MHz, CDCl.sub.3), .delta.
0.85-0.82 (d and s overlapping, 6H), 1.17 (s 3H), 1.24 (s 3H),
1.78-1.72 (m 2H), 1.93-1.85 (2 br s, 1H), 2.09-1.96 (m 1H), 2.09 (s
3H), 2.24-2.12 (m 1H), 2.42-2.27 (m 1H), 2.58-2.47 (m 2H),
3.58-3.52 (m 1H); .sup.13C NMR (62.5 MHz, CDCl.sub.3) .delta. 16.4,
22.6, 24.8, 25.7, 26.3, 30.4, 35.1, 36.9, 41.6, 42.7, 44.6, 47.3,
59.5, 208.2, 219.9.
[0032] (b) Starting from Compound 6b: The terminal olefin Compound
6b (220 mg, 1 mmol), mercuric acetate (320 mg, 1 mmol), and
methanol (2 mL) were stirred under nitrogen at room temperature for
15 minutes. The mixture was then cannulated into a reaction flask
containing a solution of LiCl (9 mg, 0.21 mmol), PdCl.sub.2 (18 mg,
0.1 mmol), and CuCl.sub.2 (40 mg, 3 mmol) in methanol (1 mL). The
mixture was allowed to react at 55.degree. C. for 1 hour. Aqueous
NaHCO.sub.3 was then added to the mixture, and the product was
extracted with ether. The organic layer was washed with water,
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated via rotary evaporator to provide the crude material.
Column chromatography (with a 90:10/Hexane:EtOAc solvent) provided
Compound 7 in purified form (0.16 g, 73%). .sup.1H NMR: (250 MHz,
CDCl.sub.3), .delta. 0.85-0.82 (d and s overlapping, 6H), 1.17 (s
3H), 1.24 (s 3H), 1.78-1.72 (m 2H), 1.93-1.85 (2 br s, 1H),
2.09-1.96 (m 1H), 2.09 (s 3H), 2.24-2.12 (m 1H), 2.42-2.27 (m 1H),
2.58-2.47 (m 2H), 3.58-3.52 (m 1H); .sup.13C NMR (62.5 MHz,
CDCl.sub.3) .delta. 16.4, 22.6, 24.8, 25.7, 26.3, 30.4, 35.1, 36.9,
41.6, 42.7, 44.6, 47.3, 59.5, 208.2, 219.9.
EXAMPLE 11
[0033]
(4R,4aS,6R)-4,4a,5,6,7,8-hexahydro-4,4a-dimethyl-6-(1-chloro-1-met-
hylethyl)-2(3H)-naphthalenone (Compound 8). A dry 3-neck round
bottom flask was fitted with a porous gas frit and two gas flow
adapters. Under a steady stream of argon, this flask was charged
with a solution of purified Compound 7 in glacial acetic acid
(99.6%, Aldrich). Anhydrous, gaseous HCl (lecture bottle, Aldrich)
was bubbled through the porous frit at room temperature until the
solution was saturated with HCl. After 21 hours stirring at room
temperature, the mixture was poured into ice, and was then
extracted with dichloromethane. The organic layer was washed with
water, washed with brine, dried over MgSO.sub.4, filtered, and
concentrated via the rotary evaporator to provide the crude
material in oil form. Recrystallization from hexane provided
nootkatone hydrochloride, Compound 8 as colorless needles. Yield,
74%. .sup.1H NMR: (250 MHz, CDCl.sub.3), .delta. 5.75 (s, 1H),
2.53-2.34 (m, 2H), 2.31-2.22 (m, 2H), 2.20-1.91 (m, 4H), 1.59 (d,
6H, CH.sub.3, J =4.3Hz), 1.39-1.25 (m, 2H), 1.10 (s, 3H, CH.sub.3),
1.00-0.97 (d, 3H, CH.sub.3, J=6.76Hz); .sup.13C NMR (62.5 MHz,
CDCl.sub.3) .delta. 199.7, 170.1, 124.9, 74.1, 45.8, 42.4, 40.8,
40.5, 39.5, 32.3, 30.9, 30.5, 28.5, 17.3, 15.3.
EXAMPLE 12
[0034] Nootkatone (Compound 9). Sodium acetate trihydrate (0.22 g,
1.6 mmol) was added to a single-neck round bottom flask that had
been fitted with a reflux condenser. A solution of the chloroenone
Compound 8 (0.14 g, 0.54 mmol) in glacial acetic acid (4 mL) was
injected into the flask, and the mixture was heated to 100.degree.
C. and held at that temperature for 2 hours. The reaction mixture
was then cooled to room temperature, poured into cold water, and
extracted with chloroform. The organic layer was then washed with
successive portions of 2% aqueous KOH, 2 N HCl, NaHCO.sub.3, and
brine, and then dried over MgSO.sub.4. The excess solvent was
removed via rotary evaporator to provide nootkatone as a yellow oil
(93%). The overall yield from .beta.-pinene to nootkatone was 23%
using path b, and 25% using path a, both of which are relatively
high overall yields. Because the Oxy-Cope reaction and the
methylation both provided the desired enantiomeric product, the
enantiomeric purity of the final nootkatone product was little
changed from that of the .beta.-pinene starting product.
Qualitatively, the fragrance of the synthesized nootkatone was
identical to the fragrance of nootkatone derived from other
sources. NMR data matched that previously reported for nootkatone:
.sup.1H NMR: (250 MHz, CDCl.sub.3), .delta. 5.77 (s, 1H), 4.75-4.72
(m, 2H), 2.62-2.43 (m, 1H), 2.41-2.22 (m, 4H), 2.09-1.87 (M, 3H),
1.46-1.38 (m, 1H), 1.12-1.10 (m, 4H), 0.98 (d, 3H).
[0035] Additionally, alternative phase transfer agents or
metal-chelating agents might be used in lieu of 18-crown-6 in the
Oxy-Cope reaction to reduce costs, for example quaternary ammonium
compounds (quats), PEG [poly(ethyleneglycol)], or
tris[2-(2-methoxyethoxy)ethyl]amine.
EXAMPLE 13
[0036] In an alternative embodiment, the Oxy-Cope rearrangement and
the methylation are carried out in one step, further improving
efficiency. An example follows:
[0037]
3,6,6-trimethyl-3-(1-methyl-but-3-enyl)-bicyclo[3.3.1]heptan-2-one
(Compound 6b): A 50-mL round bottom flask, a reflux condenser, a
septum, and a magnetic stir bar are placed in a dry box. Under an
Ar atmosphere, oil-free KH (0.058 g, 1.44 mmol) is added to the
flask. The apparatus is assembled and then removed from the dry
box. Freshly distilled THF (14 mL) is injected, and the apparatus
is submerged in a jacketed beaker, surrounded by ice, and placed
under a positive pressure of Ar. The homoallylic alcohol Compound
4b (0.25 g, 1.2 mmol) is then injected via the reflux condenser.
Then 18-crown-6 (0.32 g, 1.2 mmol) in THF (7 mL) is immediately
added via cannulation. The mixture is allowed to react at 0.degree.
C. for approximately 5 hours. After the Oxy-Cope rearrangement is
essentially complete, flame-dried LiBr (0.172 g, 1.98 mmol) in THF
(5 mL) is cannulated into the reaction mixture. After 10 minutes,
the reaction mixture is warmed to 40.degree. C. with a water bath,
and freshly distilled, dry MeI (0.374 mL, 0.85 g, 6 mmol) is
injected via syringe. The reaction mixture is warmed to 45.degree.
C., and is maintained at that temperature for 17 hours. Additional
portions of MeI (0.18 mL, 3 mmol) are added to the reaction mixture
every 2 hours during this period. After 17 hours the resulting
solution is quickly partitioned between a saturated aqueous
NH.sub.4Cl solution and ethyl ether. The combined organic layers
are washed with water, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product is
purified via column chromatography (with a 9:1/Hexane:EtOAc
solvent) to give pure compound 6b.
EXAMPLE 14
[0038] Nootkatone made through this synthesis may also be used as
an intermediate in preparing nootkatone derivatives, some of which
also have activity in repelling termites and other invertebrate
pests. For example, following the methods of K. Stevens et al.,
"Odour character and threshold values of nootkatone and related
compounds," J. Sci. Fd. Agric., vol. 21, pp. 590-593 (1970),
nootkatone may be converted into isonootkatone,
tetrahydronootkatone, 11,12-dihyydronootkatone, or
1,10-dihydronootkatone. Following the methods of B. Zhu et al.,
"Structure-activity of valencoid derivatives and their repellence
to the Formosan subterranean termite," J. Chem. Ecol., vol. 29, pp.
2695-2701 (2003), nootkatone may be converted into nootkatol.
EXAMPLE 15
[0039] An alternative synthetic route to substituted nootkatones is
depicted in FIG. 2. Except as otherwise stated, the reactions are
carried out in the same general manner as previously described for
the reaction scheme of FIG. 1. The groups R.sub.1 to R.sub.4 may be
the same or different, e.g., --H or substituted or unsubstituted
alkyl groups, for example Et, Pr, i-Pr, Bu, s-Bu, i-Bu, t-Bu,
##STR1## where R.sub.5 to R.sub.8 may be the same or different,
e.g., --H or C.sub.1 to C.sub.4 substituted or unsubstituted alkyl
groups.
[0040] The reagents and solvents for the various reaction steps in
FIG. 2 are as follows: (a) KMnO.sub.4, Al.sub.2O.sub.3 (b)
R.sub.1--CHO (c) CH.sub.2.dbd.C(CH.sub.2Cl)(CH.sub.2R.sub.2), Mg,
THF (d) KH, 18-crown-6, THF (e) NaNH.sub.2, R.sub.3--I, solvent (f)
KMnO.sub.4, Al.sub.2O.sub.3 (g) HCl (h) AcOH, NaOAc (i) H.sub.2,
Pd/C (j) Li (or Na), NH.sub.3 (l), EtOH (as in FIG. 3).
EXAMPLE 16
[0041] An alternative synthetic route to tetrahydronootkatone from
Compound 8 is depicted in FIG. 3. The conversion of an enone to the
corresponding saturated ketone, as shown in the figure, may be
carried out with an alkali metal (e.g., Na or Li) in the presence
of a proton source (such as liquid ammonia, ethanol, or both). See
generally D. Caine, Organic Reactions (New York), vol. 23, pp. 1 ff
(1976); and W. Adcock et al., J. Org. Chem., vol. 47, pp. 2951 ff
(1982).
[0042] The complete disclosures of all references cited in this
specification are hereby incorporated by reference. In the event of
an otherwise irreconcilable conflict, however, the present
specification shall control.
* * * * *