Rose oxides: A facile chemo and chemo-enzymatic approach

Article abstract of DOI:10.1080/00397910500186425

Nonracemic rose oxides were synthesized from racemic or nonracemic monoterpene alcohol citronellol by a novel chemo and chemo-enzymatic route. After the key step of bromomethoxylation of citronellol, the intermediate was dehydrobrominated by a base, followed by an acid catalyzed demethoxylation along with cyclization to furnish rose oxides in high yield. The racemic dehydrobrominated precursor was also kinetically resolved using various lipases to produce nonracemic rose oxides. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500186425

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Rose Oxides: A Facile Chemo
and Chemo‐Enzymatic
Approach
Subhash C. Taneja a , Vijay K. Sethi a , Samar S.
Andotra a , Surrinder Koul a & Ghulam N. Qazi a
a Bio‐Organic Chemistry Unit , Regional Research
Laboratory (CSIR) , Jammu Tawi, India
Published online: 18 Aug 2006.
To cite this article: Subhash C. Taneja , Vijay K. Sethi , Samar S. Andotra , Surrinder
Koul & Ghulam N. Qazi (2005) Rose Oxides: A Facile Chemo and Chemo‐Enzymatic
Approach, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:17, 2297-2303
To link to this article: http://dx.doi.org/10.1080/00397910500186425
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Synthetic Communicationsw, 35: 2297–2303, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500186425
Rose Oxides: A Facile Chemo and
Chemo-Enzymatic Approach
Subhash C. Taneja, Vijay K. Sethi, Samar S. Andotra,
Surrinder Koul, and Ghulam N. Qazi
Bio-Organic Chemistry Unit, Regional Research Laboratory (CSIR),
Jammu Tawi, India
Abstract: Nonracemic rose oxides were synthesized from racemic or nonracemic
monoterpene alcohol citronellol by a novel chemo and chemo-enzymatic route.
After the key step of bromomethoxylation of citronellol, the intermediate was dehydro-
brominated by a base, followed by an acid catalyzed demethoxylation along with cycli-
zation to furnish rose oxides in high yield. The racemic dehydrobrominated precursor
was also kinetically resolved using various lipases to produce nonracemic rose oxides.
Keywords: Bromomethoxylation, cis- and trans-rose oxides, citronellol, cyclization,
dehydrobromination, lipases
Rose oxides, the monoterpenic cyclic ethers, are the minor but essential
olfactory constituents of Bulgarian rose, Geranium bourbon, as well as
other natural oils. These oils consist of cis-(2)-(2S,4R)-2-(2-methyl-1-
propenyl)-4-methyltetrahydropyran as the main constituent, whereas the
other three isomers are also known. Rose oxides were first isolated from
rose oil[1] and later on they were also found in the essential oils of
Geranium bourbon and Eucalyptus citriodora.[2]
Rose oxides are well known for their refreshing floral green note;
however, the odor as well as the threshold may vary from one diastereoisomer
to another. For example l-cis-rose oxide, which is a major constituent of
Received in India April 22, 2005
Address correspondence to Subhash C. Taneja, Bio-Organic Chemistry Unit,
Regional Research Laboratory (CSIR), Canal Road, Jammu Tawi 180001, India.
E-mail: sc_taneja@yahoo.co.in
2297

2298
S. C. Taneja et al.
Bulgarian rose oil, has the lowest threshold index compared with three other
isomers. Odor threshold of cis-(2)-(2S,4R)-rose oxide is reported to be of
the order of 0.5 ppb, whereas it is 50 ppb for its (þ)-(2R,4S)-enantiomer.
Trans-(þ)-(2S,4S)-rose oxide, conversely, is reported to have a much
higher threshold index (i.e., 80 ppb) and in its corresponding (2)-(2R,4R)-
enantiomer it is 160 ppb.[4]
Racemic rose oxides have been partially synthesized from citronellol,
which occurs in Java citronella oil. It is an abundantly available raw
material with largest industrial applications in perfumery. Synthetically
racemic citronellol is prepared from nerol/geraniol or citral by hydrogenation
method.
There are a few of reported synthesis of optically active rose oxides.
Generally the known synthetic routes involve acid-catalyzed cyclization of
3,7-dimethyl-5,7-octadien-1-ol or 3,7-dimethyl-1,7-dihydroxyoct-5-ene pro-
duced in various ways from citronellol.[3,4] Ohloff prepared trans-3,7-
dimethyl-1,7-dihydroxyoct-5-ene by photosensitized air oxidation of citronellol
to give alkyl hydroperoxide, which upon reduction and subsequent cyclization
with an acid furnished a mixture of cis and trans-rose oxides.[3] Eschinasi
prepared the rose-oxide mixture by acid-catalyzed cyclization of trans-8-
acetoxy-2,6-dimethyl-1,3-octadiene obtained from pyrolysis of 2,6-dimethyl-
2,3,8-triacetoxyoctane.[5]
In 1984, total synthesis of cis-(2S,4R)-rose oxide was carried out by P.
Audin et al. using chiral catalysts, which is more of an academic interest.[6]
Recently a stereoselective synthesis of optically active rose oxide has been
reported by Yamamoto et al.[4] using Pd-BINAP–catalyzed cyclization of
an optically active intermediate 3,7-dimethyl-5,7-octadien-1-ol.
RESULTS AND DISCUSSION
In the present communication, we disclose a novel and practical synthetic
methodology for the preparation of cis-(þ)-(2R,4S) and trans-(þ)-(2S,4S)-
rose oxides 4 and cis-(2)-(2S,4R) and trans-(2)-(2R,4R)-rose oxides 8
starting from racemic as well as nonracemic citronellol using a facile chemo
as well as chemo-enzymatic approach.
The proposed synthetic routes to rose oxides essentially consist of a coha-
logenation reaction[7] of nonracemic citronellol [e.g., natural (þ)-citronellol 1
(Scheme 1)] or racemic citronellol with a brominating agent such as 1,3-
dibromo-5,5-dimethylhydantoin (DDH) or N-bromosuccinimide (NBS) in
dry methanol to furnish corresponding 3-bromo-2,6-dimethyl-2-methoxy-8-
octanol 2 in .92% yield. Dehydrobromination of bromomethoxy intermedi-
ate is effected with an alkali in an organic solvent. In our hands potassium
hydroxide in dioxane at reflux temperature gave the best results with least
side products, furnishing trans-2,6-dimethyl-2-methoxy-3-octen-8-ol 3 in
ꢀ90% yield. In the final step methoxy octenol 3 was directly converted to

Rose Oxides
2299
Scheme 1.
optically enriched (þ)-rose oxides (cis : trans, 73 : 27) in overall yield of
77–80% via an acid-catalyzed demethoxylation and concomitant cyclization.
For the preparation of nonracemic rose oxides from racemic citronellol,
an additional step of kinetic resolution of the racemic intermediate 3 was
envisaged (Scheme 2). In the proposed scheme, the intermediate (+)-(E)-2-
methoxy-2,6-dimethyl-3-octen-8-ol 3 was first converted to (+)-acyloxy
derivative 5. Using a panel of commercial hydrolases, the intermediate
(+)-(E)-8-acyloxy-2,6-dimethyl-2-methoxy-3-octene
5 could easily be
Scheme 2.

2300
S. C. Taneja et al.
resolved through preferential hydrolysis of one of the enantiomers. Notice-
ably, out of six commercial lipases used, only Pseudomonas cepecia
(Amano) lipase (PSL) was found to be the most suitable from selectivity
point of view. PSL exhibited highest preference for R-enantiomer in hydro-
lyzing the acetyl derivative that is followed by Candida cylindraceae lipase
(CCL). In the present studies, besides PSL, only CCL displayed moderate
selectivity during hydrolysis whereas the rest of the lipases displayed low
selectivity. In general most of the kinetic resolution reactions were terminated
after 22–26 h of reaction time except pig liver acetone powder (PLAP) and
Candida antarctica lipase (CAL), where the rate of hydrolysis was compara-
tively slow and both enzymes displayed preference for (S)-enantiomer. No
attempts were made to optimize the enantiopurity of the hydrolyzed
products through medium or substrate engineering. As a result of stereo-
selective hydrolysis in the phosphate buffer medium, a mixture of optically
enriched hydrolyzed alcohol 6 and unhydrolysed ester 7 were obtained,
which could easily be separated by column chromatography to provide an
optically enriched 2,6-dimethyl-2-methoxy-3-octen-8-ol 6 and its acyloxy
ester (i.e., 8-acetyloxy-2,6-dimethyl-2-methoxy-3-octene 7). The optically
enriched ester 7 on alkaline hydrolysis furnished a primary alcohol. In the
final step, optically enriched primary alcohols 6 and 7 were separately
cyclized in presence of an acid catalyst as shown in Scheme 2 to produce
enriched d- and l-rose oxides respectively.[8]
The ratios of the cis and trans-rose oxides in 4 and 8 calculated on the
basis of their GC analysis varied in the range of 70 : 30 to 94 : 06. Higher
homologues of the ester 5 (i.e., propyl and butyl esters) displayed low enantio-
selectivity but high diastereoselectivity in the presence of PPL and PLAP
(cis : trans, 95 : 05). PSL, conversely, displayed higher enantioselectivity but
comparatively low diastereoselectivity. The unoptimized data of lipase-
catalyzed hydrolysis reactions are presented in Table 1.
In conclusion the present strategy of synthesis of rose oxides is applicable
to both racemic as well as nonracemic rose oxides.
EXPERIMENTAL
Racemic citronellol (95%) was purchased from M/s Aldrich Chemicals. (þ)-
Citronellol (ꢀ97%) was prepared by steam distillation of citronella oil
1
followed by its fractionation. H NMR spectra in CDCl3 were recorded on a
Bruker 200-MHz spectrometer with TMS as the internal standard. Chemical
shifts were expressed in parts per million (d ppm). Reagents and solvents
used were of analytical/HPLC grade. Silica-gel-coated aluminum plates
from M/s Merck were used for TLC. Specific rotations were determined on
Perkin-Elmer 241 polarimeter in indicated solvents. GC analysis was
carried out on Shimadzu GC 17A analytical GC using BP-10 (cyanopropyl-
phenyl polysiloxane) column and helium gas as carrier.

Table 1. Lipase-catalysed hydrolysis of (+) 5
Entry 5
Rose oxide (from alcohol 6)
Rose oxide (from acyloxy deriv. 7)
R ¼
Lipasea
Time (h)
Conv. (%)
Yield % (z : e)b
[a]D
Yield % (z : e)b
[a]D
c
CH3
PSL
PSL
22
24
30.5
36.8
38.9
37.0
56.0
55.0
51.0
51.0
50.0
46.0
51.0
62.7
37.3
50.0
53.0
61.4
56.3
48.0
23.0 (68 : 32)
35.0 (83 : 17)
25.0 (72 : 28)
31.6 (73 : 27)
35.0 (74 : 26)
32.7 (74 : 26)
29.0 (73 : 27)
27.0 (73 : 27)
25.4 (71 : 29)
28.3 (74 : 26)
33.9 (73 : 27)
35.0 (74 : 26)
22.3 (73 : 27)
27.0 (74 : 26)
31.0 (70 : 30)
31.5 (73 : 27)
30.0 (72 : 28)
29.0 (74 : 26)
þ36.0
þ21.6
þ7.0
25.1
23.0
23.5
27.4
26.1
25.6
þ 14.6
þ7.3
þ5.0
þ6.5
þ5.0
þ4.2
27.2
28.8
210.0
38.0 (74 : 26)
38.1 (71 : 29)
33.2 (74 : 26)
32.3 (74 : 26)
30.0 (89 : 11)
25.2 (95 : 05)
31.5 (74 : 26)
30.0 (94 : 06)
35.3 (96 : 04)
33.1 (70 : 30)
25.0 (72 : 28)
20.0 (73 : 27)
34.0 (78 : 22)
28.0 (91 : 09)
25.3 (72 : 28)
28.0 (84 : 16)
25.8 (73 : 27)
30.0 (73 : 27)
213.2
26.8
26.1
þ2.2
þ6.2
þ5.8
þ10.0
þ8.7
þ7.0
210.3
24.2
23.2
29.2
26.5
22.3
þ9.6
þ7.5
þ8.2
C2H5
C3H7
CH3
PSL
PPL
24
24
C2H5
C3H7
CH3
PPL
PPL
26
26
PLAP
PLAP
PLAP
CCL
CCL
CCL
CRL
CRL
CRL
CAL
CAL
CAL
26
96
C2H5
C3H7
CH3
96
24
C2H5
C3H7
CH3
24
24
24
24
C2H5
C3H7
CH3
24
250
250
250
C2H5
C3H7
aPSL ¼ Pseudomanas cepecia lipase (Amano), PPL ¼ Porcine pancreatic lipase (Sigma), PLAP ¼ pig liver acetone powder, CCL ¼ Candida
cylindraceae lipase (Sigma), CRL ¼ Candida rugosa lipase (Sigma), and CAL ¼ Candida antarctica lipase (A þ B) (Sigma).
bz : e ratios estimated by GC on BP-10 column.
cSpecific rotation measured in chloroform at 258C (c ¼ 1).

2302
S. C. Taneja et al.
General Synthesis of Racemic and Nonracemic Rose Oxides
1,3-Dibromo-5,5-dimethyl hydantoin (DDH) (10 g, 35 mmol) was slowly
added to a stirring solution of (þ)-citronellol 1 (10.0 g, 64 mmol), [a]D27
þ3.48 (CHCl3, c, 1) in dry methanol (50 mL) at 08C under nitrogen. The
reaction mixture stirred for 2 h, keeping the temperature below 58C. The
reaction was terminated by pouring the contents in ice-cold water (100 mL)
and extraction with dichloromethane. Removal of the solvent gave crude
oil, purified on silica-gel column by eluting with n-hexane–ethyl acetate
(19 : 1) to furnish 2 (16.0 g, 94%) as a colorless liquid, [a]2D7 þ 9.38 (neat).
1H NMR (200 MHz, CDCl3) d: 0.93 (3H, d, J ¼ 5.6 Hz, CH3), 1.30 & 1.33
(6H, s, 2x CH3), 1.45–2.20 (7H, m, 3x CH2 and CH), 3.23 (3H, s, OCH3),
3.43–4.13 (3H, m, CH2OH and CHBr).
Potassium hydroxide (5.0 g, 89.0 mmol) was added to a solution of 2
(15.0 g, 56 mmol) in dioxane (75 mL) and the mixture refluxed for 5 h. After
the completion of the reaction, the contents were cooled and poured in
water, extracted with dichloromethane, and concentrated to give 3 (9.51 g,
90.7%) as a pale-yellow liquid [a]2D7 þ 18 (neat). 1H NMR (200 MHz,
CDCl3) d: 0.91 (3 H, d, J ¼ 6.3 Hz, CH3), 1.25 (6H, s, 2x CH3), 1.33–1.43,
1.50–1.73, and 1.86–2.13 (5 H, m, CH & 2x CH2), 3.10 (3H, s, OCH3),
3.69 (2H, t, J ¼ 6.3 Hz, OCH2), 5.41 (1H, d, J ¼ 15.9 Hz, ¼CH), 5.50 (1H,
ddd, J ¼ 6.5, 15.7, 15.9 Hz, ¼CH). The crude intermediate 3 (9.0 g,
48 mmol) and 4% HCl (2.5 mL) in n-hexane (50 mL) were stirred at 108C
for 3 h. Water (60 mL) was added, and the organic layer was separated,
washed with water, and concentrated. Steam distillation of crude product
furnished pure rose oxide 4 (7.0 g, 94%) as a colorless oil (overall yield
79.8%, cis : trans, 68 : 32 by GC), [a]2D5 þ38.48 (CHCl3, c, 1.0).
Lipase-Catalyzed Method of Kinetic Resolution of (+)-8-Acyloxy-
2-methoxy-2,6-dimethyl-3-octene 5
Compound (+)-3 (5 g, 265 mmol), acetic anhydride (2.9 mL, 280 mmol), and
DMAP (30 mg) were stirred at room temperature for 12 h and worked up in the
usual fashion, followed by column chromatography on silica gel to furnish
(+)-5 (5 g, 90%).
Pseudomonas cepecia lipase (PSL) (M/s Amano Japan, 100 mg dry
powder) was added to (+) 5 (0.93 g, 40 mmol) in 0.1 M of sodium
phosphate buffer (9 mL, pH 7.0) at 258C. The contents were stirred at
200 rpm; pH 7 was maintained by adding 0.5 N of NaOH solution. The
progress of the reaction was monitored by GLC (column BP-10 cyanopropyl-
phenyl polysiloxane). After 24 h, the reaction mixture was extracted with
dichloromethane and concentrated to produce an oily material that, on silica
gel chromatography and gradient elution with n-hexane–ethyl acetate
(95 : 5 to 80 : 20), furnished (2)-7 (0.59 g, 63%), [a]2D5 21.58 (CHCl3, c,

Rose Oxides
2303
2.0); 1H NMR (200 MHz, CDCl3): d 0.91 (3H, d, J ¼ 6.3 Hz, CH3), 1.25 (6H,
s, CH3), 1.39–1.48, 1.55–1.71, and 1.86–2.15 (5H, m, 2 x CH2 and CH), 2.04
(3H, s, OCOCH3), 3.14 (3H, s, OCH3), 4.15 (2H, t, J ¼ 6.2 Hz, CH2O), 5.41
(1H, d, J ¼ 15.9 Hz, ¼CH), 5.52 (1H, ddd, J ¼ 6.3, 15.9, 15.7 Hz, ¼CH), and
(þ)-6 (0.174 g, 34%), [a]2D5 þ 4.28 (CHCl3, c, 3.8). The alcohol (þ)-6 was
converted directly to (þ)-rose oxide 4 (0.145 g) [a]2D5 þ368 (CHCl3, c, 1.8)
by the method as described previously in general synthesis.
The acetate (2)-7 obtained previously and methanolic KOH (4%, 5 mL)
were warmed at 45–508C for 10 min. After 2 h, the reaction mixture was
diluted with water and extracted with n-hexane, concentrated, and converted
to (2)-rose oxide 8 (0.36 g) [a]2D5–13.28 (CHCl3, c, 0.89).
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