Synthesis and olfactory evaluation of all stereoisomers of the fragrance Nectaryl

Article abstract of DOI:10.1016/j.tetasy.2008.03.011

The fragrance Nectaryl 1 was prepared by the radical addition of cyclopentanone to (+)-limonene. All the four stereoisomers of this fragrance were prepared by the enzymatic acetylation of the corresponding alcohols in good de. The absolute configurations have been unambiguously assigned by the chemical correlation and X-ray crystal structure of a dinitrobenzoate derivate. The olfactory evaluation is also reported. The odour perception is mainly related to the configuration at the stereocentre α to the carbonyl group. Chiral protonations of the lithium enolate or the enolester of 1 to give a diastereomeric enriched mixture of 1 are reported.

Full text of DOI:10.1016/j.tetasy.2008.03.011

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 800–807
Synthesis and olfactory evaluation of all stereoisomers
of the fragrance NectarylÒ
Elisabetta Brenna, Claudio Fuganti, Francesco G. Gatti,* Luciana Malpezzi and Stefano Serra
Dipartimento di Chimica dei Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico,
CNR-Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy
Received 21 December 2007; revised 3 March 2008; accepted 13 March 2008
Available online 15 April 2008
Abstract—The fragrance NectarylÒ 1 was prepared by the radical addition of cyclopentanone to (+)-limonene. All the four stereoisomers
of this fragrance were prepared by the enzymatic acetylation of the corresponding alcohols in good de. The absolute configurations have
been unambiguously assigned by the chemical correlation and X-ray crystal structure of a dinitrobenzoate derivate. The olfactory
evaluation is also reported. The odour perception is mainly related to the configuration at the stereocentre a to the carbonyl group.
Chiral protonations of the lithium enolate or the enolester of 1 to give a diastereomeric enriched mixture of 1 are reported.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
pene unit attached a to the carbonyl group of cyclopenta-
none. This fragrance has found several applications as an
ingredient of cosmetic formulations and of laundry pow-
ders. Hence, we prepared 1 by the radical addition of cyclo-
pentanone to (+)-limonene, catalyzed by Mn(OAc)2
combined with Co(OAc)2 under O2 atmosphere, in 72%
yield (Scheme 1).4 The cyclopentanone radical adds regio-
selectively to the exocyclic double bond of the limonene.
The preparation of fragrances in their enantiomerically
pure forms is an emerging area of synthetic chemistry.1 In-
deed, the relationship between the stereochemistry of chiral
odorant molecules and their human perception is still not
well understood.2 Thus, over the last decade we were inter-
ested in the synthesis and olfactory evaluation of the enan-
tiomers of many commercial fragrances3 (see Fig. 1).
Nectaryl®
4''
3''
O
2''
O
O
H1''
2'
H
H
H
1
1
2
O
1'
Figure 1. Chemical structure of commercial NectarylÒ.
(2S,2'R,1''R)-1a
(2R,2'S,1''R)-1b
+
H
Herein, we report the preparation and the olfactory evalu-
ation of the stereoisomers of the commercial fragrance
NectarylÒ 1.
(+)-limonene
O
H
O
H
H
H
2. Results and discussion
(2S,2'S,1''R)-1c
(2R,2'R,1''R)-1d
The fragrance NectarylÒ produces a pleasant scent of
peach and apricot. Its structure is composed of a monoter-
Scheme 1. Reagents and conditions: O2, cat. Mn(OAc)2 and cat.
Co(OAc)2, refluxing AcOH.
*
A comparison of the specific rotation value of 1 prepared
by our method {½aꢀD ¼ þ228 (c 1, CHCl3)} with that of
Corresponding author. Tel.: +39 02 23993072; fax: +39 02 23993080;
e-mail: Francesco.Gatti@polimi.it
20
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.011

E. Brenna et al. / Tetrahedron: Asymmetry 19 (2008) 800–807
801
20
the commercial NectarylÒ {½aꢀD ¼ þ235 (c 1, CHCl3)}
using the same procedure as described above, furnished,
respectively, alcohol (1S,2S,20S,100R)-2c (36% yield, de
82%) and (1R,2R,20R,100R)-2 (28% yield, 88% de). Finally,
the Dess–Martin oxidation of alcohol (1S,2S,20R,100R)-2a
in CH2Cl2 at 0 °C gave ketone (2S,20R,100R)-1a (92% yield,
de 81% by GC).7 The other alcohols were oxidized in the
same manner giving (2R,20S,100R)-1b (92% yield, de 89%),
(2S,20S,100R)-1c (92% yield, de 80%) and (2R,20R,100R)-1d
(92% yield, de 86%), respectively.
indicates that the latter is prepared starting from (+)-
limonene.
Moreover, the 13C NMR spectra of 1 shows the presence of
an equimolar mixture of all four possible stereoisomers of
1, respectively, (2S,20R,100R)-1a, (2R,20S,100R)-1b, (2S,20S,
100R)-1c and (2R,20R,100R)-1d (Fig. 3).
The synthesis of all the single stereoisomers of NectarylÒ is
summarized in Scheme 2. First, the carbonyl group of 1
was reduced with L-Selectride in THF at ꢁ78 °C to give
an equimolar mixture of cis-cyclopentanol alcohols 2a–d
2.1. Absolute stereochemistry assignment
The absolute stereochemical configuration at C(100) was (R)
for all the stereoisomers of 1 because, we used the (+)-
limonene as the starting material. Regarding the stereo-
chemistry at the C(20), we prepared a mixture of two
diastereoisomers with the (R)-configuration at C(100) and
(S)-configuration at C(20), that is, (2R,20S,100R)-1b and
(2S,20S,100R)-1c. The synthesis of these two diastereoiso-
mers is shown in Scheme 3. The tosyl derivate of alcohol
(2R,10R)-68 reacted with NaI in refluxing acetone to give
the iodo derivate (2R,40R)-7 in 90% yield. Next, the cyclo-
pentanone enolate, generated with LDA in THF and
DMPU at ꢁ78 °C, was alkylated at ꢁ30 °C with 6 to give
1b and 1c in 26% yield (Scheme 3).
13
[by integration of the C NMR signals of C(30)] in 80%
yield.5 Purification by chromatography allowed the separa-
tion of the less polar alcohols (1S,2S,20R,100R)-2a and
(1R,2R,20S,100R)-2b (ratio 1:1 by GC) from the more polar
(1S,2S,20S,100R)-2c and (1R,2R,20R,100R)-2d (ratio 1:1 by
13C NMR). The enzymatic (lipase PS) acetylation of
(1S,2S,20R,100R)-2a and (1R,2R,20S,100R)-2b in t-butylmeth-
ylether (t-BuOMe), using vinyl acetate as an acetylating
agent, afforded, after 1 day, the acetate (1R,2R,20S,100R)-
3b (37% yield, 92% de by 13C NMR) and the non-converted
alcohol (1S,2S,20R,100R)-2a (56% yield, 70% de).6 The latter
was separated by column chromatography. Next, the ace-
tate (1R,2R,20S,100R)-3b was hydrolyzed with NaOH in
EtOH to give the alcohol (1R,2R,20S,100R)-2b in 94% yield.
Since, the de of the recovered alcohol was not sufficiently
high, the latter was submitted to the same enzymatic reso-
lution affording (1S,2S,20R,100R)-2 with 84% de in 28%
yield. The enzymatic acetylation of the other two alcohols,
The absolute configuration at C(2) was initially assigned by
the 19F NMR analysis of the (S)-MTPA ester 4a–d
prepared from alcohols 2 (Scheme 2).9 Since, the relative
stereochemistry between C(2) and C(1) is cis, the deter-
mination of the absolute configuration at C(1) leads
OH
OH
OR
OR
ii
+
H
H
H
+
H
H
H
H
H
(1S,2S,2'R,1''R)-2a
(1R,2R,2'S,1''R)-2b
R=H, (1S,2S,2'R,1''R)-2a
R=OAc, (1R,2R,2'S,1''R)-3b
v
O
iii
i
R=H, (1R,2R,2'S,1''R)-2b
R=(S)-MTBE, 4a
H
v
R=(S)-MTBE, 4b
(+)-1
OH
H
OH
OH
OR
ii
+
H
H
H
H
H
H
H
+
R=Ac, (1R,2R,2'R,1''R)-3d
R=H,(1S,2S,2'S,1''R)-2c
(1S,2S,2'S,1''R)-2c
(1R,2R,2'R,1''R)-2d
v
iii
R=(S)-MTBE, 4c
R=H, (1R,2R,2'R,1''R)-2d
v
R=(S)-MTBE, 4d
OR
O
iv
H
H
H
H
R=H, (1S,2S,2'R,1''R)-2a
(2S,2'R,1''R)-1a
NO2
vi
R=
O
NO2
(1S,2S,2'R,1''R)-5a
Scheme 2. Reagents and conditions: (i) L-Selectride, ꢁ78 °C, THF; (ii) PS Lipase, vinyl acetate, t-BuOMe; (iii) NaOH, EtOH; (iv) DMP, CH2Cl2, 0 °C;
(v) (S)-MTPCl, CH2Cl2, 0 °C DMAP; (vi) pyridine, 3,5-dinitrobenzoyl chloride.

802
E. Brenna et al. / Tetrahedron: Asymmetry 19 (2008) 800–807
Finally, we report a selected region of 13C NMR spectra of
O
the C(30) signals, elucidating the correct absolute configura-
tion assignment of all stereoisomers of NectarylÒ (Fig. 3
and Table 1).
4'
1'
3'
2'
2'
3'
ii)
O
O
i)
H
H
H
H
2.2. Olfactory evaluation and structure–odour relationships
4'
1'
+
H
H
H
H
1
OH
I
2
All the samples of NectarylÒ were submitted to profes-
(2R,2'S,1''R)-1b
(2S,2'S,1''R)-1c
(2R,1'R)-6
(2R,4'R)-7
sional olfactory evaluation with the following results.
Scheme 3. Reagents and conditions: (i) (a) TsCl, pyridine; (b) NaI,
refluxing acetone; (ii) LDA, DMPU, THF, ꢁ30 °C to rt.
ꢂ (+)-NectarylÒ: Power in the direction of peach and apri-
cot. Odour threshold: 0.354 ng/L air.
ꢂ (2S,20R,100R)-1a: Rather weak and uncharacteristic fru-
ity-lactonic odour with some additional resemblance of
green apple, it does not contribute much to the commer-
cial NectarylÒ. Odour threshold: 11.2 ng/L air.
ꢂ (2R,20S,100R)-1b: Powerful, very intense, sweet and dry
fruity-lactonic odour in the direction of peach and apri-
cots, with some floral undertone, does contribute much
to the overall odour of commercial NectarylÒ. Odour
threshold: 0.094 ng/L air.
to the assignment of the stereochemistry at C(2). The trend
observed was similar to the one described for (S)-MTPA
esters of 2-substituted cyclopentanols. The criteria adopted
assigns the (S)-configuration to the Mosher’s ester with the
most shielded CF3 signal.10 The 19F NMR data of (S)-
MTPA esters and the absolute configurations assignments
are reported in Table 1.
ꢂ (2S,20S,100R)-1c: The same as 1a. Odour threshold:
Table 1. 19F NMR (235.3 MHz) data of (S)-MTPA ester derivates 4a–d of
alcohol 2 in CDCl3 and their absolute configuration assignment
14.9 ng/L air.
ꢂ (2R,20R,100R)-1d: The same as 1b. Odour threshold:
0.112 ng/L air.
Ester d (CF3) (ppm)a AC
Correct stereochemistry
4a
4b
4c
4d
ꢁ72.326
ꢁ72.436
ꢁ72.360
ꢁ72.487
(1R,2R,20R,100R)-2 (1S,2S,20R,100R)-2a
(1S,2S,20S,100R)-2 (1R,2R,20S,100R)-2b
(1R,2R,20S,100R)-2 (1S,2S,20S,100R)-2c
(1S,2S,20S,100R)-2 (1R,2R,20R,100R)-2d
2.3. Synthesis of the most odorant diastereoisomers
The olfactory evaluation has shown that the (R) configura-
tion at C(2) seems to be crucial for the odour perception of
NectarylÒ, therefore, it might be interesting to design a
selective synthesis for the preparation of those stereoiso-
mers. Due to the low cost of this fragrance, such a synthesis
should be simple and straightforward. Keeping this in
mind, we envisaged on the enantioselective protonation
of prochiral enolates or enol esters to be the shortest way
to prepare the target compounds (Scheme 4).11
a C6F6 was used as reference d = 0.0 ppm.
The 3,5-dinitrobenzoate ester 5 of alcohol 2a gave crystals
suitable for X-ray structure determination (Fig. 2). How-
ever, the absolute configuration obtained from the crystal
structure of 5, fixing the (R)-configuration at C(100) was
in disagreement with that obtained by Mosher’s ester
analysis.
Concerning the chemo- and enantioselective protonation of
enolates, among the many reagents so far developed, we
have chosen the amino alcohols (+)-8 and (ꢁ)-8.12 Thus,
the treatment of the silyl ether (20RS,10R)-8 with BuLi in
THF at 0 °C generated the lithium enolate of 1. The latter
at ꢁ78 °C was quenched with a stoichiometric amount of
(+)-8 and after 1 h with 0.1 equiv of Me3SiCl, gave a mix-
ture of 1 with a low enrichment of the stereoisomers with a
(2S)-configuration (detot ꢁ21%, Table 2, entry 1), and the
recovered (20RS,10R)-9.13
When using (ꢁ)-8, as a chiral proton donor, it gave a mix-
ture of 1 with the modest enrichment of (R) stereoisomers
(detot = 41%, Table 2, entry 2). Next, we performed the
reaction in Et2O in the presence of 5 equiv of LiBr, since
it is known from the literature that the formation of mixed
aggregates might increase the enantioselectivity.14 How-
ever, we obtained a mixture of 1 with a low enrichment
in the direction of the most odorant stereoisomers. Surpris-
ingly, the chiral protonation of the enolate with a
(20R,100R)-configuration gave a mixture of 1 with a 58%
de, whereas the enolate with a (20R,100R)-configuration gave
a mixture of 1 with ꢁ22% de. The reaction was carried out
at ꢁ50 °C because at the lower temperatures the enolate
Figure 2. ORTEP draw of 5.

E. Brenna et al. / Tetrahedron: Asymmetry 19 (2008) 800–807
803
Figure 3. Selected region of 13C NMR (100 MHz) spectra of 1 in CDCl3: (a) NectarylÒ. (b) Pair of diastereoisomers 1b and 1c. (c) Diastereoisomer 1a
coming from the remaining alcohol 2a of the enzymatic resolution of the less polar alcohols 2a and 2b, stereochemistry (2S0,20R,100R) known from an X-ray
structure. (d) Diastereoisomer 1b coming from the acetate 3b of the enzymatic resolution of the less polar alcohols 2a and 2b. (e) Diastereoisomer 1c
coming from the remaining alcohol 2c of the enzymatic resolution of the most polar alcohols 2c and 2d. (f) Diastereoisomer 1d coming from the acetate 3d
of the enzymatic resolution of the most polar alcohols 2c and 2d.
precipitated. Finally, we repeated the chiral protonation in
THF in the presence of LiBr improving the detot up to 45%.
HO
Ph
N
HO
Ph
N
The enzymatic hydrolysis of the enolacetate (20RS,100R)-9,
using EtOH as the proton source in t-BuOMe at room tem-
perature, furnished 1 with low detot. The results are sum-
marized in Table 2.15 The lipase PS supported on ceramic
gave detot in the direction of the less odorant stereoisomers.
As in the case of entry 3 the selectivity was mismatching.
Indeed, the enolacetate (20R,100R)-10 was hydrolyzed to
give 1 with ꢁ58% de, whereas (20R,100R)-10 was hydrolyzed
to give 1 with 34% de. The similar results were obtained
with the enzyme Novazim.
Me
Me
(-)-8
(+)-8
Si(Me)3
O
O
i)
H
H
(2'RS,1''R)-9
ii)
1
iii)
3. Conclusion
Ac
The enzymatic acetylation proved to be a simple and effi-
cient method of preparing all of the stereoisomers of
NectarylÒ.
O
iv)
H
+
O
O
H
H
H
H
(2'RS,1''R)-10
The olfactory results clearly show that the pleasant apricot
and peach odour of NectarylÒ are strongly related to the
(R) configuration of the stereocentre in a to the carbonyl
group, indeed, the two diastereoisomers having such con-
figuration are the two orders of magnitude more intense
of those having opposite configuration. This difference
(2R,2'R,1''R)-1d
(2R,2'S,1''R)-1b
Scheme 4. Reagents and conditions: (i) Si(Me)3Cl, pyridine, NaI, MeCN;
(ii) (a) BuLi, 0 °C; (b) 1.1 equiv (+)-7 or (ꢁ)-7, see Table 2 for solvent,
temp conditions, 0.1 equiv Si(Me)3Cl; (iii) Ac2O, cat. HClO4, CCl4; (iv)
enzyme, t-butylmethylether, EtOH.

804
E. Brenna et al. / Tetrahedron: Asymmetry 19 (2008) 800–807
Table 2. Asymmetric protonation of lithium enolate with (+)-8 or (ꢁ)-8, and asymmetric hydrolysis of enolacetate with enzymes
Entry
Reagents and conditions
Conv.a (%)
1d versus 1a
1b versus 1c
detc (%)
deb (%)
deb (%)
1
2
3
4
5
6
(+)-7, THF, ꢁ78 °C, 1 h
89
92
74
70
85
50
ꢁ33
31
ꢁ8.0
50
58
46
34
ꢁ21
40
18
(ꢁ)-7, THF, ꢁ78 °C, 1 h
(ꢁ)-7, Et2O, LiBr, ꢁ50 °C, 1 h
(ꢁ)-7, THF, LiBr, ꢁ50 °C, 1 h
Lipase-PS CII, t-BuOMe, EtOH, rt, 1 d
Novazim, t-BuOMe, EtOH, rt, 1 d
ꢁ21
44
45
ꢁ58
ꢁ33
ꢁ12
24
ꢁ10
a The conversions are determined by GC.
b The de has been determined by integration of C NMR signals of C(30) assuming that the relaxation times of diastereoisomers are similar.
13
c The det is the average of the de.
might be even greater, because all the stereoisomers pre-
pared are not completely diastereomerically pure. More-
over, the stereochemistry at the other stereocentres does
not contribute to the final odour perception. Attempts to
prepare the best odorants by means of chiral protonation
of the Li-enolate or the enzyme-mediated hydrolysis of
the enolester gave the modest results. However, the enzy-
matic method seems to be the less promising, because all
in AcOH (60 mL) was refluxed for 8 h and bubbled with
air. The AcOH and cyclopentanone were evaporated under
reduced pressure and the resulting mixture was diluted in
Et2O (200 mL), washed with NaHCO3 (3 ꢃ 100 mL) and
brine (1 ꢃ 100 mL). The organic phase was dried over
Na2SO4 and the solvent was removed under reduced pres-
sure. The resulting liquid was distilled under reduced pres-
sure to give 1 as a colourless liquid (6.3 g, 72%): 97%
20
the enzymes tested have exhibited
selectivity.
a
mismatching
chemical purity by GC; ½aꢀD ¼ þ228 (c 1.1, CHCl3); for
1H and 13C NMR data, see the single stereoisomers; GC/
MS: tr = 22.01, 22.10, 22.30 min (1:1:2); for the m/z, see
the single stereoisomers.
4. Experimental
4.4. Reduction of NectarylÒ
4.1. General methods
To a solution of 1 (6.0 g, 27.0 mmol) in THF at ꢁ78 °C was
added dropwise a solution of L-Selectride (27.0 mL, 1 M).
After 3 h, the reaction mixture was quenched with a solu-
tion of satd NH4Cl (100 mL), and diluted with Et2O
(100 mL). The organic phase was washed with brine
(1 ꢃ 50 mL), and dried over Na2SO4. The solvent was
removed under reduced pressure to give a yellow oil, which
was submitted to column chromatography (hexane/AcOEt,
95:5) separation to give in order of elution: 2a together
with 2b (2.4 g, 40%), and 2c with 2d (2.4 g, 40%).
All the solvents and reagents were purchased by the suppli-
ers and used without further purification. Burkholderia
cepacia lipase (Lipase PS, Amano Pharmaceuticals Co., Ja-
pan) was employed in this work. The THF and the Et2O
were distilled on LiAlH4. GC/MS analyses were performed
on a HP 6890 gas-chromatograph equipped with a 5973
mass-detector, using
a
HP-5MS column (30 m ꢃ
0.25 mm ꢃ 0.25 mm). The following temperature program
was employed: 60 °C (1 min)/6°/min/150° (1 min)/12°/
min/280° (5 min). 1H NMR spectra were recorded in
CDCl3 solutions, on a Bruker spectrometer; DMX (400
1H MHz), the 19F spectra have been recorded on a Bruker
spectrometer Avance 500 (500 1H MHz). The chemical
shift scale was based on internal TMS. J values are in
Hz. The optical rotations were measured on a Dr. Kern-
chen Propol digital automatic polarimeter. TLC analyses
were performed on Merck Kieselgel 60 F254 plates.
Data for 2a and 2b: 97% chemical purity by GC; for 1H and
13C NMR data, see the single stereoisomers; GC/MS:
tr = 21.98, 22.02, 22.18 min, (48:48:4); for the m/z see the
single stereoisomers.
Data for 2c and 2d: 96% chemical purity by GC; for 1H and
13C NMR data see the single stereoisomers; GC/MS:
tr = 21.98, 22.02, 22.18 min, (2:2:96); for the m/z see the
single stereoisomers.
4.2. X-ray crystallographic data for 5a
C22H28N2O6, Mw = 416.5, monoclinic, space group P21,
´
˚
Z = 2, a = 19.104(4), b = 5.914(1), c = 9.834(2) A, b =
4.5. General procedure for the enzymatic resolution of
alcohols 2a–d
´
91.940(5)°, V = 1110.4(2) A , Dx = 1.246 g cmꢁ3. CCDC
3
˚
671244 (for 5) contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.ac.uk/data_request/cif.
To a suspension of the alcohol (1.2 g, 5.4 mmol), lipase PS
(3 g), vinyl acetate (5 mL) and t-BuOMe (30 mL) were stir-
red at r.t. until the conversion reached ca. 40% (Checked by
GC). The residue obtained by evaporation under reduced
pressure of the filtered mixture was submitted to column
chromatography (hexane/AcOEt, 9:1) for the separation
of the acetate from the alcohol. The recovered alcohol
was re-submitted to the same procedure.
4.3. Synthesis of (+)-NectarylÒ
A mixture of cyclopentanone (33.6 g, 0.4 mol), Mn(OAc)2
(0.1 g), Co(Ac)2 (0.1 g) and (+)-limonene (5.4 g, 40 mmol)

E. Brenna et al. / Tetrahedron: Asymmetry 19 (2008) 800–807
805
4.5.1. Resolution of alcohols 2a and 2b. According to the
general procedure, were obtained (1R,2R,20S,100R)-3b
(0.53 g, 37%, de 92%) and (1S,2S,20R,100R)-2a (0.35 g,
25%, de 84).
CH@), 2.19–1.16 (m, 20H), 0.89 (d, J = 6.8, 3H, H–
C(30)); 13C NMR d = 133.8, 121.0, 74.3, 43.5, 38.6, 35.7,
33.8, 32.2, 30.9, 29.4, 27.6; 25.1, 23.3, 21.7, 16.6. GC/MS:
tr = 22.02 min; m/z: 204 (M+ꢁ18, 15), 148 (90), 121
(100). Anal. Calcd for C15H26O: C, 81.02; H, 11.79. Found:
C, 81.04; H, 11.63.
Data for (1R,2R,20S,100R)-3b: 99% chemical purity by GC;
20
1
½aꢀD ¼ þ43:2 (c 1.1, CHCl3); H NMR, d = 5.38 (m, 1H,
CH@), 5.16 (t, J = 5.5, 2.0, 1H, H–C(1)), 2.1–1.2 (m,
19H), 0.84 (d, J = 6.8, 3H, H-(30)); 13C NMR d = 170.8,
134.0, 121.0, 77.3, 42.0, 38.5, 35.6, 33.4, 32.7, 31.0, 30.4,
27.6; 26.9, 23.4, 22.0, 21.2, 16.4. GC/MS: tr = 23.15 min;
m/z: 204 (M+ꢁ60, 10), 148 (60), 121 (100). Anal. Calcd
for C17H28O2: C, 77.22; H, 10.67. Found: C, 77.29; H,
10.59.
4.6.2. (1R,2R,20R,100R)-2d. According to the general pro-
cedure, was obtained (1R,2R,20R,100R)-2d (0.37 g, 94%):
20
99% chemical purity by GC; ½aꢀD ¼ þ69:8 (c 1.1, CHCl3);
1H NMR, d = 5.51 (br t, 1H, H–C(1)), 5.23 (m, 1H,
CH@), 2.19–1.16 (m, 20H), 0.89 (d, J = 6.8, 3H, H–
C(30)); 13C NMR d = 133.8, 121.0, 74.3, 43.5, 38.6, 35.7,
33.8, 32.2, 30.9, 29.4, 27.6; 25.1, 23.3, 21.7, 16.6. GC/MS:
tr = 22.18 min; 204 (M+ꢁ18, 15), 148 (90), 121 (100). Anal.
Calcd for C15H26O: C, 81.02; H, 11.79. Found: C, 81.04; H,
11.63.
Data for (1S,2S,20R,100R)-2a: 99% chemical purity by GC;
20
1
½aꢀD ¼ þ82:8 (c 0.9, CHCl3); H NMR, d = 5.38 (m, 1H,
1H, CH@), 4.12 (br t, 1H, H–C(1)), 2.19–1.16 (m, 19H),
0.89 (d, J = 6.8, 3H, H–(C30)); 13C NMR d = 133.8,
121.0, 74.3, 43.5, 38.6, 35.7, 33.8, 32.2, 30.9, 29.4, 27.6;
25.1, 23.3, 21.7, 16.6. GC/MS: tr = 21.98 min; m/z: 204
(M+ꢁ18, 10), 148 (90), 121 (100). Anal. Calcd for
C15H26O: C, 81.02; H 11.79. Found: C, 81.14; H, 11.69.
4.7. General procedure for the oxidation of alcohols 2a–d
To an ice-cold solution of alcohol (0.3 g, 1.35 mmol) in
CH2Cl2 (10 mL) was added DMP (0.75 g, 1.76 mmol)
and stirred at rt until no alcohol was indicated by TLC
(2 h). The reaction mixture was then poured in a satd solu-
tion of Na2S2O3 (30 mL) and after 15 min was extracted
with Et2O (2 ꢃ 50 mL). The combined organic phase was
4.5.2. Resolution of alcohols 2c and 2d. According to the
general procedure, were obtained (1R,2R,20R,100R)-3d
(0.52 g, 36%, de 88%) and (1S,2S,20S,100R)-2c (0.36 g,
28%, de 82%).
washed with
a
saturated solution of NaHCO3
(1 ꢃ 50 mL) and brine solution (1 ꢃ 50 mL), and dried
over Na2SO4. The solvent was removed under reduced
pressure to give a liquid residue, which was submitted to
the column chromatography purification (hexane/ AcOEt,
95:5) to give the ketone as a liquid. The ketone was
then purified by bulb-to-bulb distillation (140–150 °C,
0.15 mm Hg).
Data for (1R,2R,20R,100R)-3d: 99% chemical purity by GC;
20
1
½aꢀD ¼ þ52:1 (c 1.3, CHCl3); H NMR, d = 5.39 (m, 1H,
CH@), 5.16 (dt, J = 5.5, 2.0, 1H, H–C(1)), 2.1–1.2 (m,
19H), 0.84 (d, J = 6.8, 3H, H–(C30)); 13C NMR d =
171.1, 134.3, 121.4, 79.0 42.4, 39.3, 35.9, 33.5, 32.8, 31.2,
29.7, 29.6; 25.7, 23.7, 22.3, 21.5, 16.5. GC/MS:
tr = 23.15 min; m/z: 204 (M+ꢁ60, 20), 148 (60), 121
(100). Anal. Calcd for C17H28O2: C, 77.22; H, 10.67.
Found: C, 77.23; H, 10.69.
4.7.1. Compound (2S,20R,100R)-1a. According to the gen-
eral procedure, the oxidation of alcohol 2a gave the ketone
1a (0.28 g, 92% after column chromatography, de 81% by
13C NMR) as a white solid: 99% chemical purity by GC;
20
1
Data for (1S,2S,20S,100R)-2c: 99% chemical purity by GC;
½aꢀD ¼ ꢁ31:4 (c 1.3, CHCl3); H NMR, d = 5.38 (m, 1H,
CH@), 2.4–1.4 (m, 18H), 1.23 (m, 1H), 1.08 (ddd,
J = 7.1, 8.6, 14, 1H), 0.84 (d, J = 6.8, 3H, H–(C30)); 13C
NMR d = 221.5, 134.1, 121.1, 47.5, 37.9, 37.4, 35.1, 34.6,
30.9, 30.7, 29.8, 24.3; 23.4, 20.7, 16.5. GC/MS:
tr = 22.01 min; m/z: 220 (M+, 12), 202 (50), 121 (100).
Anal. Calcd for C15H24O: C, 81.76; H, 10.98. Found: C,
81.59; H, 10.99.
20
½aꢀD ¼ þ62:9 (c 1.1, CHCl3); 1H NMR, d = 5.51 (br t,
1H, H–C(1)), 5.23 (m, 1H, CH@), 2.19–1.16 (m, 20H),
0.89 (d, J = 6.8, 3H, H–C(30)); 13C NMR d = 133.8,
121.0, 74.3, 43.5, 38.6, 35.7, 33.8, 32.2, 30.9, 29.4, 27.6;
25.1, 23.3, 21.7, 16.6. GC/MS: tr = 22.18 min; m/z: 204
(M+ꢁ18, 15), 148 (90), 121 (100). Anal. Calcd for
C15H26O: C, 81.02; H, 11.79. Found: C, 81.04; H, 11.63.
4.6. General procedure for the hydrolysis of acetates 3b and
3d
4.7.2. Compound (2R,20S,100R)-1b. According to the gen-
eral procedure, the oxidation of alcohol 2b gave ketone
1b (0.28 g, 92% after column chromatography, de 89% by
To a solution of acetate (0.5 g, 3.0 mmol) in EtOH (10 mL)
was added KOH (0.17 g, 6.0 mmol). After 5 h, the reaction
mixture was concentrated under reduced pressure and di-
luted in Et2O (30 mL). Then, the organic phase was washed
with brine (1 ꢃ 20 mL) and the solvent was removed under
reduced pressure to give the alcohol as a colourless oil.
13C NMR) as a colourless liquid: 99% chemical purity by
20
GC; ½aꢀD ¼ þ197:4 (c 0.8, CHCl3); 1H NMR, d = 5.30
(m, 1H, CH@), 2.3–1.2 (m, 19H), 0.99 (ddd, J = 7.1, 8.6,
14, 1H), 0.78 (d, J = 6.8, 3H, H–(C30)); 13C NMR
d = 221.4, 133.9, 120.9, 47.3, 37.9, 37.1, 35.4, 34.8, 31.1,
30.7, 27.6, 26.4; 23.4, 20.7, 16.1. GC/MS: tr = 22.10 min;
m/z: 220 (M+, 10), 202 (60), 121 (100). Anal. Calcd for
C15H24O: C, 81.76; H, 10.98. Found: C, 81.69; H, 10.90.
4.6.1. (1R,2R,20S,100R)-2b. According to the general pro-
cedure, (1R,2R,20S,100R)-2b was obtained (0.36 g, 92%):
20
99% chemical purity by GC; ½aꢀD ¼ þ42:2 (c 1.1, CHCl3);
4.7.3. (2S,20S,100R)-1c. According to the general proce-
dure, the oxidation of alcohol 2c gave ketone 1c (0.28 g,
1H NMR, d = 5.51 (br t, 1H, H–C(1)), 5.23 (m, 1H,

806
E. Brenna et al. / Tetrahedron: Asymmetry 19 (2008) 800–807
92% after column chromatography, de 80% by 13C NMR)
as a colourless liquid: 99% chemical purity by GC;
brine (50 mL). The organic phase was dried over Na2SO4,
and the solvent was removed under reduced pressure to
give a residue, which after bulb-to-bulb distillation fur-
20
1
½aꢀD ¼ ꢁ71:7 (c 1.4, CHCl3); H NMR, d = 5.37 (m, 1H,
CH@), 2.4–1.2 (m, 20H), 0.85 (d, J = 6.8, 3H, H–(C30));
13C NMR d = 221.9, 134.0, 120.8, 47.3, 39.1, 38.1, 35.2,
34.4, 30.9, 29.9, 27.8, 26.8; 23.4, 20.7, 15.3. GC/MS:
tr = 22.30 min; m/z: 220 (M+, 8), 202 (60), 121 (100). Anal.
Calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 81.73; H,
10.88.
nished (2R,40R)-7 (1.75 g, 79%): 99% chemical purity by
20
GC; ½aꢀD ¼ þ37:5 (c 2.0, CHCl3); 1H NMR, d = 5.36,
(m, 1H, H–C(20)), 3.25 (AB, 2H, CH2I), 2.1 (m, 3H), 1.8–
1.7 (m, 2H), 1.64 (s, CH3C@), 1.54 (m, 1H), 1.42 (m,
1H), 1.28 (m, 1H), 0.99 (d, J = 6.6, 3H, H–C(30)); 13C
NMR d = 137.9, 120.3, 39.2, 38.0, 30.4, 27.7, 26.9, 23.3,
17.4, 16.0. GC/MS: tr = 17.33 min; m/z: 264 (M, 10), 137
(20), 95 (100). Anal. Calcd for C10H17I: C, 45.47; H,
6.49. Found: C, 45.45; H, 6.51.
4.7.4. (2R,20R,100R)-1d. According to the general proce-
dure, the oxidation of alcohol 2d gave ketone 1d (0.28 g,
92% after column chromatography, de 86% by 13C
NMR) as a colourless liquid: 99% chemical purity by
4.10. Preparation of (2R,20S,100R)-1b and (2S,20S,100R)-1c
20
GC; ½aꢀD ¼ þ238:2 (c 1.1, CHCl3); 1H NMR, d = 5.36
(m, 1H, CH@), 2.31 (m, 1H), 2.23 (m, 1H), 2.16–1.89 (m,
6H), 1.83–1.65 (m, 4H), 1.63 (s, 3H, CH3C@), 1.50–1.35
(m, 3H), 1.30–1.20 (m, 2H), 0.87 (d, J = 6.8, 3H, H–
(C30)); 13C NMR d = 221.9, 133.9, 120.9, 47.4, 39.2, 38.1,
35.1, 34.1, 30.8, 29.8, 29.2, 25.7, 23.4, 20.7, 15.5. GC/MS:
tr = 22.30 min; m/z: 220 (M+, 8), 202 (60), 121 (100). Anal.
Calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 81.69; H,
10.90.
To an ice-cold solution of DIPA (0.5 g, 5.0 mmol) in THF
(10 mL) under a nitrogen atmosphere was added a solution
of BuLi in hexane (2.0 mL, 2.5 M). After 1 h, the tempera-
ture was lowered to ꢁ78 °C and was added dropwise a
solution of cyclopentanone (0.35 g, 4.1 mmol) in THF
(2 mL). After 1 h, the solution was warmed to ꢁ30 °C
and DMPU and a solution of 6 (1.3 g, 5.0 mmol) were
added. After 1 h, the reaction mixture was quenched with
satd solution of NH4Cl (20 mL) and washed with Et2O
(2 ꢃ 50 mL). The organic phase was dried over Na2SO4,
and the solvent was removed under reduced pressure to
give a residue, which was purified by column chromatogra-
phy (hexane/AcOEt, 9:1) to give a liquid. Then, the liquid
was purified by bulb-to-bulb distillation (140–150 °C,
0.15 mm Hg) to give 1b and 1c (0.23 g, 26%): 95% chemical
4.8. (1S,2S)-2-[(R)-2-[(R)-4-Methylcyclohex-3-enyl]prop-
yl]cyclopentyl 3,5-dinitrobenzoate-(1S,2S,20R,100R)-5
To a stirred solution of 2a (0.5 g, 2.3 mmol) in CH2Cl2
(5 mL) and pyridine (1 mL) was added portionwise the
3,5-dinitrobenzoylchloride (0.6 g, 2.6 mmol). After 4 h,
the reaction mixture was diluted with CH2Cl2 (20 mL)
and washed with an aqueous solution of HCl (0.1 M,
2 ꢃ 10 mL) and brine (1 ꢃ 10 mL). The organic phase
was dried over Na2SO4, and the solvent was removed un-
der reduced pressure to give a yellow oil, which was puri-
fied on a pad of silica gel, using hexane/AcOEt (8:2)
1
purity by GC. For H and 13C NMR data, see the single
stereoisomers.
4.11. Trimethyl(2-((R,S)-2-((R)-4-methylcyclohex-3-
enyl)propyl)cyclopent-1-enyloxy)silane (20R S,10R)-9
affording (1S,2S,20R,100R)-5 as a yellow-white powder
To a stirred and ice-cold mixture of 1 (5.0 g, 22.7 mmol),
NaI (2.2 g, 28.3 mmol) and pyridine (2.23 g, 28.3 mmol)
in MeCN (30 mL), was added dropwise TMSiCl (3.05 g,
28.3 mmol). After 8 h, the reaction mixture was poured
into an ice-cold solution of satd NH4Cl (20 mL) and
washed with hexane (2 ꢃ 50 mL). The combined organic
layers were dried over Na2SO4. The solvent was removed
under reduced pressure to give a yellow liquid which was
distilled (150–170 °C, 0.5 mmHg) to give (20RS,10R)-9
(6.0 g, 90%) as a colourless liquid: 95% chemical purity
by GC (1% of 1 and 4% of the other regioisomers of 9);
1H NMR, d = 5.37 (m, 1H, CH@), 2.4–1.2 (m, 19H),
0.79 (d+d, J = 6.8, 3H, H–(C30)), 0.17 (s+s, 9H); 13C
NMR d = 147.2, 147.1, 134.0, 133.8, 121.3, 116.2, 53.3,
38.3, 38.2, 35.8, 35.6, 33.7, 31.5, 31.2, 31.1, 31.0, 29.8,
27.5, 27.4, 25.1, 23.4, 20.0, 16.3, 16.0, 0.69. GC/MS: tr =
22.52 min; m/z: 292 (M+, 10), 202 (15), 169 (100). Anal.
Calcd for C18H32OSi: C, 73.90; H, 11.03. Found: C,
73.83; H, 10.88.
20
(0.86 g, 90%): 99% chemical purity by GC; ½aꢀD ¼ þ114:8
1
(c 1.0, CHCl3); H NMR, d = 9.20, (t, J = 2.0, 1H, ArH),
9.10 (d, J = 2.0, 2H, ArH), 5.51 (br t, 1H, H–C(1)), 5.23
(m, 1H, CH@), 2.19–1.16 (m, 20H), 0.89 (d, J = 6.8, 3H,
H–C(30)); 13C NMR d = 162.1, 148.7, 134.6, 134.0, 129.2,
122.2, 120.7, 80.8, 42.6, 38.6, 35.5, 33.4, 32.8, 30.7, 30.6,
29.2, 25.3, 23.3, 22.0, 16.7; Anal. Calcd for C22H28N2O6:
C, 63.45; H, 6.78. Found: C, 63.45; H, 6.81.
4.9. (R)-4-((R)-1-Iodopropan-2-yl)-1-methylcyclohex-1-ene
(2R,40R)-7
To an ice-cold solution of (2R,10R)-6 (1.3 g, 8.4 mmol) in
pyridine (10 mL) was added TsCl (1.9 g, 10.0 mmol). After
4 h, the reaction mixture was concentrated under reduced
pressure, diluted in Et2O (50 mL), and washed with a solu-
tion of NaHCO3 (0.1 M, 1 ꢃ 50 mL), HCl dil. (1 M,
2 ꢃ 50 mL) and brine (1 ꢃ 50 mL). The organic phase
was dried over Na2SO4, and the solvent was removed un-
der reduced pressure to give the tosyl derivate in sufficient
purity. A mixture of the tosyl derivate and NaI (5 g) in ace-
tone (50 mL) was stirred at reflux for 5 h. Then, the solvent
was concentrated under reduced pressure, diluted with
Et2O (850 mL), washed with dil HCl (1 M, 50 mL) and
4.12. 2-((R,S)-2-((R)-4-Methylcyclohex-3-enyl)propyl)-
cyclopent-1-enyl acetate (2RS,10R)-10
To a stirred and ice-cold solution of 1 (3.0 g, 13.6 mmol)
and acetic anhydride (3.0 g, 27.2 mmol) in CCl4 (10 mL)

E. Brenna et al. / Tetrahedron: Asymmetry 19 (2008) 800–807
807
was added a cat. amount of HClO4. After 3 h, the reaction
Acknowledgements
mixture was quenched with ice (50 g), and washed with
CH2Cl2 (2 ꢃ 50 mL). The combined organic layers were
dried over Na2SO4. The solvent was removed under re-
duced pressure to give a yellow liquid, which was purified
by column chromatography (hexane/AcOEt, 8:2) to give
(20RS,10R)-10 as a slightly yellow oil: 95% chemical purity
by GC; 1H NMR, d = 5.37 (m, 1H, CH@), 2.47 (br t, 2H),
2.3–1.2 (m, 20H), 0.79 (d+d, J = 6.8, 3H, H–(C30)); 13C
NMR d = 168.4, 145.0, 144.9, 137.0, 133.6, 125.8, 120.8,
120.7, 38.2, 37.9, 35.5, 35.1, 31.4, 31.3, 31.2, 31.0, 30.8,
30.7, 29.6, 27.5, 27.4, 24.9, 23.2, 20.5, 19.9, 16.0, 16.0,
15.8. GC/MS: tr = 22.92 min; m/z: 262 (M+, 1), 220 (15),
202 (100). Anal. Calcd for C17H26O2: C, 77.82; H, 9.99.
Found: C, 77.93; H, 9.79.
The authors are indebted to Dr. Philip Kraft and Mr. Jean-
Jacques Rouge (Givaudan Schweiz AG, Fragrance Re-
search, Switzerland) for the odour evaluation. Dr. D. Tess-
aro is acknowledged for the kind gift of Novazim and
lipase C-II. Cofin-Murst is acknowledged for financial
support.
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4.13. Typical procedure for chemo enantioselective
protonation of 9
To a stirred and ice-cold solution of 9 (0.7 g, 2.37 mmol) in
THF (5 mL) was added dropwise BuLi (2.5 M, 1.05 mL,
2.6 mmol) under a nitrogen atmosphere. After 1 h, the
reaction mixture was brought at ꢁ78 °C, and was added
a solution of (ꢁ)-7 (0.56 g, 2.6 mmol), in THF (1 mL).
After 1 h, TMSiCl (0.3 g) was added and the reaction mix-
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ice-cold solution of satd NH4Cl (20 mL) and washed with
hexane (2 ꢃ 30 mL). The combined organic layers were
dried over Na2SO4. The solvent was removed under
reduced pressure to give a liquid, which was purified by
column chromatography (hexane/AcOEt, 95:5, 0.1%
NEt3) to give a diastereomeric enriched mixture of 1
(0.45 g, 79%) and recovered 9. The conversion was
analyzed by GC. The de (see Table 2) was determined by
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4.14. General procedure for enzymatic enantioselective
protonation of 10
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A mixture of 10 (0.18 g, 0.69), enzyme (20 mg), in t-
BuOMe was added to EtOH (400 mL, 6.4 mmol). After 1
day, the mixture was filtered, and the filtrate was concen-
trated under reduced pressure to give a mixture of 1 and
9. The conversion was analyzed by GC. The de was
determined by 13C NMR on the not purified compound
(see Table 2).