Synthesis, sensory properties and structures of substituted dodecanolides

Article abstract of DOI:10.1016/S0040-4020(00)00336-7

The liquid odorants (R)-6 and (R)-7 and their corresponding crystalline model substances (R)-8 and (R)-13 were synthesized. Based on the X-ray analyses of (R)-8 and (R)-13, geometries for (R)-6 and (R)-7 were determined using semiempirical calculations. (

Full text of DOI:10.1016/S0040-4020(00)00336-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4129±4137
Synthesis, Sensory Properties and Structures of
Substituted Dodecanolides
Birgit Seyberlich,a Peter Laackmann,a Eva-Maria Peters,b Karl Peters,b
Hans Georg von Schneringb and Werner Tochtermanna,
*
a
È È
Institut fur Organische Chemie der Universitat Kiel, Olshausenstraûe 40, D-24098 Kiel, Germany
b
È
È
Max-Planck-Institut fur Festkorperforschung, Heisenbergstraûe 1, D-70506 Stuttgart, Germany
Dedicated to Professor Rolf Huisgen on the occasion of his 80th birthday
Received 15 March 2000; accepted 12 April 2000
AbstractÐThe liquid odorants (R)-6 and (R)-7 and their corresponding crystalline model substances (R)-8 and (R)-13 were synthesized.
Based on the X-ray analyses of (R)-8 and (R)-13, geometries for (R)-6 and (R)-7 were determined using semiempirical calculations. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
shown in Scheme 1 for (R)-6. The synthesis started with
the alkylation of cyclononanone (1)9 with the chiral building
block (S)-210 yielding about 40% of (R,RS)-3a/b. The
following steps were the acid catalysed cyclization to the
enol ether (R)-4 and the oxidative cleavage of the enol ether
double bond by ruthenium tetroxide oxidation.11 The keto-
lactone was obtained in a yield of about 80% over these two
steps. The keto functionality of (R)-5 was then reduced via
the corresponding tosylhydrazone in a modi®ed Caglioti
reaction.4,12 The target compound (R)-6 was received in an
yield of about 60%. (S)-6 was prepared by the same pro-
cedure from the corresponding building block (R)-210 (see
Experimental).
In previous studies1±4 we have shown that the sensory
properties of new macrolides and especially their musk
notes strongly depend on various structural features such
as ring size, the chain length of alkyl substituents, the abso-
lute con®guration of stereogenic centres and the position of
carbon±carbon double bonds. Predictions concerning the
relationship between odour and structure of these
compounds are dif®cult or even impossible for the following
reasons. On the one hand the structure of the corresponding
protein receptors5 is not known, on the other hand highly
¯exible macrocyclic compounds can adopt an enormous
diversity of conformers differing only slightly in energy.6
The sensory analysis revealed interesting properties of (R)-
6: a faint musk note with very fresh nuances of clary sage
and bergamot is accompanied by cedar-wood accents. Only
a slightly earthy-musty undertone has to be accounted. The
smell of (S)-6 does not differ much in its sensory qualities,
however it is of weaker intensity. As the (R)-compound
turned out to possess a more intensive odour than its
enantiomer all further evaluations were carried out with
(R)-6. In the course of our studies we have shown that the
introduction of a semicyclic methylene group can improve
the odour characteristics signi®cantly.2,4 Therefore, we
prepared (R)-7 from (R)-5 by a Wittig reaction.13 (R)-7,
which has a relatively strong smell, was obtained in 69%
yield. An unconventional fresh and pointed musk note is
accompanied by woody, cedar-like and camphoraceous
nuances. The smell of (R)-7 appears to be slightly
aqueous-aldehydic but interesting as a musk top note.
Whereas the structure of crystalline odorants can be studied
by X-ray analysis,5,7 it is still a major task to supply infor-
mation about the geometric and electronic properties of
liquid compounds. In this paper, a link between X-ray
analysis and computational chemistry for the musk odorants
(R)-6 and (R)-7 is described, providing information about
geometries including volumes and surfaces as well as dipole
moments and the topology of the electrostatic potential
surfaces.
As enantiomers generally differ in their sensory character-
istics,1,4,8 we ®rst determined which of the enantiomers of 6
is the more interesting one. Both enantiomers of 6 were
synthesized according to our ring enlargement sequence1
Keywords: macrolides; ¯avours and fragrances; X-ray crystal structures;
computer-assisted methods.
* Corresponding author. Tel.: 149-431-880-2440; fax: 149-431-880-
1558; e-mail: wtochtermann@email.uni-kiel.de
Having shown that (R)-6 and (R)-7 possess clearly different
sensory characteristics we wanted to get information about
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00336-7

4130
B. Seyberlich et al. / Tetrahedron 56 (2000) 4129±4137
Scheme 1. Synthesis of (R)-6 from cyclononanone (1)9 and the chiral building block (S)-2.10 (a) LDA/DMPU, THF. (b) Amberlyst 15, CH2Cl2. (c) RuCl3/
NaIO4, MeCN/CCl4/H2O. (d) H2NNHTs, MeOH; catecholborane, THF. (e) CH3PPh3Br/KO-tBu, Et2O.
structural differences of these two liquid odorants. For this
purpose we synthesized crystalline derivatives suitable for
X-ray analysis.
Obviously, the exo-methylene functionality is sterically
more demanding than the keto group. So (R)-11 was trans-
formed via Wittig reaction into (R)-12 which unfortunately
did not crystallize even at low temperatures. Therefore, we
decided to use (R)-13 as crystalline model substance for
(R)-7. The hydrazone (R)-13 should be suf®ciently spatially
demanding to mimic the exomethylene functionality. (R)-13
was obtained in a yield of 56% from (R)-5 as orange crystals
(Fig. 3).
(R)-8 obtained from (R)-6 by standard conditions14 ful®lled
these prerequisites. Its X-ray analysis at ambient tempera-
ture showed the coexistence of two different conformers
(Fig. 1).
In analogy we chose (R)-11 and (R)-12 as model compounds
for (R)-7. The introduction of the phenylthio substituents
was accomplished by the sequence outlined in Scheme 2
(for details see Experimental). (R)-11 provided suitable
crystals whereas (R)-12 did not crystallize even at low
temperature.
The X-ray analyses of the model substances (R)-8 and
(R)-13 now provided the basis for the theoretical part of
our work. The procedure used here implied the conversion
of X-ray data of the model substances (R)-8 and (R)-13 in
order to perform semiempirical calculations17 of the sensory
molecules (R)-6 and (R)-7.
The X-ray analysis of (R)-11 (Fig. 2) shows that the keto
oxygen atom is directed towards the middle of the macro-
cyclic ring. This conformational feature had been already
observed for medium sized ring ketones by Prelog.15 This
may be the reason for the relatively rare cases of oxo-
lactones which show a musk note. One example is a
homologue of (R)-5 with two additional methylene
groups.16
This is described in detail for the conformer (R)-6A: starting
with X-ray data from (R)-8A, primary geometry re®nements
were carried out using the AM1 method.18 The resulting
conformer, which was topologically identical, was subse-
quently modi®ed, replacing the phenylthio groups by
hydrogen atoms. This was done by application of the
MM2 molecular mechanics method19,20 on the bonds of

B. Seyberlich et al. / Tetrahedron 56 (2000) 4129±4137
4131
Figure 1. (R)-8 and its two conformers A and B in the crystal; arbitrary numbering.
only the particular carbon atom. Then the geometry of the
obtained conformer of (R)-6A was fully optimized using
the AM1 method18 in three re®nement steps, including the
Eigenvector±Following method20 which is known to give
results of best precision. No constraints were applied. The
integrity of the ®nal results has been validated by calcula-
tion of the force constants and the resulting vibrational
frequencies. Superposition of (R)-8A and (R)-6A revealed
an excellent concordance between the two geometries.
Supplementary PM321 calculations support the results. No
interference between the lactone ring and the substituents or
between the substituents themselves is observed, which can
be explained by the suf®cient length of the C±S bonds in
(R)-8A.
Scheme 2. Synthesis of (R)-12 from (R)-5. (a) Amberlyst 15/2,2-dimethyl-propane-1,3-diol, toluene. (b) LDA/PhSSPh, THF. (c) Amberlyst 15, CH2Cl2.
(d) CH3PPh3Br/KO-tBu, Et2O.

4132
B. Seyberlich et al. / Tetrahedron 56 (2000) 4129±4137
conformer (R)-6A, the lactone carbonyl oxygen is directed
transversally into the plain whereas in conformer (R)-6B the
lactone carbonyl oxygen lies vertically above the plain of
the macrocycle.
For the exo-methylene compound (R)-7, the geometry opti-
mization was carried out in the same way as above. The
replacement of the hydrazone group of (R)-13 by the
exomethylene functionality was the key step in the genera-
tion of (R)-7. The hydrazone group is an appropriate sub-
stituent that mimics the exomethylene functionality in this
case. The resulting geometry for (R)-7 is the nearly quad-
rangular conformer shown in Fig. 5. The macrocycle and the
lactone group are arranged very similar to that of (R)-6B.
The methyl and the exo-methylene groups are residing in the
same edge of the macrocycle, but on different sides of the
macrocyclic ring. This might be explained by their sterical
demands. The result that only one conformer exists in the
crystals at ambient temperature could be due to a lower
¯exibility of the macrocycle with an sp2 con®gurated carbon
atom.
Figure 2. One molecule of (R)-11 in the crystal; arbitrary numbering.
The same procedure was carried out for conformer (R)-8B
to give (R)-6B. The calculated gas phase conformers (R)-6A
and (R)-6B show rather similar structures with the macro-
cycles in an `inverted' conformation (Fig. 4). In both
conformers, all trans edges are linked by gauche corners
with the Z ester moiety localized in a zigzag chain, its
a-carbon atom being a corner atom. Also the methyl
group is situated on a corner atom in both conformers. In
To gain further insight into the geometry of the compounds,
the molecular volumes22 and surfaces23 as well as the dipole
moments were determined (Table 1). The water accessible
surfaces and water excluded volumes24 were calculated as
Figure 3. Crystalline model substance (R)-13 and one molecule of (R)-13 in the crystal; arbitrary numbering.
Figure 4. Calculated geometries of (R)-6A (left) and (R)-6B (right) (AM1).

B. Seyberlich et al. / Tetrahedron 56 (2000) 4129±4137
4133
and reagents were puri®ed and dried according to
common procedures. Reactions with organometallic
compounds were performed under an argon atmosphere.
(2R,20R)- and (20R,2S)-2-[30-(tert-Butyl-dimethyl-silyl-
oxy)-2-methyl-propyl]-cyclononanone (R,RS)-3a/b. 57.2
mL (91.5 mmol) of a 1.6 M solution of n-butyllithium in
n-hexane were added to a stirred solution of 12.4 mL
(94.0 mmol) diisopropylamine in 200 mL anhydrous THF
and 100 mL 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi-
dinone at 2788C. The mixture was stirred for 10 min and
then for 30 min at 08C. After recooling to 2788C 8.80 g
(62.0 mmol) cyclononanone (1) were added and stirring
was continued for 1 h. Then 19.7 g (62.8 mmol) (2S)-
(1)-(tert-butyl-dimethyl)-(3-iodo-2-methyl-propoxy)-silane
((S)-2)10 were injected. After 30 min the reaction mixture
was allowed to warm to room temp. and stirred overnight.
Then it was poured into a mixture of 400 mL water and
400 mL of Et2O. The organic layer was separated and the
aqueous layer was extracted three times with 200 mL of
Et2O. The combined organic extracts were dried with
MgSO4 and concentrated in vacuo. The crude product was
puri®ed by CC (Et2O/pentane 1:20) on silicagel to yield
7.6 g (37%) (R,RS)-3a/b (Rfˆ0.23) as a colourless oil. IR
(®lm): nˆ2928/2856 cm21 (s, n C±H), 1702 cm21 (s, n
CvO, ketone), 1471 cm21 (m, das CH3), 1095 cm21 (m, n
C±OSi), 838 cm21 (s, n O±Si), 775 cm21 (m, n O±Si±
CH3). 1H NMR (200 MHz, CDCl3): dˆ0.02 (s, 6H,
SiMe2), 0.85±0.91 (m, 12H, CMe3, 20-Me), 1.25±1.91 (m,
15H), 2.27±2.57 (m, 2H, 9-H2), 2.70 (mc, 1H, 2-H), 3.31
(dd, Jˆ9.8 and 5.4 Hz, 1H, 30-H, part of an AB-system)/
3.37 (dd, Jˆ9.8 and 5.2 Hz, 1H, 30-H, part of an AB-
system), 3.40 (dd, Jˆ9.1 and 5.9 Hz, 1H, 30-H, part of an
AB-system)/3.45 (dd, Jˆ9.1 and 5.7 Hz, 1H, 30-H, part of
an AB-system) for the other diastereomer. 13C NMR
(50 MHz, CDCl3): dˆ25.40 (q, 4C, Si±Me2), 16.65/17.36
(q, 20-Me), 18.30 (s, 2C, C-Me3), 24.29/24.38/24.78/24.97/
25.05/25.15/25.94 (t, 10C, C-4±C-8), 26.11/26.14 (q, 6C,
C-Me3), 30.43/31.50 (t, C-3), 33.60/33.72 (d, C-20), 36.23/
37.05 (t, C-10), 41.57/41.83 (t, C-9), 51.03/51.12 (d, C-2),
68.01/68.41 (t, C-30), 219.85/219.95(s, C-1). MS (CI): m/z
(%)ˆ327 (100) [M%1H], 269 (51) [M%2C4H10], 195 (98)
[M%2C6H16OSi]. C19H38O2Si (326.3): calcd C 69.87%, H
11.73%; found C 69.99%, H 11.76%.
Figure 5. Calculated geometry of (R)-7 (AM1).
Table 1. Calculated values for heat of formation (DH); dipole moment (m);
van der Waals surface and-volume (VdW-Vol.); water accessible surface
(Acc. surface) and water excluded volume (Excl. volume)
(R)-6A
(R)-6B
(R)-7
DH18,26 (kcal/mol) (AM1)
DH21,26 (kcal/mol) (PM3)
m18,26 [D] (AM1)
2148.67
2133.24
1.77
2150.68
2135.72
1.67
2125.63
2113.18
1.41
m21,26 [D] (PM3)
1.78
1.81
1.48
Ê 2
VdW surface23,27 (A )
297.6
424.0
309.4
700.3
302.5
425.6
310.4
704.1
313.4
438.3
323.8
731.4
Ê 2
Acc. surface22,28 (A )
Ê 3
VdW volume19,24 (A )
Ê 3
Excl. volume24,29 (A )
biologically interesting parameters.25 Together with the van
der Waals values,21,23 comparative studies may be per-
formed by means of database search strategies.
Conclusion
The synthesis of two novel musk odorants, (R)-6 and (R)-7,
is described. In addition a combined method of semi-
empirical calculations17 and X-ray analysis of model
compounds suitable for highly ¯exible macrolides is
presented. (R)-8 and (R)-13 proved to be suitable solid
derivatives for the procedure described here. Along with
additional data such as the dipole moment and the electro-
static potential mapping, the geometries including molecu-
lar surfaces and volumes give an excellent picture of the
investigated molecules. The visualization20 of the electro-
statical potential topology is available as supplementary
material.16
(12R)-12-Methyl-oxacyclotridecane-2,10-dione ((R)-5).
A solution of 7.49 g (22.6 mmol) (R,RS)-3a/b in 350 mL
anhydrous CH2Cl2 was treated with 3.00 g Amberlystw 15
and stirred overnight at room temp. The resin was ®ltered
off and extracted thoroughly with CH2Cl2. The organic
extracts were combined and the solvent was evaporated in
vacuo. The crude product was dissolved in 120 mL aceto-
nitrile and 180 mL CCl4. 180 mL water, 104 mg (0.052
mmol) ruthenium trichloride-trihydrate and 19.3 g
(90.2 mmol) sodium periodate were added to the stirred
solution. After stirring overnight at room temp. the solution
was diluted with CH2Cl2. The organic layer was separated
and the aqueous one was extracted with CH2Cl2. The
combined organic extracts were dried with MgSO4, ®ltered
over silica gel and the solvents were removed in vacuo. CC
of the crude product (Et2O/pentane 1:4) provided 4.01 g
(77%) (R)-5 (Rfˆ0.29) as a colourless liquid. IR (®lm):
nˆ2936/2855 cm21 (s, n C±H), 1726 cm21 (s, n CvO,
Experimental
IR: Perkin±Elmer FTIR 1600, 1625; Paragon 1000 FTIR.
1
UV: Zeiss DMR 10. H/13C NMR: Bruker AC 200 P, AM
300, DRX 500; TMS int. standard. MS: Finnigan MAT 8200
and MAT 8230; direct inlet (EI: 70 eV; CI isobutane).
Column Chromatography (CC): Baker Silica gel 40±
60 mm. TLC: Macherey-Nagel SIL G/UV254. Melting points
(uncorrected): BuÈchi 510. Optical rotations (CHCl3):
Perkin±Elmer 241. Elemental Analyses: Mikroanalytisches
Laboratorium Ilse Beetz, D-96301 Kronach. All solvents

4134
B. Seyberlich et al. / Tetrahedron 56 (2000) 4129±4137
lactone), 1702 cm21 (s, n CvO, ketone), 1458 cm21 (m, das
CH3), 1177 cm21 (s, n C±O±C). 1H NMR (200 MHz,
CDCl3): dˆ1.01 (d, Jˆ6.9 Hz, 3H, 20-Me), 1.15±1.45 (m,
6H), 1.53±1.80 (m, 4H), 2.20±2.55 (m, 6H), 2.77 (dd,
Jˆ17.5 and 6.8 Hz, 1H, 3-H), 3.91 (dd, Jˆ10.9 and
8.2 Hz, 1H, 13-H), 4.12 (dd, Jˆ10.9 and 3.8 Hz, 1H, 13-
H). 13C NMR (50 MHz, CDCl3): dˆ17.81 (q, 12-Me),
23.11/24.26/26.36/27.30/27.52 (t, C-4±C-10), 27.76 (d,
C-12), 34.17 (t, C-3), 42.30 (t, C-9), 45.94 (t, C-11), 68.15
(t, C-13), 173.94 (s, C-2), 210.32 (s, C-10). MS (EI): m/z
(%)ˆ226 (7) [M%], 208 (5) [M%2H2O], 169 (22)
[M%2C4H9], 151 (9) [M%2C4H11O], 98 (100) [C6H10O%],
83 (43) [C6H11%], 69 (21) [C5H9%]. [a]2D1ˆ120.9,
C H22O3 ber.
13
20
[a] ˆ2104.1, (cˆ3.0, CHCl3).
365
12
226.1568, gef. 226.1569.
(12S)-12-Methyl-oxacyclotridecan-2-one ((S)-6). Prepared
according to (R)-6 from (S)-5 in 67% yield. For spectro-
scopic data see (R)-6. [a]Dˆ225.1, [a]578ˆ226.2,
[a]546ˆ230.3, [a]436ˆ249.8, [a]365ˆ278.6; (cˆ2.9,
12
CHCl3, 208C). C13H24O2 ber. 212.1776, gef. 212.1775;
12
C
12
13CH24O2 ber. 213.1809, gef. 213.1807.
(12R)-12-Methyl-10-methylene-oxacyclotridecan-2-one
((R)-7). A suspension of 598 mg (1.67 mmol) methyltri-
phenylphosphonium bromide and 175 mg (1.57 mmol)
potassium-tert-butoxide in 10 mL anhydrous Et2O was
re¯uxed under argon atmosphere for 30 min. The mixture
was allowed to cool to room temp., then 250 mg
(1.12 mmol) (R)-5 in 5 mL anhydrous Et2O were added
dropwise and the mixture was heated to re¯ux for 1.5 h.
The reaction mixture was hydrolysed by addition of 8 mL
water at room temp. Usual workup and CC at silica gel
(Et2O/pentane 1:20) provided 172 mg (69%) (R)-7
(Rfˆ0.36) as colourless oil. IR (®lm): nˆ2932/2862 cm21
(s, n C±H), 1735 cm21 (s, n CvO, lactone), 1634 cm21 (s,
n CvC), 1461 cm21 (m, d CH3), 1239 cm21 (s, nas C±O±C,
lactone). 1H NMR (300 MHz, CDCl3): dˆ0.92 (d,
Jˆ6.9 Hz, 3H, 14-Me), 1.25±1.67 (m, 9H, 4-H±8-H2),
1.67 (ddd, Jˆ13.7, 9.7 and 1.2 Hz, 1H, 11-H), 1.74 (ddd,
Jˆ14.0, 8.0 and 3.6 Hz, 1H, 4-H), 1.90±1.95 (m, 1H, 12-H),
1.91 (dddd, Jˆ17.1, 7.0, 6.9 and 3.2 Hz, 1H, 9-H), 1.98 (mc,
1H, 9-H), 2.32 (ddd, Jˆ14.2, 8.8 and 3.8 Hz, 1H, 3-H), 2.34
(ddd, Jˆ14.0, 4.4 and 1.2 Hz, 1H, 11-H), 2.42 (ddd, Jˆ14.2,
8.0 and 3.6 Hz, 1H, 3-H), 3.82 (`t', Jˆ10.6 Hz, 1H, 13-H),
4.09 (dd, Jˆ10.6 and 3.2 Hz, 1H, 13-H), 4.70 (dddd, Jˆ1.2,
1.2, 1.2 and 1.2 Hz, 1H, CvCH2), 4.77 (dddd, Jˆ1.2, 1.2,
1.2 and 1.2 Hz, 1H, CvCH2). 13C NMR (75 MHz, CDCl3):
dˆ16.48 (q, 12-Me), 24.68/25.71/25.95/26.01/26.18 (t,
C-4±C-8), 31.69 (d, C-12), 33.59 (t, C-9), 34.57 (t, C-11),
39.10 (t, C-3), 68.83 (t, C-13), 111.46 (t, 10ˆCH2), 148.29
(s, C-10), 173.97 (s, C-2). MS (EI): m/z (%)ˆ224 (11) [M%],
209 (8) [M%2CH3], 195 (5) [M%2C2H5], 181 (7)
[M%2C3H7], 167 (7) [M%2C4H9], 96 (100) [C7H12%], 81
21
578
21
546
21
436
21
365
[a] ˆ122.3, [a] ˆ125.8, [a] ˆ150.0, [a]
ˆ
198.6 (cˆ0.7, CHCl3). C13H22O3 (226.2): calcd
C
68.99%, H 9.80%; found C 68.99%, H 9.71%.
(12R)-12-Methyl-oxacyclotridecan-2-one ((R)-6). 4.01 g
(17.7 mmol) (R)-5 and 3.63 g (19.5 mmol) 4-toluenesul-
fonohydrazide were dissolved in 50 mL anhydrous
methanol and re¯uxed for 45 min under argon. The solvent
was removed under vacuo. After the crude product had been
dried in a high vacuum line for 4 h it was dissolved in 70 mL
anhydrous CHCl3. 19.5 mL (19.5 mmol) of a 1 M solution
of catecholborane in toluene were added at 08C. The
mixture was stirred for 2 h. Then 4.32 g (52.7 mmol)
sodium acetate-trihydrate were added and the mixture was
re¯uxed for 1 h. The cooled reaction mixture was poured
into 400 mL Et2O and 200 mL water, the organic layer was
separated and washed twice with water. The organic phase
was dried with MgSO4 and the solvent was evaporated in
vacuo. CC at silica gel (Et2O/pentane 1:30) provided 2.11 g
(56%) (R)-6 (Rfˆ0.17) as a colourless oil. IR (®lm):
nˆ2930/2860 cm21 (s, n C±H), 1734 cm21 (s, n CvO,
lactone), 1462 cm21 (m, das CH3), 1250 cm21 (s, n C±O±
C). 1H NMR (200 MHz, CDCl3): dˆ0.92 (d, Jˆ7.0 Hz, 3H,
20-Me), 1.05±1.15 (m, 1H, 11-H), 1.25±1.45 (m, 12H, 5-
H2±10-H2), 1.50 (mc, 1H, 11-H), 1.67 (mc, 2H, 4-H2), 1.79
(mc, 1H, 12-H), 2.30 (ddd, Jˆ14.3, 7.1 and 5.6 Hz, 1H, 3-
H), 2.42 (ddd, Jˆ14.3, 11.6 and 5.7 Hz, 1H, 3-H), 3.87 (dd,
Jˆ10.8 and 9.7 Hz, 1H, 13-H), 4.01 (dd, Jˆ10.8 and 3.4 Hz,
1H, 13-H). 13C NMR (50 MHz, CDCl3): dˆ17.16 (q, 12-
Me), 24.46/24.49/24.84/25.27/25.79/26.35/26.42 (t, C-4±C-
10), 31.96 (t, C-11), 32.22 (d, C-12), 34.61 (t, C-3), 69.24 (t,
C-13), 173.93 (s, C-2). MS (EI): m/z (%)ˆ212 (5) [M%], 194
(13) [M%2OH], 139 (18) [%2C10H19], 125 (17) [C9H17%],
111 (27) [C8H15%], 98 (57) [C7H13%], 83 (52) [C6H11%], 69
25
25
546
(81) [C6H9%]. [a]D25ˆ13.2, [a] ˆ13.2, [a] ˆ13.6,
578
25
436
25
365
[a] ˆ14.4, [a] ˆ13.4, (cˆ2.2, CHCl3). C14H24O2
ber. C 74.95%, H 10.78%; gef. C 75.08%, H 10.76%.
(12R)-12-Methyl-3,3-bis-phenylsulfanyl-oxacyclotri-
decan-2-one ((R)-8). 1.60 mL (2.53 mmol) of a 1.6 M solu-
tion of n-butyllithium in n-hexane were added to 0.36 mL
(2.53 mmol) diisopropylamine in 10 mL THF at 2788C.
After stirring for 15 min, 300 mg (1.41 mmol) (R)-6 were
added. The mixture was allowed to warm to 2208C and then
552 mg (2.53 mmol) diphenyldisulphide in 5 mL THF were
added dropwise. The mixture was stirred for 1 h at ambient
temperature. Subsequently, the reaction mixture was poured
into 50 mL Et2O and 50 mL 2 N hydrochloric acid. The
organic phase was separated and washed with 20 mL 2 N
hydrochloric acid. Thereafter it was neutralized with satu-
rated NaHCO3, dried with MgSO4 and concentrated in
vacuo. CC on silica gel (Et2O/pentane 1:40) provided
233 mg (38%) (R)-8 (Rfˆ0.11) as colourless crystals
which were recrystallized from (Et2O/pentane). Mp.
86±888C. IR (®lm): nˆ2928/2863 cm21 (s, n C±H),
1717 cm21 (s, n CvO, lactone), 1472/1438 cm21 (m, n
20
20
(100) [C5H9%]. [a]D20ˆ125.4, [a] ˆ126.4, [a]
ˆ
578
546
20
436
20
365
129.9, [a] ˆ150.4, [a] ˆ177.7, (cˆ2.2, CHCl3).
C13H24O2 (212.2): calcd C 73.54%, H 11.39%; found C
73.57%, H 11.40%.
(2R,20S)- and (2S,20S)-2-[30-(tert-Butyl-dimethyl-silyloxy)-
2-methyl-propyl]-cyclononanone((RS,S)-3a/b). Prepared
according to (R,RS)-3a/b from cyclononanone (1)
and (2R)-tert-butyl-(3-iodo-2-methyl-propoxy)-dimethyl-
silane (R)-2 in 44% yield. For spectroscopic data see
(R,RS)-3a/b.
(12S)-12-Methyl-oxacyclotridecane-2,10-dione ((S)-5).
Prepared according to (R)-5 from (RS,S)-3a/b in 87%
yield. For spectroscopic data see (R,RS)-3a/b. [a]2D0ˆ
20
578
20
546
20
436
221.6, [a] ˆ222.8, [a] ˆ226.5, [a] ˆ252.0,

B. Seyberlich et al. / Tetrahedron 56 (2000) 4129±4137
4135
phenyl), 1240 cm21 (s, nas C±O±C, ester), 755/692 cm21 (s,
phenyl). UV (MeCN): lmax (lg e)ˆ223 (5.132), 263
(7.12 mmol) of a 1.6 M solution of n-butyllithium in
n-hexane were added to 0.980 mL (7.12 mmol) diisopropyl-
amine in 40 mL THF at 2788C and then stirred for 20 min
at 08C. The mixture was recooled to 2788C and 740 mg
(2.37 mmol) (R)-9 were added via syringe and then stirred
for 30 min. Subsequently, 1.55 g (7.12 mmol) diphenyl-
disulphide in 10 mL THF were added while cooling with
an ice bath. The mixture was allowed to warm to room
temperature and stirred for further 30 min. Then the reaction
mixture was poured into 300 mL Et2O and washed succes-
sively with 50 mL 2 N hydrochloric acid and 50 mL water.
The organic layer was neutralized with sat. aqueous
NaHCO3, dried with MgSO4 and concentrated in vacuo.
CC at silica gel (Et2O/pentane 1:10) provided 985 mg
(78%) (R)-10 (Rfˆ0.20) as a colourless, highly viscous
oil. IR (®lm): nˆ2954/2849 cm21 (s, n C±H), 1724 cm21
(s, n CvO, lactone), 1467 cm21 (m, das CH3), 1465/
1436 cm21 (m, n phenyl), 1234 cm21 (s, nas C±O±C,
lactone), 1129 cm21 (s, n C±O±C, acetal), 746/690 cm21
(s, phenyl). UV (MeCN): lmax (lg e)ˆ219 (4.352), 264
1
(4.657). H NMR (500 MHz, CDCl3): dˆ0.88 (d, Jˆ7.0,
3H, 12-Me), 1.06±1.90 (m, 17H, 4-H2±11-H2, 12-H), 3.89
(d, Jˆ6.6, 2H, 13-H2), 7.33±7.43 (m, 6H, 30-H±50-H and
300-H±500-H), 7.61 (dd, Jˆ8.1 and 1.2 Hz, 2H, 20-H and 60-
H), 7.73 (dd, Jˆ8.1 and 1.4 Hz, 2H, 200-H and 600-H). 13C
NMR (125 MHz, CDCl3): dˆ17.16 (q, 12-Me), 23.05/
24.58/24.74/25.72/26.56 (t, C-5±C-10), 31.82 (d, C-12),
32.25 (t, C-11), 35.36 (t, C-4), 45.50 (t, C-11), 71.45p (t,
C-13), 71.50p (s, C-3), 128.55/128.58 (d, C-30, C-50 and C-
300, C-500), 129.31/129.44 (d, C-40 and C-400), 130.94/131.31
(s, C-10 and C-100), 136.29/136.31 (d, C-20, C-60and C-200, C-
600), 169.67 (s, C-2). MS (EI): m/z (%)ˆ428 (1) [M%], 319
(100) [M%2C6H5S], 209 (5) [M%2C12H11S2], 109 (23)
20
20
[C7H5S%]. [a]2D0ˆ242.7, [a] ˆ245.2, [a] ˆ253.5,
578
546
20
436
20
365
[a] ˆ2118.9, [a] ˆ2271.7, (cˆ2.3, CHCl3).
X-ray analysis of (R)-8:29 The data of a crystal (Et2O/
pentane) with the approximate dimensions 0.15£0.4£
1.3 mm were obtained with a Siemens P4 diffractometer
(Mo Ka radiation, graphite monochromator). Cell dimen-
sions: aˆ1079.9(1), bˆ1053.3(1), cˆ2082.7(2) pm; bˆ
93.146(8)8, Vˆ2365.3(4)£106 pm3, monoclinic, space
group P21; Zˆ4. rcalcdˆ1.204 g/cm3, 10895 unique re¯ec-
tions, of which 8810 [F0.3s(F)] were observed in the u
range 1.75±27.58, measured with v-scan technique. The
structure was solved by using direct-phase determination
and re®ned on F by using SHELXTL-PLUS. Positional
parameters, anisotropic displacement parameters for all
atoms except for hydrogen atoms, groupwise isotropic
displacement parameters for all hydrogen atoms, treated
as rigid groups. Rˆ0.057, Rwˆ0.057, wˆ1/s2(F).
1
(sh, 3.673). H NMR (200 MHz, CDCl3): dˆ0.87 (s, 3H,
3-Me), 1.00 (s, 3H, 3-Me), 1.01 (d, Jˆ6.8 Hz, 3H, 80-Me),
1.15±2.00 (m, 15H, 7-H2, 8-H, 13-H2±18-H2), 3.34±3.49
(m, 4H, 2-H2, 4-H2), 3.698 (t, Jˆ10.47 Hz, 1H, 9-H),
4.102 (dd, Jˆ10.47 and 2.9 Hz, 1H, 9-H), 7.27±7.46 (m,
8H, 20-H, 30-H, 50-H, 60-H, 200-H, 300-H, 500-H and 600-H),
7.65±7.70 (m, 2H, 40-H and 400-H). 13C NMR (75 MHz,
CDCl3): dˆ18.55 (q, 8-Me), 20.21p (t, C-14), 22.52 (q,
3-Me), 22.88p (t, C-16), 25.35p (t, C-15), 26.23p (t, C-17),
28.85 (q, 3-Me), 29.83 (t, C-18), 30.73 (s, C-3), 30.73 (d, C-
8), 34.40 (t, C-13), 38.16 (t, C-7), 69.91/70.04/70.13 (t, C-2,
C-4, C-9), 70.17 (s, C-12), 101.05 (s, C-6), 128.35/128.49/
128.53/128.59 (d, C-30, C-50 and C-300, C-500), 129.32/
129.44 (d, C-40 and C-400), 131.01/131.20 (s, C-10 and
C-100), 133.45/133.84/136.09/136.49 (d, C-20, C-60and C-
200, C-600), 169.46 (s, C-11). [a]2D0ˆ10.5, [a]25708ˆ19.1,
(8R)-3,3,8-Trimethyl-1,5,10-trioxa-spiro[5.12]octadecan-
11-one ((R)-9). 100 mg Amberlystw 15 were added to a
solution of 1.00 g (4.46 mmol) (R)-5 and 2.00 g
(19.2 mmol) 2,2-dimethyl-1,3-propanediol in 100 mL
anhydrous toluene. The mixture was re¯uxed in a Dean
apparatus for 48 h. The resin was ®ltered off and the ®ltrate
concentrated in vacuo. The crude product was puri®ed by
CC at silica gel (Et2O/pentane 1:10). 905 mg (66%) (R)-9
(Rfˆ0.20) were obtained as colourless oil besides 174 mg
(17%) (R)-5. IR (®lm): nˆ2950/2866 cm21 (s, n C±H),
1732 cm21 (s, n CvO, lactone), 1461 cm21 (m, das CH3),
1193 cm21 (s, n C±O±C, acetal). 1H NMR (200 MHz,
CDCl3): dˆ0.89 (s, 3H, 3-Me), 1.02 (s, 3H, 3-Me), 1.04
(d, Jˆ7.2 Hz, 3H, 80-Me), 1.16±1.96 (m, 15H, 7-H2, 8-H,
13-H2±18-H2), 2.36 (m, 2H, 12-H2), 3.37±3.56 (m, 4H, 2-
H2, 4-H2), 3.68 (t, Jˆ10.7 Hz, 1H, 9-H), 4.12 (dd, Jˆ10.7
and 2.9 Hz, 1H, 9-H). 13C NMR (50 MHz, CDCl3):
dˆ18.61 (q, 8-Me), 22.55/22.89 (q, 3-Me), 20.75/24.03/
25.52, 26.00/26.65/29.03/29.93/ 30.53 (t, C-13±C-18),
34.40 (t, C-12), 38.43 (t, C-7), 69.87/70.00/70.15 (t, C-2,
C-4, C-9), 101.15 (s, C-6), 173.71 (s, C-11). MS (CI): m/z
(%)ˆ313 (100) [M%1H], 227 (53) [M%2C4H6O2]. [a]2D8ˆ
20
20
20
[a] ˆ110.4, [a] ˆ118.9, [a] ˆ132.5; (cˆ1.2,
546
436
365
CHCl3). MS (EI): m/z (%)ˆ528 (3) [M%], 419 (100)
[M%2C6H5S], 419 (94) [M%2C11H15OS]. C30H40O4S2 ber.
528.2368, gef. 528.2364.
(12R)-12-Methyl-3,3-bis-phenylsulfanyl-oxacyclotride-
cane-2,10-dione ((R)-11). 150 mg Amberlystw 15 were
added to a solution of 732 mg (1.38 mmol) (R)-10 in
25 mL CH2Cl2 and stirred overnight at ambient temperature.
The resin was ®ltered off and extracted with CH2Cl2. The
solvent was removed in vacuo and the product puri®ed by
CC at silica gel (Et2O/pentane 1:10) to yield 277 mg (45%)
(R)-11 (Rfˆ0.23) as colourless crystals. mp. 128±1298C. IR
(®lm): nˆ2957/2920 cm21 (s, n C±H), 1719 cm21 (s, n
CvO, lactone, ketone), 1470 cm21 (m, das CH3),
1233 cm21 (s, n C±O±C), 753/688 cm21 (s, phenyl). UV
1
(MeCN): lmax (lg e)ˆ220 (4.595), 278 (3.942). H NMR
(300 MHz, CDCl3): dˆ0.98 (d, 3H, Jˆ7.1 Hz, 12-Me),
1.10±1.65 (m, 8H, 5-H2±8-H2), 1.69 (ddd, Jˆ14.1, 10.5
and 4.6 Hz, 1H, 4-H),), 1.90 (ddd, Jˆ14.1, 10.6 and
5.2 Hz, 1H, 4-H), 2.17 (dd, Jˆ18.1 and 5.0 Hz, 1H,
11-H), 2.25 (dd, Jˆ7.9 and 5.1 Hz, 1H, 9-H), 2.35 (mc,
1H, 12-H), 2.36 (ddd, Jˆ14.1, 6.8 and 4.5 Hz, 1H, 9-H),
2.73 (dd, Jˆ18.1 and 6.6 Hz, 1H, 11-H), 3.88 (dd, Jˆ10.8
and 8.1 Hz, 1H, 13-H), 3.97 (dd, Jˆ10.8 and 3.6 Hz, 1H,
13-H), 7.30±7.50 (m, 6H, 30-H±50-H and 300-H±500-H), 7.63
(dd, Jˆ7.9 and 1.5 Hz, 2H, 20-H, 60-H), 7.72 (dd, Jˆ7.6 and
28
28
28
110.3, [a]578ˆ110.8, [a]546ˆ112.0, [a] ˆ 118.4,
436
28
[a] ˆ128.7,
365
(cˆ1.8,
CHCl3).Ð12C18H32O4
ber.
12
312.2300, gef. 312.2300;
gef. 313.2334.
C
13CH32O4 ber. 313.2334,
17
(8R)-3,3,8-Trimethyl-12,12-bis-phenylsulfanyl-1,5,10-
trioxa-spiro[5.12]octadecan-11-one ((R)-10). 4.45 mL

4136
B. Seyberlich et al. / Tetrahedron 56 (2000) 4129±4137
1.5 Hz, 2H, 200-H, 600-H). 13C NMR (75 MHz, CDCl3):
dˆ17.76 (q, 12-Me), 23.30/24.12/26.50/26.70 (t, C-5±C-
8), 27.30 (d, C-12), 35.34 (t, C-4), 42.29 (t, C-9), 45.50 (t,
C-11), 69.89 (t, C-13), 71.42 (s, C-3), 128.61/128.66 (d, C-
30, C-50 and C-300, C-500), 129.31/129.50 (d, C-40 and C-400),
131.00/131.70 (s, C-10 and C-100), 135.95/136.23 (d, C-20,
C-60 and C-200, C-600), 169.57 (s, C-2), 210.07 (s, C-10).
oxacyclotridecan-2-one
((R)-13).
From
100 mg
(0.88 mmol) (R)-5 and 0.40 g (2.03 mmol) 2,4-dinitro-
phenylhydrazine 142 mg (56%) of (R)-13 were obtained
as orange crystals under standard conditions; Rfˆ0.31
(Et2O/pentane 1:4). Mp. 102±1048C. IR (®lm):
nˆ3333 cm21 (s, N±H), 2949/2864 cm21 (s, n C±H),
1731 cm21 (s, n CvCO, lactone), 1614 cm21 (s, n CyN),
1591/1329 cm21 (s, n NO2), 1169 cm21 (s, nas C±O±C),
840 cm21 (s, n 1,2,4-trisubstitution). UV (MeCN): lmax
(log e)ˆ233 (5.080), 365 (5.226). 1H NMR (500 MHz,
CDCl3): dˆ1.07 (d, 3H, Jˆ6.9 Hz, 12-Me), 1.30±1.54/
1.65±1.80 (m, 10H, 4-H2±8-H2), 2.19 (dd, Jˆ15.1 and
8.1 Hz, 1H,11-H), 2.25±2.40 (m, 4H, 3-H, 9-H2, 12-H),
2.50 (dd, Jˆ14.7 and 7.2 Hz, 1H, 3-H), 2.69 (dd, Jˆ15.1
and 4.0 Hz, 1H, 11-H), 3.93 (dd, Jˆ10.8 and 9.1 Hz, 1H,
13-H), 4.24 (dd, Jˆ10.8 and 3.4 Hz, 1H, 13-H), 7.94 (d,
Jˆ9.6 Hz, 1H, 60-H), 8.31 (dd, Jˆ9.6 and 2.5 Hz, 1H, 50-
H), 9.14 (d, Jˆ2.5 Hz, 1H, 30-H), 11.26 (s, NH). 13C NMR
(125 MHz, CDCl3): dˆ16.96 (q, 12-Me), 22.78/24.38/
25.81/26.44/26.98/27.84 (t, C-4±C-9), 30.51 (d, C-12),
34.38 (t, C-3), 40.54 (t, C-11), 67.93 (t, C-13), 116.32 (d,
C-60), 123.55 (d, C-30), 128.93 (s, C-20), 130.03 (d, C-50),
137.60 (s, C-40), 145.21 (s, C-10), 160.60 (s, C-10), 173.83
(s, C-2).ÐMS (CI): m/z (%)ˆ407 (100) [M%1H], 377 (6)
[M%1H2NO], 347 (4) [M%1H2N2O2], 226 (7)
33
33
33
[a]3D3ˆ220.1, [a] ˆ221.2, [a] ˆ225.0, [a]
ˆ
578
546
436
33
253.9, [a] ˆ2118.8; (cˆ2.0, CHCl3). C23H30O3S2
365
(442.2) ber. C 67.84%, H 6.83%; gef. C 67.79%, H
6.68%.
X-ray analysis of (R)-11:29 The data of a crystal (Et2O/
pentane) with the approximate dimensions 0.45£0.4£
0.2 mm were obtained with a Siemens P4 diffractometer
(MoKa radiation, graphite monochromator). Cell dimen-
sions: aˆ730.60(4), bˆ964.95(6), cˆ3332.5(2) pm; Vˆ
2349.4(2)£106 pm3, orthorhombic, space group P212121;
Zˆ4. rcalcdˆ1.251 g/cm3, 5350 unique re¯ections, of
which 4052 [F0.3s(F)] were observed in the u range
1.75±27.58, measured with v-scan technique. The structure
was solved by using direct-phase determination and re®ned
on F by using SHELXTL-PLUS. Positional parameters,
anisotropic displacement parameters for all atoms except
for hydrogen atoms, groupwise isotropic displacement para-
meters for all hydrogen atoms, treated as rigid groups.
Rˆ0.054, Rwˆ0.047, wˆ1/s2(F).
[M%2C6H2N3O4]. [a]1D6ˆ259.9, [a] ˆ260.0, [a]
ˆ
16
578
16
546
256.4, (cˆ1.5, CHCl3). C19H26N4O6 (406.2): ber. C
56.16%, H 6.45%; gef. C 56.25%, H 6.30%.
(12R)-12-Methyl-10-methylene-3,3-bis-phenylsulfanyl-
oxacyclotridecan-2-one ((R)-12). Prepared according to
(R)-7. From 180 mg (0.41 mmol) (R)-11 and 242 mg
(0.68 mmol) methyltriphenylphosphonium bromide 84 mg
(47%) of (R)-12 were obtained as a slightly yellow oil;
Rfˆ0.48 (Et2O/pentane 1:10). IR (®lm): nˆ2931 cm21 (s,
n C±H), 1726 cm21 (s, n CvO, lactone), 1642 cm21 (s, n
CvC), 1434 cm21 (m, das CH3), 1234 cm21 (s, n C±O±C),
749/691 cm21 (s, phenyl). UV (MeCN): lmax (lg e)ˆ221
(5.322), 262 (4.696). 1H NMR (500 MHz, CDCl3):
dˆ0.90 (d, 3H, Jˆ6.9 Hz, 12-Me), 1.20±1.56 (m, 8H, 5-
H2±8-H2), 1.61 (ddt, Jˆ14.4, 9.0 and 1.1 Hz, 1H,11-H),
1.74 (ddd, Jˆ14.2, 11.1 and 5.8 Hz, 1H, 4-H), 1.82±1.94
(m, 4H, 9-H-2, 12-H2, therein 1.86 (ddd, Jˆ14.2, 11,1 and
4.2 Hz, 4-H), 2.21 (ddd, Jˆ14.4, 3.0 and 1.2 Hz, 1H, 11-H),
3.90 (dd, Jˆ10.5 and 3.1 Hz, 1H, 13-H), 3.98 (dd, Jˆ10.5
and 10.5 Hz, 1H, 13-H), 4.63 (dt, Jˆ2.7 and 1.2 Hz, 1H,
10ˆCH2), 4.72 (ddd, Jˆ2.7, 1.2 and 1.0 Hz, 1H, 10ˆCH2),
7.32±7.42 (m, 6H, 30-H±50-H and 300-H±500-H), 7.61 (dd,
Jˆ8.1 and 1.3 Hz, 2H, 200-H, 600-H), 7.71 (dd, Jˆ8.0 and
1.4 Hz, 2H, 20-H, 60-H). 13C NMR (125 MHz, CDCl3):
dˆ16.61 (q, 12-Me), 23.41/25.31/25.79/26.04 (t, C-5±C-
8), 31.34 (d, C-12), 34.03 (t, C-9), 35.70 (t, C-4), 38.99 (t,
C-11), 70.41 (t, C-13), 71.60 (s, C-3), 111.43 (t,
10ˆCH2),128.61/128.64 (d, C-30, C-50 and C-300, C-500),
129.30/129.48 (d, C-40 and C-400), 131.12/131.35 (s, C-10
X-ray analysis of (R)-13:29 The data of a crystal (Et2O/
pentane) with the approximate dimensions 0.4£0.4£
0.4 mm3 were obtained with a Siemens P4 diffractometer
(MoKa radiation, graphite monochromator). Cell dimen-
sions: aˆ979.78(5), bˆ1359.30(7), cˆ1520.58(5) pm; Vˆ
2025.1(7)£106 pm3, orthorhombic, space group P212121;
Zˆ4. rcalcdˆ1.333 g/cm3, 4651 unique re¯ections, of
which 3763 [F0.3s(F)] were observed in the u range
1.75±27.58, measured with v-scan technique. The structure
was solved by using direct-phase determination and re®ned
on F by using SHELXTL-PLUS. Positional parameters,
anisotropic displacement parameters for all atoms except
for hydrogen atoms, groupwise isotropic displacement
parameters for all hydrogen atoms, treated as rigid groups.
Rˆ0.045, Rwˆ0.043, wˆ1/s2(F).
Acknowledgements
We would like to thank Dr H. Surburg and the perfumers of
Haarmann & Reimer GmbH, D-37601 Holzminden, for
sensory evaluation. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie.
and C-100), 136.17/136.34 (d, C-20, C-60 and C-200, C-600),
18
578
147.73 (s, C-10), 169.63 (s, C-2). [a]1D8ˆ238.4, [a]
ˆ
References
18
546
18
436
18
365
240.5, [a] ˆ248.1, [a] ˆ 2105.3, [a] ˆ2238.3;
(cˆ2.6, CHCl3). MS (EI): m/z (%)ˆ440 (4) [M%], 331
(100) [M%2C6H5S], 303 (64) [M%2C7H5OS], 221 (16)
[M%2S2C12H11]. C26H32O2S2 ber. 440.1844, gef.
440.1844; C2513CH32O2S2, ber. 441.1877, gef. 441.1877.
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Ê
éveras, A. T. Acta Chim. Scand. 1998, 52, 1110±1115.
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È
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