On the synthesis and odour impression of (Z)-normethyl-carvo-β-santalol

Article abstract of DOI:10.1007/PL00024627

The synthesis of the title compound is described. Starting with an α-alkylation of (R)-(-)-carvone in position 6 followed by a Wittig reaction, a Tebbe transformation, and a DIBAH ester reduction, this new santalol analogue was obtained which shows a weak

Full text of DOI:10.1007/PL00024627

Monatshefte fuÈr Chemie 129, 705±710 (1998)
On the Synthesis and Odour Impression
of (Z)-Normethyl-carvo-b-santalol
Ã
È
Gerhard Buchbauer , Joris Ho®nghoff, and Alexandra Froese [1]
Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria
Summary. The synthesis of the title compound is described. Starting with an ꢀ-alkylation of (R)-
(ꢀ)-carvone in position 6 followed by a Wittig reaction, a Tebbe transformation, and a DIBAH ester
reduction, this new santalol analogue was obtained which shows a weak woody odour with a dry note
of cedrol.
Keywords. Bulky group; Monoterpene ketone; Sandalwood odorants; Structure-odour relationships;
Woody odour.
È
Uber Synthese und Geruch von (Z)-Normethyl-carvo-b-santalol
Zusammenfassung. Die Synthese der Titelverbindung wird beschrieben. Ausgehend von (R)-(ꢀ)-
È
Carvon wurde zunachst durch ꢀ-Alkylierung in Position 6 und dann durch Carbonylole®nierung,
Tebbe-Transformation und zuletzt durch Esterreduktion mittels DIBAH das neue Santalolanalogon
erhalten, das einen schwachen holzigen Geruch mit einer trockenen Cedrolnote aufweist.
Introduction
In continuation of our studies on structure-odour relationships with sandalwood
odorants we focused our interest on modi®cations of the hydrophobic part, the so-
called ``bulky group'' of ꢁ-santalol (1). A moderate increase of the volume of the
hydrophobic part of this odourous sesquiterpene alcohol does not alter the odour
quality ``sandalwood'', as we were able to show recently [2, 3]. However, in these
cases a somewhat spherical bulky group remained. On the other hand, many
campholene aldehyde derivatives within the class of sandalwood odorants, like e.g.
Madrol1 (2) [3, 4], are characterized by a trimethyl-cyclopentene nucleus as a
relatively ¯at hydrophobic part. Therefore it seemed worthwhile to synthesize
further analogues of 1 with variable bulky hydrophobic groups in order to
investigate the parameters responsible for the sandalwood odour. In this paper we
report on the use of the cheap, naturally occurring monoterpene ketone (R)-(ꢀ)-
carvone (3) as the hydrophobic residue of the new santalol analogue (Z)-6-
normethyl carvo-ꢁ-santalol (7). Some structural features of 7 appear to be similar
to the cyclopentene moiety of the campholene aldehyde derivatives.
Ã
Corresponding author

706
G. Buchbauer et al.
Results and Discussion
The insertion of 2-(2-bromoethyl)-1,3-dioxolane in position 6 of the carvone
nucleus in order to create a suitable synthon for further functional group inversions
proved to be very tedious, although this ®rst step had been successful without
greater problems in a number of cases by the method of Krotz and Helmchen [6].
Using lithium cyclohexyl isopropylamide as base [7] ®nally furnished 5 in
mediocre yield and as a 50:50 epimeric mixture of 5-axial and 5-equatorial.
Despite of many efforts it was not possible either to increase the yield of 5 or to
separate the epimers. Therefore we tried to force the longer and space demanding
side chain into the equatorial position by insertion of an angular methyl group, a
procedure which has been recommended by Corey et al. [8] using norcamphor as
starting ketone for the ꢀ-alkylation. However, the desired dialkylated carvone
derivative 6 could not be obtained.
On account of the failure of the angular methylation we had to change from the
primarily aspired target molecule 4 to 6-normethyl-carvo-ꢁ-santalol (7). Because
of Fanta et al. having reported on the synthesis of 3-normethyl-ꢁ-santalol without
any change in the odour quality [9] ± obviously this angular methyl group is not
necessary for the occurrence of the sandalwood odour ±, we felt legitimized to
regard 7 as a new santalol analogue and hence as the new target molecule.
Hydrolysis of 5 by means of diluted sulfuric acid furnished aldehyde 8.
Because of the sensitivity of the aldehyde group we refrained from a thorough
puri®cation and used crude 8 for the Wittig reaction (Horner-Emmons method)
with 2-phosphonopropionic triethylester, 18-crown-6, and sodium bis(trimethyl-
silyl amide) in THF according to the procedure of Still et al. [10]. By choosing this
sodium amide instead of the more frequently used potassium-bis-(trimethylsilyl
amide), we could double the yield of the ester 9.
The GC-MS of 9 showed 4 peaks with the same mass of m/z ˆ 290 and a similar fragmentation
pattern, indicating the presence of the compounds 9-Z-axial, 9-E-axial, 9-Z-equatorial, and 9-E-
equatorial. By column chromatography on silica gel using petroleum ether (40±60ꢁC):ethyl
acetate ˆ 9:1 as mobil phase we succeeded to obtain in the ®rst fraction pure 9-Z-equatorial, whereas

(Z)-Normethyl-carvo-ꢁ-santalol
707
further fractions still consisted of inseparable mixtures. The Z-con®guration of the side chain double
bond could be established by analyzing the 1H NMR spectrum. The high-®eld shift of the triplet of
1
the ole®nic proton to 5.90 ppm proves the desired con®guration (in the H NMR spectrum of the
other fractions, this triplet could be detected at 6.61 ppm). A decision as to the epimeric status at C6
of the carvone nucleus was not yet possible, but in the 1H NMR spectrum of the next reaction
product we found a strong indication for the equatorial position of the side chain. Therefore, we
conclude that the con®guration of this ketoester fraction was already 9-Z-equatorial.
Tebbe reaction of this ®rst fraction of 9 furnished the ole®nic ester 10 which
could be reduced with DIBAH to the target molecule 6-normethyl-carvo-ꢁ-santalol
(7) without any problems.
The structure determination of 10 and hence of 9 and 7 has been performed by
1
studying a Dreiding model of 10 as well as by analyzing its H NMR spectrum.
The question of the correct substitution at C6 has not been clari®ed so far, but
considering steric reasons, only the bis-equatorial position of the isopropenyl group

708
G. Buchbauer et al.
at C5 and the ole®nic ester side chain at C6 seems plausible. In (R)-(ꢀ)-carvone
(3), the isopropenyl group adopts the equatorial position despite the ¯exibility of
the envelope part ( ˆ C4-C5-C6) of the cyclohexenone moiety. Insertion of a space
demanding substituent at C6 ®xes this position by a strong restriction of the
¯exibility of this envelope part. Rotations of both substituents at C5 and C6 are
possible without hindrance only if they are oriented equatorially. Finally, another
1
strong indication for this con®guration can be found. In the H NMR spectrum of
10 the triplet of the ole®nic proton of the side chain is high-®eld shifted to
5.84 ppm, caused by a shielding effect of the exocyclic double bond upon this
1
proton. Such a shift could not be detected in the H NMR spectrum of the other
epimeric mixtures mentioned above, because this proton is too far away to be
in¯uenced by the anisotropic effect of either the exocyclic double bond or the C=O
double bond of the cyclohexene nucleus, thus proving the equatorial position of the
side chain. With a very high probability, therefore, the con®guration of the
substituents can be established as (R)- at C5 and (S)- at C6.
The olfactoric evaluation of the target molecule 7 by perfumers showed the
following result: 7 exerts a weak odour, a bit spicy and herbaceous at the
beginning, but later on with a clear, dry woody note reminiscent of cedrol. Still
woody, 7 lacks completely the warm, sweet and soft quality which renders the
odour of ꢁ-santalol (1) so incomparable and appreciated. The relatively ¯at
hydrophobic part of 7, the accumulation of double bonds, and the space demanding
and bulky isopropenyl group probably prevents an association of 6-normethyl-
carvo-ꢁ-santalol (7) to the corresponding receptor site. Also, the distance of the
allylic hydroxyl group oxygen from a highly substituted carbon atom of the
Ê
hydrophobic part which is about 5±6 A neither meets the necessary conditions for a
Ê
sandalwood odour according to the rules of Naipawer [11] (about 4 A) nor
corresponds to our earlier de®ned postulate that the center of the bulky group
Ê
should be in a distance of 6.4 A to the allylic oxygen, a function with a strong
negative electrostatic potential [12].
Experimental
For experimental details see Refs. [3] and [13].
6-((1,3-Dioxolan-2-yl)-2-ethyl)-5-isopropenyl-2-methyl-2-cyclohexen-1-one (5)
A solution of 8.095 g (57.14 mmol) cyclohexylisopropylamine (freshly distilled in a Barchit
distillation ¯ask) in 95 ml dry THF was mixed with 34.32 ml (54.76 mmol) n-BuLi (1.6 M in
n-hexane) at 0ꢁC under argon. Upon addition of 5.0 g (33.3 mmol) carvone (3) to the yellow coloured
mixture, the colour changed to orange. Then, 9.82 ml (83.3 mmol) 1-bromo-2-(1,3)-dioxolanyl-
È
ethane (freshly dried by ®ltration through Al2O3 (Wolm)) were added, and the mixture was re¯uxed
(16 h). After quenching with saturated NH4Cl solution and extraction with diethyl ether, the organic
phase was washed with 2 N HCl, dried over Na2SO4, and evaporated. The residue was distilled in a
Kugelrohr apparatus (90ꢁC/4 torr) and afforded 5.25 g (63%) of crude 5. Further puri®cation was
performed by column chromatography (silica gel 60, mesh size 0.040±0.063 mm, petroleum ether
(40±60ꢁC):ethyl acetate ˆ 9:1).
C15H22O3 (250.34); IR (NaCl; liquid ®lm): ꢂ ˆ 3081, 1669, 1452, 1376, 1143, 1044, 896 cmꢀ1
;
1H NMR (CDCl3); ꢃ ˆ 1.40±1.79 (m, 10H), 2.21±2.68 (m, 4H), 3.72±3.90 (m, 4H, 14-H, 15-H),

(Z)-Normethyl-carvo-ꢁ-santalol
709
4.69±4.87 (m, 3H, 8-H, 80-H, 13-H), 6.59 (m, 1H) ppm; 13C NMR (CDCl3): ꢃ ˆ 202.4/200.9 (C=O),
145.4/144.7 (C-7), 143.3/142.7 (CH, C-3), 135.0/133.6 (C-2), 113.3/112.0 (CH2, C-8), 104.7/104.2
(CH, C-13), 64.7 (CH2 of the side chain, C-14, C-15), 48.7/48.2 (CH, C-6), 47.4 (CH, C-5), 44.8 (CH),
30.7/30.6 (CH2, C-4), 21.9/21.8 (CH2, C-11), 18.7 (CH3, C-9), 16.0/15.9 (CH3, C-10) ppm; MS: m/z
‡
(r.I.) ˆ 250 (M ), 188 (4), 173 (3), 149 (11), 99 (25), 82 (10), 73 (100), 55 (9), 45 (26), 41 (16).
3-(5-Isopropenyl-2-methyl-1-oxo-2-cyclohexen-6-yl)-propanal (8)
Ketone 5 (0.515 g, 2.46 mmol), dissolved in some ml of diethyl ether, was hydrolyzed with 5.7 ml
2 N H2SO4. After stirring for 48 h at room temperature, the mixture was extracted with diethyl ether.
The organic phase was washed with water, dried over anhydrous MgSO4, and evaporated. A brown,
oily liquid of crude 8 remained (0.440 g, 86.8%).
‡
C13H18O2 (206.28); MS: m/z (r.I.) ˆ 206 (M , 3), 191 (5), 173 (9), 150 (14), 135 (24), 121 (29),
109 (28), 82 (100), 41 (40).
5-(5-Isopropenyl-2-methyl-1-oxo-2-cyclohexen-6-yl)-2-methyl-2-pentenoic acid ethylester (9)
A solution of 0.47 ml (2.18 mmol) 2-phosphonopropionic acid triethylester and of 2.84 g
(10.73 mmol) 18-Crown-6 (freshly crystallized from acetonitril) in 50 ml dry THF was cooled to
ꢀ80ꢁC and mixed with 2.24 ml (2.24 mmol) sodium-bis-(trimethylsily-amide) (1.0 M in THF). Then,
aldehyde 8 (0.440 g, 2.14 mmol) in dry THF was added, and the mixture was stirred for 4 h at ꢀ75ꢁC.
After quenching with saturated NH4Cl solution, the mixture was extracted with diethyl ether (3Â),
and the ethereal phase was dried over anhydrous MgSO4. After evaporation of the solvent, the
residue was puri®ed by column chromatography (silica gel 60, mesh size 0.040±0.063 mm, solvent
system: petroleum ether:ethyl acetate ˆ 9:1) As the ®rst fraction, 0.065 g (15.1%) of pure 9 were
obtained.
C18H26O3 (290.40); IR (NaCl; liquid ®lm) ꢂ ˆ 3080, 1713, 1671, 1452, 1373, 1219, 1136, 1028,
1
896 cmꢀ1; H NMR (CDCl3): ꢃ ˆ 1.29 (t, J ˆ 7.0 Hz, 3H, 14-H), 1.57±1.67 (m, 1H), 1.71 (s, 3H,
CH3), 1.76 (s, 3H, CH3), 1.88 (s, 3H, 12-H), 2.34±2.56 (m, 6H), 2.61±2.72 (m, 1H), 4.18 (q,
J ˆ 7.0 Hz, 2H, 13-H), 4.80 (s, 1H, 17-H), 4.82 (s, 1H, 170H), 5.90 (t, J ˆ 7.5 Hz, 1H, 9-H), 6.64 (m,
1H, 3-H) ppm; 13C NMR (CDCl3): ꢃ ˆ 201.0 (C=O), 168.1 (COOR), 145.5 (C-16), 142.7/142.5 (C-3,
C-9), 135.1 (C-2), 127.2 (C-10), 113.3 (C-17), 60.0 (C-13), 48.7/47.1 (C-7, C-8), 20.6/18.8/16.0
‡
(3ÂCH3, C-12, C-15, C-18), 14.2 (C-14) ppm; MS: m/z (r.I.) ˆ 290 (M ), 282 (1), 250 (1), 245 (5),
207 (11), 150 (4), 149 (14), 105 (11), 99 (100), 91 (16), 86 (15), 73 (84), 45 (21).
5-(5(R)-Isopropylen-1-methyliden-2-methyl-2-cyclohexen-6(S)-yl)-2-methyl-2-(Z)-pentenoic
acid ethylester (10)
A solution of 0.120 g (0.41 mmol) 9 in 4 ml dry THF was cooled to 0ꢁC. Then, 1.02 ml (0.51 mmol)
of the Tebbe reagent (0.5 M in toluene) were added slowly at this temperature which was maintained
for at least 1 hour. After stirring for 17 h under an argon atmosphere, 15 ml of diethyl ether and 12
drops of methanol were added. This mixture was mixed with celite, ®ltered through another layer of
celite, and this layer was washed with 150 ml of diethyl ether. After evaporation of the solvent, the
yellow solution was roughly puri®ed by column chromatography (sationary phase: Al2O3). The ®nal
puri®cation was performed by preparative TLC (DC-Alu-foil, Merck, Art.Nr. 5554, silica gel 60 F254
,
20Â20 cm, 0.2 mm, solvent system petroleum ether:ethyl acetate ˆ 9:1). The desired ester could be
found in the second fraction from above; yield: 0.036 g (29.8%) of 10.
C19H28O2 (288.43); IR (NaCl; liquid ®lm): ꢂ ˆ 3081, 1715, 1646, 1441, 1374, 1187, 1128,
886 cmꢀ1; 1H NMR (CDCl3): ꢃ ˆ 1.22 (m, 3H, 14-H), 1.43±1.51 (m, 3H), 1.64 (s, 3H, CH3), 1.71 (s,
3H, CH3), 1.82 (s, 3H, CH3, 12-H), 2.25±2.35 (m, 3H), 2.38±2.47 (m, 2H), 4.12 (q, J ˆ 7.2 Hz, 2H,

710
G. Buchbauer et al.: (Z)-Normethyl-carvo-ꢁ-santalol
13-H), 4.63/4.67/4.69 (3Âs, 3H, 17-H, 170-H, 19-H), 4.91 (s, 1H, 190-H) 5.47 (m, 1H, 3-H), 5.84 (t,
J ˆ 7.4 Hz, 1H, 9-H) ppm; 13C NMR (CDCl3): ꢃ ˆ 168.2 (COOR, C-11), 147.9 (C-1), 145.7 (C-16),
142.8 (C-9), 131.2 (C-2), 127.2 (C-10), 124.8 (C-3), 110.1/109.8 (C-17, C-19), 60.0 (C-13), 44.2/
44.0 (C-5, C-6), 33.6 (C-4), 27.4/27.1 (C-7, C-8), 21.4/20.7/19.8 (3ÂCH3, C-12, C-15, C-18), 14.3
‡
(C-14) ppm; MS: m/z (r.I.) ˆ 288 (M , 6), 273 (1), 259 (1), 242 (2), 214 (2), 201 (2), 199 (6), 187
(11), 171 (16), 161 (18), 148 (30), 133 (100), 119 (60), 105 (70), 91 (76), 41 (71).
5-(5(R)-Isopropylen-1-methyliden-2-methyl-2-cyclohexen-6(S)-yl)-2-methyl-2-(Z)-pentenol
(7, (Z)-6-Normethyl-carvo-ꢁ-santalol)
A solution of 10 (0.036 g, 0.12 mmol) in dry CH2Cl2 was cooled to ꢀ78ꢁC and mixed with 0.54 ml
(0.77 mmol) of a 20% solution of DIBAH in n-hexane. After stiring overnight (the mixture warmed
up to room temperature) and renewed cooling to ꢀ20ꢁC, 0.15 ml methanol/water (1:1) were added
and the mixture was stirred for another 3 hours. The white muddy solution was mixed with celite,
®ltered through a layer of celite, and washed with ethyl acetate. Finally, the solvent was evaporated
and the residue puri®ed by TLC as mentioned above.
Yield: 0.021 g (68.7%) of 7; C17H26O (246.39); IR (NaCl; liquid ®lm) ꢂ ˆ 3327, 3084, 1727,
1
1644, 1605, 1440, 1376, 1007, 886, 826 cmꢀ1; H NMR (CDCl3): ꢃ ˆ 1.37±1.45 (m, 3H), 1.64 (s,
3H), 1.72 (s, 6H), 1.99±2.31 (m, 5H), 4.05 (s, 2H, 11-H), 4.64±4.68 (m, 3H, 15-H, 150-H, 17-H), 4.92
(s, 1H, 170-H), 5.24 (t, 1H, 9-H), 5.47 (m, 1H, 3-H) ppm; 13C NMR (CDCl3): ꢃ ˆ 147.9 (C-1), 145.9
(C-14), 131.3 (C-2), 128.6 (C-9), 124.9 (C-3), 110.2/109.6 (C-15, C-17), 91.9 (C-10), 61.7 (C-11),
44.3/43.8) (C-5, C-6), 34.0 (C-4), 27.4/25.1 (C-7, C-8), 21.3/19.8 (3ÂCH3, C-12, C-13, C-16) cmꢀ1
;
‡
MS: m/z (r.I.) ˆ 246 (M , 6), 231 (1), 228 (1), 215 (1), 213 (2), 204 (2), 200 (1), 188 (5), 187 (10),
145 (36), 133 (100), 119 (36), 105 (60), 91 (63), 41 (68).
Acknowledgements
The authors are grateful to Mag. Dr. I. Piringer for valuable discussions, Mr. V. Hausmann and Mr.
È
W. Hoppner (chief perfumers of Dragoco, Vienna) for the olfactoric evaluation, and Dragoco,
Vienna, for interest in this study.
References
[1] Froese A (1997) Diploma thesis, University of Vienna
[2] Buchbauer G, Spreitzer H, Koller U (1997) Monatsh Chem 128: 619
[3] Buchbauer G, Spreitzer H, Zechmeister-Machhart F, Haunschmidt C, Troscher F (1996) Monatsh
È
Chem 127: 747
[4] Naipawer RE, Easter WM (1977) US Patent: 4052341
[5] Buchbauer G, Lebada P, Wiesinger L, Weiû-Greiler P, Wolschann P (1997) Chirality 9: 380
[6] Krotz A, Helmchen G (1990) Tetrahedron Asymmetry 1: 537
[7] Dworan E, Buchbauer G (1981) Chem Ber 114: 2357
[8] Corey EJ, Hartmann R, Vatakencherry PA (1962) J Am Chem Soc 84: 2611
[9] Fanta WI, Erman WF (1972) J Org Chem 37: 1624
[10] Still WC, Gennari C (1983) Tetrahedron Lett 24: 4405
[11] Naipawer RE, Purzycki KL, Shaffer GW, Erickson RE (1981) In: Mookherjee BD, Mussinan CJ
(eds) Essential Oils. Allured Publ Corp, Wheaton, Illinois, pp 105
[12] Buchbauer G, Hillisch A, Mraz K, Wolschann P (1994) Helv Chim Acta 77: 2286
[13] Buchbauer G, Zechmeister-Machhart F, Weiû-Greiler P, Wolschann P (1997) Arch Pharm 330: 112
Received December 11, 1997. Accepted December 17, 1997