Analogues of α-campholenal (=(1R)-2,2,3-trimethylcyclopent-3-ene-1- acetaldehyde) as building blocks for (+)-β-necrodol (=(1S,3S)-2,2,3- trimethyl-4-methylenecyclopentanemethanol) and sandalwood-like alcohols

Article abstract of DOI:10.1002/hlca.200690236

To complete our panorama in structure-activity relationships (SARs) of sandalwood-like alcohols derived from analogues of α-campholenal (=(1R)-2,2,3-trimethylcyclopent-3-ene-1-acetaldehyde), we isomerized the epoxy-isopropyl-apopinene (-)-2d to the corresponding unreported α-campholenal analogue (+)-4d (Scheme 1). Derived from the known 3-demethyl-α-campholenal (+)-4a, we prepared the saturated analogue (+)-5a by hydrogenation, while the heterocyclic aldehyde (+)-5b was obtained via a Bayer-Villiger reaction from the known methyl ketone (+)-6. Oxidative hydroboration of the known α-campholenal acetal (-)-8b allowed, after subsequent oxidation of alcohol (+)-9b to ketone (+)-10, and appropriate alkyl Grignard reaction, access to the 3,4-disubstituted analogues (+)-4f,g following dehydration and deprotection. (Scheme 2). Epoxidation of either (+)-4b or its methyl ketone (+)-4h, afforded stereoselectively the trans-epoxy derivatives 11a,b, while the minor cis-stereoisomer (+)-12a was isolated by chromatography (trans/cis of the epoxy moiety relative to the C₂ or C₃ side chain). Alternatively, the corresponding trans-epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from trans-epoxy aldehyde (+)-11a or by stereoselective epoxidation of the α-campholenol (+)-15a or of its acetate (-)-15b, respectively. Their cis-analogues were prepared starting from (+)-12a. Either (+)-4h or (-)-11b, was submitted to a Bayer-Villiger oxidation to afford acetate (-)-16a. Since isomerizations of (-)-16 lead preferentially to β-campholene isomers, we followed a known procedure for the isomerization of (-)-epoxyverbenone (-)-2e to the norcampholenal analogue (+)-19a. Reduction and subsequent protection afforded the silyl ether (-)-19c, which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)-20c. Further oxidation and epimerization furnished the trans-ketone (-)-17a, a known intermediate of either (+)-β-necrodol (=(+)-(1S,3S)-2,2,3-trimethyl-4-methylenecyclopentanemethanol; 17c) or (+)-(Z)-lancifolol (=(1S,3R,4Z)-2,2,3-trimethyl-4-(4-methylpent-3-enylidene) cyclopentanemethanol). Finally, hydrogenation of (+)-4b gave the saturated cis-aldehyde (+)-21, readily reduced to its corresponding alcohol (+)-22a. Similarly, hydrogenation of β-campholenol (=2,3,3-trimethylcyclopent-1-ene- 1-ethanol) gave access via the cis-alcohol rac-23a, to the cis-aldehyde rac-24.

Full text of DOI:10.1002/hlca.200690236

2638
Helvetica Chimica Acta – Vol. 89 (2006)
Analogues of a-Campholenal (=(1R)-2,2,3-Trimethylcyclopent-3-ene-1-
acetaldehyde) as Building Blocks for (+)-b-Necrodol (=(1S,3S)-2,2,3-
Trimethyl-4-methylenecyclopentanemethanol) and Sandalwood-like
Alcohols1)
by Christian Chapuis*, Michel Barthe, Carole Cantatore, Christine Saint-LØger, and Patrick Wyss
Firmenich SA, Corporate R & D Division, P. O. Box 239, CH-1211 Geneva 8
Dedicated to Dr. Karl-Heinz Schulte-Elte2)
To complete our panorama in structure–activity relationships (SARs) of sandalwood-like alcohols
derived from analogues of a-campholenal (=(1R)-2,2,3-trimethylcyclopent-3-ene-1-acetaldehyde), we
isomerized the epoxy-isopropyl-apopinene (ꢀ)-2d to the corresponding unreported a-campholenal ana-
logue (+)-4d (Scheme 1). Derived from the known 3-demethyl-a-campholenal (+)-4a, we prepared the
saturated analogue (+)-5a by hydrogenation, while the heterocyclic aldehyde (+)-5b was obtained via a
Bayer-Villiger reaction from the known methyl ketone (+)-6. Oxidative hydroboration of the known a-
campholenal acetal (ꢀ)-8b allowed, after subsequent oxidation of alcohol (+)-9b to ketone (+)-10, and
appropriate alkyl Grignard reaction, access to the 3,4-disubstituted analogues (+)-4f,g following dehy-
dration and deprotection. (Scheme 2). Epoxidation of either (+)-4b or its methyl ketone (+)-4h, afforded
stereoselectively the trans-epoxy derivatives 11a,b, while the minor cis-stereoisomer (+)-12a was isolated
by chromatography (trans/cis of the epoxy moiety relative to the C2 or C3 side chain). Alternatively, the
corresponding trans-epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from
trans-epoxy aldehyde (+)-11a or by stereoselective epoxidation of the a-campholenol (+)-15a or of its
acetate (ꢀ)-15b, respectively. Their cis-analogues were prepared starting from (+)-12a. Either (+)-4h
or (ꢀ)-11b, was submitted to a Bayer-Villiger oxidation to afford acetate (ꢀ)-16a. Since isomerizations
of (ꢀ)-16 lead preferentially to b-campholene isomers, we followed a known procedure for the isomer-
ization of (ꢀ)-epoxyverbenone (ꢀ)-2e to the norcampholenal analogue (+)-19a. Reduction and subse-
quent protection afforded the silyl ether (ꢀ)-19c, which was stereoselectively hydroborated under oxida-
tive condition to afford the secondary alcohol (+)-20c. Further oxidation and epimerization furnished the
trans-ketone (ꢀ)-17a, a known intermediate of either (+)-b-necrodol (=(+)-(1S,3S)-2,2,3-trimethyl-4-
methylenecyclopentanemethanol; 17c) or (+)-(Z)-lancifolol (=(1S,3R,4Z)-2,2,3-trimethyl-4-(4-methyl-
pent-3-enylidene)cyclopentanemethanol). Finally, hydrogenation of (+)-4b gave the saturated cis-alde-
hyde (+)-21, readily reduced to its corresponding alcohol (+)-22a. Similarly, hydrogenation of b-campho-
lenol (=2,3,3-trimethylcyclopent-1-ene-1-ethanol) gave access via the cis-alcohol rac-23a, to the cis-alde-
hyde rac-24.
1
)
Presented in part at the ꢀXVth Int. Conf. Organomet. Chem.ꢁ, 9–14 August 1992, Warsaw, Poland;
ꢀColgate Annual Symposiumꢁ, 29–30 May 1996, Leuwen, Belgium; ꢀXIth European Symposium on
Quantitative SARꢁ, 1–6 Sept. 1996, Lausanne Switzerland, abstract P55-A; University of Leipzig, 22
November 1996, Germany.
2
)
Retired from Firmenich SA since February 1994.
ꢂ 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
2639
Introduction. – We have already described the synthesis of a-campholenal ana-
logues [1], necessary for both the building of a large database of new sandalwood-
like alcohols, and the validation of a structure–activity relationship (SAR) model
based on an olfactive comparison of their enantiomers. To pursue with the second chap-
ter of this study, which shall compare, complete, and refine models (see Bc,d in [2]3))
resulting from superimposition (see A in [3]), we now whish to present the preparation
of some new key starting materials.
Results and Discussion. – Epoxidation of a-pinene analogues (ꢀ)-1 [1][4] allows, by
two independent pathways, the transformation of the corresponding epoxy derivatives
(ꢀ)-2, either to the fencholenal analogues (+)-3b,c [5][6] or to the a-campholenal ana-
logues (+)-4a–c [1][6][7] (Scheme 1). We thus completed our structure collection by
oxidation of the known isopropyl apopinene (ꢀ)-1d4) [8] (AcO2H, toluene; 70%) to
the unreported epoxy derivative (ꢀ)-2d. Further isomerization (ZnCl2, toluene;
26%) afforded, after an efficient distillation, aldehyde (+)-4d, an analogue of a-cam-
pholenal (=(1R)-2,2,3-trimethylcyclopent-3-ene-1-acetaldehyde). Interested in inves-
tigating the electronic or H-bond acceptor influence on receptor(s) interactions5)
when the unsaturation is situated in the lipophilic cyclic part of the molecule, we
chose to hydrogenate aldehyde (+)-4a to the corresponding saturated aldehyde (+)-
5a (H2, 5% Pd/C, EtOH; 88%), to avoid stereochemical complications resulting from
a supplementary substituent.
Also curious with respect to the role played by the lipophilicity, we prepared the
oxaanalogue (+)-5b via a Bayer-Villiger oxidation (MCPBA, CH2Cl2; 98%) of the
known ketone (+)-66) [10] (Scheme 1). The resulting acetate (+)-7a was saponified
(KOH, H2O, EtOH; 63%), and the corresponding alcohol (+)-7b was oxidized
(PCC, CH2Cl2; 55%) to (+)-5b.
Although we had already reached some conclusions about the steric influence of
the substitutions in either position C(3) or C(4) of (+)-4a and analogues, we were
also interested in preparing analogues with substitution in both positions. Accordingly,
the known acetal (ꢀ)-8b [11a] was submitted to a stereoselective hydroboration
(BH3·Me2S, THF, NaOH, H2O2; 98%) (Scheme 2). The resulting secondary alcohol
G
(+)-9b was then oxidized (PCC, CH2Cl2; 77%) to ketone (+)-10, prior to either a
Me (98%) or Et (96%) Grignard addition affording stereoselectively the tertiary alco-
hols (+)-9f,g. Further dehydration (P2O5, toluene; 98%) furnished the unsaturated ace-
3
)
)
)
See the conclusion in [3].
[a]2D0 =ꢀ29.6 (c=1.0, EtOH).
4
5
At Givaudan AG, Bieri and co-workers identified endogenous olfactory receptors present in rat pri-
mary olfactory receptor neurons, for which activation was dependent on the presence of a rigidifying
C=C bond (or a cyclopropane ring of similar electronic density) in the side chain of a same class of
olfactively active a-campholenal-derived hydroxy-substituted agonists. Neither the typical sandal-
wood-like (3a, 5a)-androst-16-en-3-ol nor the octanal, as negative control, activated these receptors
[9]. Their conclusions are unfortunately based on racemic material. We are indebted to the main
author for this confirmation.
)
a2D0 =+10.4. 13C-NMR: 21.9 (q); 24.3 (t); 27.5 (q); 29.9 (q); 31.8 (t); 43.0 (t); 48.1 (d); 64.8 (t); 81.6 (s);
208.4 (s); herbaceous. (ꢀ)-(R)-6: a2D0 =ꢀ10.7; phenolic, urine, aromatic, artemisia.
6

2640
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 1
a)AcO2H, AcOH, NaHCO3, toluene; or 30% H2O2 soln., NaOH, MeOH. b) HBr, Et2O, then
A
t
AgNO3, BuOH. c) ZnBr2, toluene, 1108. d) H2, 5% Pd/C, EtOH. e) MCPBA (3-chloroperbenzoic
acid), CH2Cl2, 408. f) KOH, H2O, EtOH, 858. g) PCC (pyridinium chlorochromate), CH2Cl2.
tals (+)-8f,g, which were readily hydrolyzed to the corresponding aldehydes (+)-4f7),g
(10% aqueous HCl solution, THF; 81–40%). By epoxidizing the commercially avail-
A
that the diastereoisomers possessing the O-atom cis with respect to the side chain
were stronger in odor than those with a corresponding trans-epoxy moiety [13a].
Since this synthetic approach is restricted to mono-unsaturated skeletons as starting
materials, often as mixtures of diastereoisomers in their branched saturated side
chain, we were only interested in preparing a-campholenal analogues (+)-11a9)
[11b][14] and (+)-12a, already possessing the appropriate epoxy configuration, for fur-
7
)
)
)
Independently, Schulze and co-workers followed another approach for the preparation of 4f, which,
like 4a, is of undefined absolute configuration in [12].
8
9
2-Methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol (=b,2,2,3-tetramethylcyclopent-3-ene-1-
butanol), chiroptical properties not reported.
[a]2D0 =+6.8 (c=1.1, EtOH). 13C-NMR: 13.2 (q); 19.0 (q); 20.6 (q); 32.0 (t); 37.3 (d); 41.3 (s); 44.2 (t);
62.1 (d); 68.3 (s); 202.0 (s); odorless.

Helvetica Chimica Acta – Vol. 89 (2006)
2641
ther aldol condensations. Epoxidation of a-campholenal (+)-4b (AcO2H, AcONa,
CH2Cl2; 78% [11b]) afforded a 95 :5 mixture of (+)-11a/(+)-12a, separated by column
chromatography (CC) on SiO2. Their independent reductions (NaBH4, MeOH) gave
the corresponding unreported alcohols (+)-13a (80%) and (+)-14a (83%), while fur-
ther esterification (Ac2O, py) afforded the epoxy acetates (+)-13b10) [13] (86%) and
(+)-14b (74%), respectively. Since we could not directly and satisfactorily reverse
the stereoselectivity of the epoxidation, starting from either (+)-4b, (+)-15a or (ꢀ)-
15b [1][15][16]11), we also unsuccessfully attempted an intramolecular epoxidation
(30% H2O2 solution, THF or tBuOOH, (PhCH2)Me3
NOH, THF, 208) via the trimellityl
A
anhydride monoester (ꢀ)-15c, obtained from the corresponding commercially availa-
ble acyl chloride and (+)-15a (AgCN, toluene 1108; 29%).
The known secondary alcohol (+)-15d12) [18] was oxidized to the corresponding
known ketone (+)-4h [18a][19], prior to further stereoselective epoxidation to (ꢀ)-
11b (MCPBA, CH2Cl2; 83%; 91% trans) [13a]. Alternatively, either of the methyl
ketones (+)-4h and (ꢀ)-11b was treated with an excess of MCPBA in refluxing
CH2Cl2 to afford the corresponding epoxyacetate (ꢀ)-16a (33%), which was saponified
(LiOH·H2O, THF/H2O 5 :2, 82%) to the corresponding primary alcohol (ꢀ)-16b, prior
t
to be protected as its BuMe2
N
G
71%)13). This approach, towards a potential intermediate of (+)-b-necrodol
(=(1S,3S)-2,2,3-trimethyl-4-methylenecyclopentanemethanol; (+)-17c) [16b][20]14)
via diastereoselective isomerization of epoxides 16 was nevertheless not realized, due
to the concurrent Nametkin rearrangement, leading efficiently to b-campholenic deriv-
atives [5d].
Starting from the known a-campholenic enamines (+)-18a,b15) [3][22], we also pre-
pared the a-norcampholenal (+)-19a16) by photo-oxygenation (Rose Bengal, MeOH,
H2O, AcONa, O2, hv; 35%)17). However, since this method gave partially racemized
10
)
)
[a]2D0 =+6.1, (c=1.3, EtOH). 13C-NMR: 13.2 (q); 18.7 (q); 20.8 (q); 21.0 (q); 28.6 (t); 32.0 (t); 39.6
(d); 41.3 (s); 62.3 (d); 63.8 (t); 68.7 (s); 171.1 (s); fruity, ester. (ꢀ)-13b: [a]2D0 =ꢀ6.2, (c=1.5, EtOH);
cedar, camphor.
11
(+)-15a (MCPBA, CH2Cl2, 208; 84%) afforded a 73 :27 mixture of (+)-13a/(+)-14a. Starting from
either (ꢀ)-8b or (ꢀ)-15b, Schulze and co-workers obtained up to 11–19% of cis-epoxy derivatives
using AcO2H/Na2CO3 in toluene at 1108 [13a]. For X-ray analyses of trans-epoxides, see
[11a][17a]. For cis-epoxides of fencholenic derivatives, see [5b][17b].
12
13
)
)
a2D0 =+9.7. 13C-NMR: 12.6 (q); 19.7 (q); 23.2 (q); 25.6 (q); 35.8 (t); 39.9 (t); 47.0 (s); 47.6 (d); 67.9 (d);
121.8 (d); 148.5 (s); spicy, slightly perillic.
Direct oxidation of a-campholenal (+)-4b (2.2 equiv. of MCPBA, CH2Cl2, 408; 60%) afforded epoxy
acid (+)-11c, alternatively also obtained in 39% yield by AgNO3/NaOH oxidation of (+)-11a.
For the synthesis of (ꢀ)-a-necrodol and epimers, see [16a], then [21].
14
15
)
)
(+)-(R,E)-18b: aD20 =+13.6. 13C-NMR: 13.0 (q); 20.3 (t); 24.5 (t); 25.1 (t); 25.4 (2t); 37.2 (t); 47.7 (s);
50.3 (2t); 53.1 (d); 101.8 (d); 121.8 (d); 140.6 (d); 148.4 (s). (ꢀ)-(S,E)-18b: a2D0 =ꢀ18.8.
Our initial interest in both enantiomers of this aldehyde was motivated by the opening (AlCl3/
16
)
LiAlH4, Et2O; 95–98%) of their acetals derived from optically pure butane-2,3-diol, to afford
A
oxa-sandalwood-like alcohols of well established configuration in the side chain. These twenty
years old results shall be published in due course.
We are indebted to Drs. M. Bortolussi and J. Vaillant from De Laire Cie for kindly providing us (13th
October 1987) with the detailed Exper. Part of their unpublished photo-oxygenation of (+)-18a to
(+)-19a.
17
)

2642
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 2
a) Ethylene glycol, TsOH. b) BH3·Me2
A
R1MgX, Et2
AHCTREUNG
MeOH. i) Ac2O, pyridine j) Morpholine or piperidine, TsOH, cyclohexane. k) MeOH, H2O, Rose
t
Bengal, AcONa, hn, O2. l) Me2 BuSiCl, 1H-imidazole, DMF or CH2Cl2. m) MeONa, MeOH, 658. n)
TiCl4ZnCH2Br2, THF, CH2Cl2. o) Bu4NF, THF. p) H2, 10% Pd/C, AcOEt.
A

Helvetica Chimica Acta – Vol. 89 (2006)
2643
material, we preferred the known rearrangement of epoxy-verbenone (ꢀ)-2e [23],
using the protocol of Thomas-Bessi›re-ChrØtien and co-workers (ZnBr2, toluene;
47%) [24]18). This aldehyde was either immediately reduced (LiAlH4, Et2
O, 94%) to
G
the corresponding primary alcohol (ꢀ)-19b [25]19) or submitted to a hydroboration
(BH3·Me2
S, THF; 72%) [15b][26] to stereoselectively afford diol (+)-20a20). For an
U
alternative approach to (+)-b-necrodol, we initially protected the primary OH function
with pivalic acid to afford (+)-20b (tBuCO2
H, dicyclohexylcarbodiimide (DCC), N,N-
dimethylpyridin-4-amine (DMAP), CH2Cl2; 74%), but finally, preferred a BuMe2
protection (tBuMe2
SiCl, 1H-imidazole, DMF, ꢀ308 to 208; 95%) to give (+)-20c21).
An alternative and more logical access to (+)-20c was via protection (tBuMe2
SiCl,
AHCTREUNG
t
A
AHCTREUNG
AHCTREUNG
1H-imidazole, DMF, ꢀ308 to 208; 40%) of (ꢀ)-19b to (ꢀ)-19c, followed by hydrobora-
tion and oxidation (BH3·SMe2, CH2Cl2, then H2O2; 22%). Further oxidation (PCC,
CH2Cl2; 80%) gave access to the known intermediate (ꢀ)-17a [27], after epimerization
at the Me-substituted a-position (MeONa, MeOH; 87%) [20d]. The remaining steps
consisted in a methylenation reaction (TiCl4/CH2Br2/Zn, THF, CH2Cl2; 51%) [20b], fol-
lowed by desilylation of (+)-17b (Bu4NF, THF; 93%) to the nonnatural (+)-b-necrodol
G
(+)-17c22). We completed our work by hydrogenating (+)-a-campholenal (+)-4b (H2,
10%Pd/C, AcOEt; 78%) to the known but uncharacterized saturated cis-aldehyde (+)-
21 [29]. Its reduction (LiAlH4, Et2O; 95%) afforded the known but also uncharacter-
E
ized cis-alcohol (+)-22a [16c][30]. Alternatively, this latter was also obtained by a ster-
eoselective hydrogenation of alcohol (+)-15a (H2, 10%Pd/C, AcOEt; 90%; >94%
cis)23), prior to further re-oxidation (PCC, CH2Cl2; 98%) to aldehyde (+)-2124). Simi-
larly, hydrogenation (10% Raney-Ni, 90 bar, EtOH; 53%)25) of b-campholenol
(=2,3,3-trimethylcyclopent-1-ene-1-ethanol) [31] gave the unreported saturated cis-
analogue rac-23a, which was oxidized (PCC, CH2Cl2; 98%) to the corresponding cis-
aldehyde rac-24.
18
)
)
The absolute configuration of (ꢀ)-2e is erroneously depicted in the French paper.
Its epoxidation (MCPBA, CH2Cl2, 208; 72%) afforded a 1:1 mixture of (ꢀ)-16b and 4,4,5-trimethyl-
6-oxabicyclo[3.1.0]hexane-1-methanol. Similarly, (ꢀ)-19c was epoxidized (MCPBA, CH2Cl2, 208;
77%) to (ꢀ)-16c. For rac-19b, see [26].
19
20
21
)
)
For the corresponding stereoisomer, see [27].
Although being a multi-step procedure, (+)-20c may alternatively be obtained via a bis-protection/
regio-monodeprotection process (tBuMe2
N
N
22
)
Isolated from the defensive spray of the red-lined carrion beetle Necrodes surinamensis [28], natural
(ꢀ)-b-necrodol may be similarly obtained from the antipodal (+)-epoxy-verbenone (+)-2e
(a2D0 =+119.2) via (ꢀ)-20a ([a]2D0 =ꢀ30.6, (c=1.0, EtOH)). The report [16b] prompted us to stop
our efforts in that direction, as well as in chemical-yields optimization.
23
)
An identical stereoselectivity was observed by hydrogenation of alcohol (+)-15a under various con-
ditions such as: Crabtreeꢁs, [Ir(cod)(py)(PCy3)]+(PF6)ꢀ in CH2
N
N
hexane (93% cis); Pearlmanꢁs, 20% Pd(OH)2/C in cyclohexane (93% cis); Raney-Ni in cyclohexane
(94% cis) or PtO2 in cyclohexane (94% cis).
Acylation of (+)-22a (Ac2O, pyridine, 95%) afforded the known but uncharacterized acetate (+)-
22b [30].
With 10% Pd/C in AcOH under 90 bar H2, a 5 :3 cis/trans mixture of rac-23a was obtained via dou-
ble-bond migration, contaminated by 20% of isomerized alcohol rac-22a. Acetylation of rac-23a
(Ac2O, pyridine; 56%) afforded rac-23b.
24
25
)
)

2644
Helvetica Chimica Acta – Vol. 89 (2006)
Conclusions. – In connection with SAR studies of sandalwood-like alcohols derived
from a-campholenal (+)-4b, we prepared the sterically demanding unreported ana-
logue (+)-4d, starting from the known isopropyl-a-apopinene derivative (ꢀ)-1d. The
new analogues (+)-5a,b should help us in comparing both the lipophilicity and H-
bond influence, in the absence of steric effects, between their appropriate derivatives,
with those derived from the dimethyl aldehyde (+)-4a. Oxidative hydroboration of the
protected a-campholenal acetal (ꢀ)-8b allowed, after oxidation to ketone (+)-10, the
introduction of a supplementary alkyl substituent onto the C=C bond of the a-campho-
lenal analogue (+)-4f,g, via a Grignard reaction, dehydration, and deprotection
sequence. The stereoselective epoxidation of either a-campholenal (+)-4b or its corre-
sponding alcohol (+)-15a, permitted the synthesis of the main trans-epoxy-aldehyde
(+)-11a, as well as the isolation of the minor cis-stereoisomers (+)-12a and (+)-14a.
Over-oxidation of methyl ketones (+)-4h or (ꢀ)-11b, with MCPBA afforded the
trans-epoxy ester (ꢀ)-16a. The known ZnBr2 isomerization of epoxyverbenone (ꢀ)-
1e delivered the norcampholenal analogue (+)-19a. Its corresponding alcohol (ꢀ)-
19b was protected as its silyl ether (ꢀ)-19c, prior to an oxidative hydroboration. The
resulting secondary alcohol (+)-20c was oxidized, thus allowing isolation of epimerized
ketone (ꢀ)-17a. This latter was then transformed to (+)-b-necrodol (+)-17c after
appropriate methylenation and deprotection. Finally, hydrogenation of b-campholenol
furnished the cis-alcohol rac-23a, prior to oxidation to the corresponding cis-aldehyde
rac-24. These new derivatives, available in both enantiomeric series, shall help us to
investigate the influence of the lipophilic part in sandalwood-like alcohols derived
from campholenal analogues.
Experimental Part
General. For optical purity of the starting materials and generalities, see [1].
(ꢀ)-(1R,2R,3S,5R)-2,3-Epoxy-2-isopropyl-6,6-dimethylbicyclo[3.1.1]heptane (=(1R,2R,4S,6R)-7,7-
Dimethyl-2-(1-methylethyl)-3-oxatricyclo[4.1.1.O2,4]octane; (ꢀ)-2d). As described in the General Proce-
dure A of [1]: (ꢀ)-2d (70%). B.p. 808/0.31 mbar. [a]2D0 =ꢀ49.3 (c=1.0, EtOH). IR: 2967, 2919, 2873,
1
1470, 1384, 1367, 1240, 1055, 1039, 919, 874. H-NMR: 0.81 (d, J=7, 3 H); 0.90 (s, 3 H); 0.95 (d, J=7,
3 H); 1.30 (s, 3 H); 1.64 (d, J=9, 1 H); 1.72 (m, 1 H); 1.79 (sept., J=7, 1 H); 1.87 (m, 1 H); 2.0 (m, 2
H); 2.11 (t, J=6, 1 H); 3.23 (d, J=5, 1 H). 13C-NMR: 16.8 (q); 17.2 (q); 20.4 (q); 25.7 (t); 26.9 (q);
27.8 (t); 30.8 (d); 40.1 (d); 40.6 (s); 42.8 (d); 55.1 (d); 66.3 (s). MS: 180 (8, M+C), 165 (32), 137 (35),
121 (40), 111 (52), 95 (90), 83 (56), 69 (84), 67 (78), 55 (70), 43 (83), 41 (100). Minty, terpenes.
(+)-(1R)-3-Isopropyl-2,2-dimethylcyclopent-3-ene-1-acetaldehyde ((+)-4d). As described in the
General Procedure B of [1], (ꢀ)-2d afforded, after 30 min, quantitatively a 56 :44 mixture of (+)-4d/
(ꢀ)-(1S,2R)-2-isopropyl-6,6-dimethylbicyclo[3.1.1]heptan-3-one. Purification by distillation through a
10 cm Vigreux column: pure (+)-4d (26%), the bicycloheptanone (32%).
Data of (+)-4d: B.p. 1008/3.8 Torr. [a]D20 =+10.4 (c=0.95, CCl4). IR: 2959, 1727, 1466, 1364. 1H-
NMR: 0.82 (s, 3 H); 1.04 (d, J=7, 3 H); 1.05 (s, 3 H); 1.07 (d, J=7, 3 H); 1.91 (m, 1 H); 2.23 (m, 2 H);
2.38 (m, 1 H); 2.5 (m, 2 H); 5.32 (br. t, 1 H); 9.80 (t, J=4, 1 H). 13C-NMR: 20.9 (q); 24.1 (q); 24.4 (q);
26.0 (q); 26.3 (d); 35.5 (t); 44.6 (d); 45.0 (t); 47.9 (s); 119.1 (d); 159.1 (s); 203.1 (d). MS: 180 (1, M+C),
136 (45), 121 (100), 105 (11), 95 (20), 91 (11), 67 (12), 41 (17).
(ꢀ)-(1S,2R)-2-Isopropyl-6,6-dimethylbicyclo[3.1.1]heptan-3-one: B.p. 608/2.7 Torr. [a]2D0 =ꢀ58.3,
(c=1.2, CHCl3). IR: 2957, 1712, 1467, 1411, 1386, 1369, 1324, 1150, 1040. 1H-NMR: 0.82 (d, J=7, 3
H); 0.88 (s, 3 H); 1.00 (d, J=7, 3 H); 1.27 (d, J=12, 1 H); 1.34 (s, 3 H); 2.06 (m, 1 H); 2.14 (dt, J=2,

Helvetica Chimica Acta – Vol. 89 (2006)
2645
7, 1 H); 2.30 (m, 1 H); 2.34 (m, 1 H); 2.42 (dd, J=2, 16, 1 H); 2.48 (m, 1 H); 2.62 (dt, J=2, 16, 1 H). 13C-
NMR: 20.1 (2q); 21.6 (q); 26.5 (q); 28.4 (d); 30.3 (t); 38.0 (d); 39.6 (d); 39.8 (s); 45.1 (t); 57.4 (t); 214.0 (s).
MS: 180 (13, M+C), 137 (8), 111 (68), 95 (21), 83 (78), 69 (100), 55 (69), 41 (78).
(+)-(1R)-2,2,3,4-Tetramethylcyclopent-3-ene-1-acetaldehyde ((+)-4f). A mixture of acetal (+)-8f
(32.6g, 155 mmol) in THF (325 ml) and 10% aq. HCl soln. (239 ml) was heated at 508 for 2.5 h. The
cold soln. was extracted with Et2O. The org. phase was washed with sat. aq. NaHCO3 soln. and H2O,
A
dried (Na2SO4), concentrated, and purified by distillation through a 15 cm Vigreux column: pure (+)-
4f (81%). B.p. 418/0.8 mbar. [a]2D0=+25.3. IR: 2957, 1727, 1470. H-NMR: 0.76 (s, 3 H); 0.98 (s, 3 H);
1
1.51 (br. s, 3 H); 1.59 (br. s, 3 H); 1.94 (m, 1 H); 2.20 (m, 1 H); 2.35 (m, 1 H); 2.38 (dd, J=4, 10, 1 H);
2.52 (ddd, J=4, 7, 10, 1 H); 9.80 (t, J=4, 1 H). 13C-NMR: 9.5 (q); 14.1 (q); 20.1 (q); 26.1 (q); 41.4 (t);
42.8 (d); 45.1 (t); 48.1 (s); 128.8 (s); 138.5 (s); 203.3 (d). MS: 166 (7, M+C), 151 (11), 122 (100), 109
(67), 107 (81), 105 (12), 91 (28), 81 (22), 41 (27). Green, fatty, floral, herbal, cocoa, camphoraceous, pun-
gent.
(+)-(1R)-4-Ethyl-2,2,3-trimethylcyclopent-3-ene-1-acetaldehyde ((+)-4g). As described for (+)-4f.
(+)-4g (40%). B.p. 658/0.7 mbar. [a]2D0 =+22.2 (c=1.0, CHCl3). IR: 2961, 2714, 1727, 1462, 1361. H-
1
NMR: 0.76 (s, 3 H); 0.97 (t, J=7, 3 H); 0.98 (s, 3 H); 1.50 (br. s, 3 H); 1.93 (m, 1 H); 2.01 (q, J=7, 2
H); 2.18 (m, 1 H); 2.37 (m, 2 H); 2.52 (ddd, J=4, 7, 16, 1 H); 9.81 (t, J=4, 1 H). 13C-NMR: 9.4 (q);
12.6 (q); 20.1 (q); 21.6 (t); 26.0 (q); 38.4 (t); 42.8 (d); 45.1 (t); 48.1 (s); 134.3 (s); 137.7 (s); 203.3 (d).
MS: 180 (10, M+C), 165 (8), 136 (70), 121 (100), 105 (14), 91 (18), 41 (20).
(+)-(1R)-2,2-Dimethylcyclopentane-1-acetaldehyde ((+)-5a). A soln. of (+)-4a (1380 mg, 10 mmol)
in EtOH (10 ml) was hydrogenated at 1 atm H2 over 5% Pd/C (70 mg). Filtration, concentration, and
bulb-to-bulb distillation afforded pure (+)-5a (88%). B.p. 618/10 mbar. a2D0 =+8.9. IR: 2955, 2716,
1727, 1466, 1367. 1H-NMR: 0.77 (s, 3 H); 1.00 (s, 3 H); 1.32 (m, 1 H); 1.46 (m, 2 H); 1.60 (m, 1 H);
1.64 (m, 1 H); 1.90 (m, 1 H); 1.97 (m, 1 H); 2.18 (ddd, J=4, 10, 16, 1 H); 2.48 (ddd, J=2, 4, 16, 1 H);
9.78 (t, J=4, 1 H). 13C-NMR: 21.4 (t); 21.9 (q); 27.7 (q); 30.5 (t); 40.7 (s); 41.2 (t); 43.7 (d); 45.2 (t);
203.2 (d). MS: 140 (5, M+C), 125 (20), 107 (32), 97 (49), 96 (47), 81 (80), 69 (54), 55 (77), 41 (100), 39
(64), 29 (50). Green, aldehydic, camphoraceous.
(ꢀ)-5a: [a]2D0 =ꢀ8.2 (c=1.0, CHCl3).
(+)-(3R)-Tetrahydro-2,2-dimethylfuran-3-acetaldehyde ((+)-5b). As described in the General Proce-
1
dure K of [3]: (+)-5b (55%). B.p. 708/1.3 mbar. a2D0 =+6.5. IR: 2972, 1725, 1368, 1153, 1050, 840. H-
NMR: 1.03 (s, 3 H); 1.26 (s, 3 H); 1.63 (m, 1 H); 2.28 (m, 2 H); 2.41 (dd, J=4, 10, 1 H); 2.54 (ddd,
J=4, 7, 16, 1 H); 3.83 (m, 2 H); 9.81 (t, J=4, 1 H). 13C-NMR: 22.4 (q); 27.3 (q); 31.9 (t); 42.1 (d); 45.2
(t); 64.9 (t); 81.3 (s); 201.2 (d). MS: 142 (0, M+C), 127 (52), 99 (11), 83 (21), 59 (72), 55 (63), 43 (100).
(ꢀ)-5b: a2D0 =ꢀ7.0.
(+)-(3R)-Tetrahydro-2,2-dimethylfuran-3-ethanol Acetate ((+)-7a). MCPBA (48.3 g, 0.15 mol) was
added to a soln. of ketone (+)-6 (17.45 g, 0.103 mol) in CH2Cl2 (175 ml). The mixture was refluxed for
92 h, while three successive portions of MCPBA (6.44g, 20 mmol) were added after 28, 52, and 68 h.
The cold mixture was washed with H2O, 15% aq. NaOH soln., and H2O to neutrality, dried (MgSO4), con-
centrated, and purified by CC (SiO2, 80 g toluene/AcOEt 95 :5): pure (+)-7a (98%). B.p. 1008/0.14 mbar.
a2D0 =+5.2. IR: 2996, 1734, 1520, 1430. 1H-NMR: 1.02 (s, 3 H); 1.25 (s, 3 H); 1.50 (m, 1 H); 1.66 (m, 1 H);
1.79 (m, 2 H); 2.06 (s, 3 H); 2.12 (m, 1 H); 3.78 (q, J=7, 1 H); 3.86 (dt, J=4, 7, 1 H); 4.11 (m, 2 H). 13C-
NMR: 21.0 (q); 22.0 (q); 27.4 (q); 29.4 (t); 31.8 (t); 45.4 (d); 63.8 (t); 64.9 (t); 81.6 (s); 171.1 (s). MS: 186
(1, M+C), 171 (10), 129 (12), 111(19), 86 (9), 68 (24), 43 (100). Tyres.
(ꢀ)-7a: a2D0 =ꢀ2.1. Spicy, sulfury.
(+)-(3S)-Tetrahydro-2,2-dimethylfurane-3-ethanol ((+)-7b). A soln. of (+)-7a (14.95g, 80.4 mmol)
and KOH (16.0 g, 285.3 mmol) in H2O (16 ml) and EtOH (64.3 ml) was heated under reflux for 30
min. The cold soln. was concentrated, then saturated with NaCl, and extracted with toluene. The org.
phase was washed to neutral with brine, dried (Na2SO4), concentrated, and purified by CC (cyclohex-
ane/AcOEt 6 :4 ! 1:1): pure (+)-7b (63%). B.p. 908/0.34 mbar. [a]2D0 =+5.6 (c=0.35, CHCl3). IR:
1
3396, 2931, 1654, 1457, 1368, 1050. H-NMR: 1.02 (s, 3 H); 1.24 (s, 3 H); 1.42 (m, 1 H); 1.63 (m, 1 H);
1.69 (m, 1 H); 1.87 (m, 1 H); 2.12 (m, 1 H); 2.20 (br. s, 1 OH); 3.62 (m, 1 H); 3.75 (m, 2 H); 3.85 (dt,
J=4, 7, 1 H). 13C-NMR: 22.0 (q); 27.4 (q); 31.8(t); 33.4 (t); 45.0 (d); 61.8 (t); 65.0 (t); 81.8 (s). MS:
144 (0, M+C), 129 (85), 111 (18), 86 (23), 68 (55), 59 (95), 55 (44), 43 (100).

2646
Helvetica Chimica Acta – Vol. 89 (2006)
(ꢀ)-7b: a2D0 =ꢀ3.1. Saffron, sulfury, phenolic.
(+)-2-{[(1R)-2,2,3,4-Tetramethylcyclopent-3-en-1-yl]methyl}-1,3-dioxolane ((+)-8f). A soln. of alco-
hol (+)-9f (28.9 g, 127 mmol) in toluene (25 ml) was added dropwise at 08 to a suspension of P2O5 (27 g,
190 mmol) in toluene (38 ml). After 3 h, the temp. was raised to 208, and after a supplementary 1.5 h, the
mixture was poured onto ice and extracted with Et2O. The org. phase was washed to neutral with H2O,
G
dried (Na2SO4), concentrated, and purified by bulb-to-bulb distillation; pure (+)-8f (98%). B.p. 608/0.09
mbar. a2D0 =+20.5. IR: 2954, 1442, 1360, 1147, 1044, 943. 1H-NMR: 0.72 (s, 3 H); 0.97 (s, 3 H); 1.48 (br. s, 3
H); 1.58 (br. s, 3 H); 1.62 (m, 1 H); 1.75 (m, 1 H); 1.86 (m, 1 H); 1.98 (m, 1 H); 2.28 (br. dd, J=7, 12, 1 H);
3.83 (m, 2 H); 3.97 (m, 2 H); 4.88 (dd, J=6,7, 1 H). 13C-NMR: 9.5 (q); 14.1 (q); 19.7 (q); 25.9 (q); 34.3 (t);
41.7 (t); 44.4 (d); 48.1 (s); 64.6 (t); 64.9 (t); 104.8 (d); 128.6 (s); 138.6 (s). MS: 210 (12, M+C), 139 (16), 133
(26), 122 (100), 109 (67), 107 (42), 73 (88). Perspiration, menthol.
(+)-{[(1R)-4-Ethyl-2,2,3-trimethylcyclopent-3-en-1-yl]methyl}-1,3-dioxolane ((+)-8g). As described
for (+)-8f: (+)-8g (98%). B.p. 908/0.26 mbar. [a]2D0 =+16.0 (c=1.0, CHCl3). IR: 2958, 2876, 1463,
1
1410, 1360, 1146, 1089, 1034, 982, 943. H-NMR: 0.72 (s, 3 H); 0.94 (t, J=7, 3 H); 0.97 (s, 3 H); 1.50
(br. s, 3 H); 1.65 (m, 1 H); 1.77 (m, 1 H); 1.86 (m, 1 H); 1.95 (m, 1 H); 2.02 (q, J=7, 2 H); 2.32 (dd,
J=7, 14, 1 H); 3.87 (m, 2 H); 3.99 (m, 2 H); 4.90 (dd, J=4, 6, 1 H). 13C-NMR: 9.4 (q); 12.8 (q); 19.7
(q); 21.6 (t); 25.8 (q); 34.3 (t); 38.6 (t); 44.4 (d); 48.1 (s); 64.6 (t); 64.9 (t); 104.8 (d); 134.5 (s); 137.9
(s). MS: 224 (21, M+C), 153 (19), 147 (19), 136 (100), 123 (78), 121 (61), 107 (18), 73 (82), 45 (33).
(+)-(1S,2S,4R)-4-[(1,3-Dioxolan-2-yl)methyl]-2,3,3-trimethylcyclopentanol ((+)-9b).
BH3·Me2
S (68 ml, 725 mmol) was added dropwise at 08 to a soln. of acetal (ꢀ)-8b (143 g, 723 mmol) in
THF (1.4 l). After an additional hour at 08, 10% aq. NaOH soln. (360 ml), then 30% H2O2 soln. (108
2O and the org. phase washed
A soln. of
AHCTREUNG
ml) were added dropwise at ꢀ108. The mixture was extracted with Et
ACHTREUNG
with H2O to neutrality, dried (Na2SO4), concentrated, and distilled: (+)-9b (98%). B.p. 1208/0.12 mbar.
a2D0 =+47.5. IR: 3422, 2957, 1411, 1367, 1145, 1062, 955, 858. 1H-NMR: 0.54 (s, 3 H); 0.91 (s, 3 H);
0.96 (d, J=7, 3 H); 1.42 (m, 2 H); 1.62 (br. s, 1 OH); 1.72 (m, 2 H); 1.81 (m, 2 H); 1.89 (m, 1 H); 3.83
(m, 2 H); 3.98 (m, 2 H); 4.83 (dd, J=4, 6, 1 H). 13C-NMR: 11.6 (q); 15.7 (q); 25.7 (q); 34.5 (t); 39.4
(t); 43.0 (s); 43.8 (d); 54.0 (d); 64.6 (t); 64.9 (t); 78.3 (d); 104.4 (d). MS: 214 (0.5, M+C), 73 (100), 45
(8). Without character.
(+)-(1R,2S,4R)-4-[(1,3-Dioxolan-2-yl)methyl]-1,2,3,3-tetramethylcyclopentanol ((+)-9f). A soln. of
MeI (45.3 g, 320 mmol) in Et
in Et2O (61 ml) then, a soln. of ketone (+)-10 (52 g, 245 mmol) in Et2
After 1 h at 208, the mixture was poured onto ice/NH4Cl. The mixture was extracted with Et2
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
org. phase was washed with H2O to neutrality, dried (Na2SO4), concentrated, and purified by bulb-to-
bulb distillation: pure (+)-9f (98%). B.p. 1008/0.14 mbar. a2D0 =+31.1. IR: 3508, 2954, 1451, 1369, 1287,
1
1145, 1022, 912. H-NMR: 0.72 (s, 3 H); 0.86 (d, J=7, 3 H); 0.89 (s, 3 H); 1.14 (br. s, 1 OH); 1.26 (s, 3
H); 1.29 (q, J=7, 1 H); 1.56 (m, 3 H); 1.77 (dd, J=8, 12, 1 H); 2.17 (m, 1 H); 3.85 (m, 2 H); 3.97 (m, 2
H); 4.85 (dd, J=4, 6, 1 H). 13C-NMR: 7.0 (q); 15.6 (q); 26.8 (q); 30.6 (q); 34.3 (t); 43.6 (s); 44.3 (d);
47.2 (t); 54.5 (d); 64.7 (t); 64.8 (t); 78.0 (s); 104.5 (d). MS: 228 (0.5, M+C), 157 (16), 73 (100), 43 (23).
Dusty, gasoline.
(+)-(1R,2S,4R)-4-[(1,3-Dioxolan-2-yl)methyl]-1-ethyl-2,3,3-trimethylcyclopentanol ((+)-9g). As
described for (+)-9f, with EtBr: (+)-9b (96%). B.p. 1008/0.11 mbar. a2D0 =+34.8. IR: 3510, 2954, 1464,
1
1367, 1144, 1031, 945, 882. H-NMR: 0.72 (s, 3 H); 0.85 (d, J=7, 3 H); 0.89 (s, 3 H); 0.93 (t, J=7, 3
H); 1.11 (br. s, 1 OH); 1.32 (q, J=7, 2 H); 1.41 (m, 2 H); 1.52 (m, 2 H); 1.78 (dd, J=6, 10, 1 H); 2.19
(dd, J=7, 10, 1 H); 3.85 (m, 2 H); 3.97 (m, 2 H); 4.85 (dd, J=4, 6, 1 H). 13C-NMR: 7.5 (q); 8.6 (q);
15.9 (q); 26.7 (q); 34.4 (t); 35.2 (t); 43.4 (s); 44.2 (t); 44.3 (d); 52.7 (d); 64.7 (t); 64.8 (t); 80.4 (s); 104.4
(d). MS: 242 (0, M+C), 213 (10), 171 (18), 125 (9), 73 (100), 57 (13), 45 (12). Floral, watery.
(+)-(2S,4S)-4-[(1,3-Dioxolan-2-yl)methyl]-2,3,3-trimethylcyclopentanone ((+)-10). As described in
the General Procedure K of [3]: (+)-10 (77%). B.p. 1108/0.22 mbar. a2D0 =+138.0. IR: 2962, 1740, 1371,
1144, 1050. 1H-NMR: 0.63 (s, 3 H); 0.95 (d, J=7, 3 H); 1.12 (s, 3 H); 1.58 (ddd, J =4, 12, 14, 1 H); 1.88
(dd, J=12, 20, 1 H); 1.96 (m, 2 H); 2.03 (m, 1 H); 2.55 (dd, J=10, 20, 1 H); 3.86 (m, 2 H); 3.98 (m, 2
H); 4.88 (dd, J=4, 5, 1 H). 13C-NMR: 7.4 (q); 15.6 (q); 25.7 (q); 33.8 (t); 40.9 (d); 41.6 (s); 41.8 (t);
56.6 (d); 64.7 (t); 65.0 (t); 104.0 (d); 219.2 (s). MS: 212 (2, M+C), 73 (100), 55 (7), 45 (10), 41 (9). Without
character.

Helvetica Chimica Acta – Vol. 89 (2006)
2647
(ꢀ)-1-[(1R,3R,5S)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hex-3-yl]propan-2-one ((ꢀ)-11b). MCPBA
(2.0 g, 12 mmol) was added to a soln. of ketone (+)-4h (1.96 g, 12 mmol) in CH2Cl2 (40 ml). After 2 h,
the mixture was extracted with brine to neutral, dried (Na2SO4), concentrated, and bulb-to-bulb distilled:
pure (ꢀ)-11b (83%). B.p. 1658/0.2 mbar. [a]2D0 =ꢀ1.9, (c=2.2, CHCl3). IR: 2963, 2936, 2873, 1713, 1467,
1444, 1421, 1365, 1241, 1166, 1145, 1046, 919, 845, 732. 1H-NMR: 0.77 (s, 3 H); 1.00 (s, 3 H); 1.25 (dd, J=7,
10, 1 H); 1.33 (s, 3 H); 1.92 (m, 1 H); 2.14 (s, 3 H); 2.15 (m, 2 H); 2.39 (dd, J=2, 10, 1 H). 13C-NMR: 13.2
(q); 18.9 (q); 20.6 (q); 29.9 (q); 32.0 (t); 38.6 (d); 41.2 (s); 44.1 (t); 62.2 (d); 68.4 (s); 208.6 (s). MS: 182 (1,
M+C), 141 (11), 123 (15), 109 (46), 97 (42), 95 (29), 81 (27), 69 (21), 55 (18), 43 (100).
(+)-(1R,3S,5S)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hexane-3-acetic Acid ((+)-11c). MCPBA (5.1 g,
29 mmol) was added in portions at 08 to a soln. of campholenal (+)-4b (4.9 g, 29 mmol) in CH2Cl2
(100 ml). After 4 h at 208, MCPBA (5.1 g, 29 mmol) was added, and the mixture was refluxed for 1 h.
The cold mixture was washed with H2O, 15% aq. NaHSO3 soln., 15% aq. NaOH soln., and H2O to neu-
trality, dried (MgSO4), concentrated, and purified by CC (SiO2, CH2Cl2/Et2O 98 :2) and bulb-to-bulb dis-
G
tillation: pure (+)-11c (60%).
Alternatively, a few drops of 10% aq. NaOH soln. were added to adjust to pH 9.5 a mixture of (+)-
11a (340 mg, 2.0 mmol) and 30% aq. AgNO3 soln. (4.4 ml) in EtOH (16 ml). The mixture was stirred for
3 h at 208 and then filtered. The precipitate was rinsed with 50% hot EtOH/H2O, and the filtrate was con-
centrated and then extracted with CH2Cl2. The aq. phase was acidified with 10% HCl soln. and extracted
with CH2Cl2 (3”50 ml). The org. phase was washed with brine to neutral, dried (Na2SO4), concentrated,
and bulb-to-bulb distilled: pure (+)-11c. B.p. 1248/0.4 mbar. [a]2D0 =+5.8 (c=1.6, CHCl3). IR: 3200, 2964,
2934, 2873, 1706, 1466, 1444, 1419, 1376, 1366, 1303, 1281, 1211, 1144, 1083, 1060, 1046, 926, 842, 785, 759.
1H-NMR: 0.77 (s, 3 H); 1.02 (s, 3 H); 1.34 (s, 3 H); 1.35 (m, 1 H); 1.93 (m, 1 H); 2.07 (dd, J=11.3, 14.3, 1
H); 2.21 (dd, J=7.2, 13.8, 1 H); 2.32 (dd, J=4.1, 14.3, 1 H); 3.27 (s, 1 H); 9.7 (br. s, 1 H). 13C-NMR: 13.2
(q); 18.8 (q); 20.5 (q); 32.0 (t); 34.4 (t); 39.3 (d); 41.0 (s); 62.2 (d); 68.7 (s); 179.3 (s). MS: 184 (0, M+C), 169
(22), 140 (21), 124 (88), 109 (92), 95 (55), 86 (47), 70 (90), 55 (51), 43 (100).
(+)-(1S,3R,5R)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hexane-3-acetaldehyde ((+)-12a). This less polar
stereoisomer was isolated in 3% yield during the chromatographic purification of (+)-11a [11b][14]
(SiO2, heptane/AcOEt 10 :1). [a]2D0 =+20.4 (c=1.5, MeOH). IR: 3021, 2971, 1741, 1467, 1377, 1272,
1
1144, 848. H-NMR: 0.99 (s, 3 H); 1.02 (s, 3 H); 1.29 (s, 3 H); 1.65 (d, J=10, 1 H); 2.09 (m, 1 H); 2.15
(m, 1 H); 2.62 (m, 2 H); 3.29 (s, 1 H); 9.72 (t, J=2, 1 H). 13C-NMR: 13.1 (q); 18.5 (q); 26.9 (q); 32.1
(t); 38.9 (d); 42.4 (s); 50.1 (t); 63.8 (d); 70.2 (s); 203.0 (d). MS: 168 (2, M+C), 153 (13), 109 (54), 83
(100), 69 (50), 55 (81), 43 (78), 41 (81). Cumin, mastic.
(+)-(1R,3S,5S)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hexane-3-ethanol ((+)-13a). NaBH4 (112.4 mg,
(2.97 mmol) was added portionwise to a soln. of (+)-11a (500 mg, 2.97 mmol) in MeOH (5 ml) at 08.
After 15 min, the mixture was equilibrated at 208, and after 30 additional min., the mixture was poured
onto ice. The aq. phase was saturated with NaCl and extracted with Et2O (3”10 ml). The org. phase was
U
dried (Na2SO4), concentrated, and bulb-to-bulb distilled: pure (+)-13a (80%). B.p. 1508/0.2 mbar.
[a]2D0 =+11.4 (c=1.1, EtOH). IR: 3412, 2934, 2871, 1467, 1442, 1375, 1364, 1144, 1077, 1052, 1028,
1
1004, 911, 843. H-NMR: 0.73 (s, 3 H); 1.00 (s, 3 H); 1.3 (m, 2 H); 1.33 (s, 3 H); 1.5 (m, 1 H); 1.6 (m, 1
H); 1.72 (br. s, 1 OH); 2.08 (dd, J=5, 8, 1 H); 3.25 (s, 1 H); 3.65 (m, 2 H). 13C-NMR: 13.2 (q); 18.7
(q); 20.8 (q); 32.1 (t); 32.7 (t); 39.4 (d); 41.3 (s); 61.7 (t); 62.7 (d); 69.1 (s). MS: 170 (17, M+C), 155
(20), 137 (21), 125 (28), 111 (100), 109 (38), 83 (50), 69 (59), 55 (83), 43 (79). 41 (77).
(ꢀ)-13a: [a]2D0 =ꢀ11.5 (c=1.1, EtOH). Camphor.
(+)-(1S,3S,5R)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hexane-3-ethanol ((+)-14a). NaBH4 (11.2 mg,
0.296 mmol) was added to a soln. of (+)-12a (50 mg, 0.297 mmol) in MeOH (2 ml) at 08. After 1 h at
208, the mixture was poured onto ice. The aq. phase was saturated with NaCl and extracted with Et2O
C
(3”20 ml). The org. phase was dried (Na2SO4), concentrated, and bulb-to-bulb distilled: pure (+)-14a
(83%). [a]2D0 =+36.6, (c=1.1, EtOH). IR: 3406, 2957, 2871, 1469, 1442, 1423, 1375, 1364, 1137, 1053,
1
1006, 935, 853, 835, 732. H-NMR: 0.97 (s, 3 H); 1.03 (s, 3 H); 1.29 (s, 3 H); 1.52 (m, 2 H); 1.63 (m, 1
H); 1.73 (m, 1 H); 1.77 (d, J=12, 1 H); 1.92 (dd, J=7, 12, 1 H); 3.28 (s, 1 H); 3.50 (m, 1 H); 3.66 (m, 1
H). 13C-NMR: 13.2 (q); 18.5 (q); 27.5 (q); 30.2 (t); 36.8 (t); 42.1 (d); 42.9 (s); 61.9 (t); 64.2 (d); 70.4
(s). MS: 170 (10, M+C), 155 (16), 137 (21), 125 (20), 111 (90), 109 (41), 83 (41); 69 (52), 55 (78), 43
(93), 41 (100).

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Helvetica Chimica Acta – Vol. 89 (2006)
(+)-(1S,3S,5R)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hexane-3-ethanol Acetate ((+)-14b). A soln. of
(+)-14a (20 mg, 0.117 mmol) and Ac2O (52.8 mg, 0.517 mmol) in pyridine (40.9 mg, 0.517 mmol) was
heated at 608 for 1 h. H2O (0.1 ml) was then added to the cold soln. Extraction with CH2Cl2 and washing
with H2O to neutral furnished, after concentration and bulb-to-bulb distillation, pure (+)-14b (74%). B.p.
1608/0.2 mbar. [a]2D0 =+27.5 (c=1.1, EtOH). IR: 2960, 2872, 1736, 1469, 1442, 1386, 1365, 1232, 1138,
1
1034, 852. H-NMR: 0.99 (s, 3 H); 1.02 (s, 3 H); 1.31 (s, 3 H); 1.55 (m, 2 H); 1.78 (d, J=12, 1 H); 1.82
(m, 1 H); 1.92 (dd, J=7, 12, 1 H); 2.04 (s, 3 H); 3.29 (s, 1 H); 3.95 (m, 1 H); 4.04 (m, 1 H). 13C-NMR:
13.2 (q); 18.5 (q); 21.0 (q); 27.4 (q); 30.2 (t); 32.7 (t); 42.4 (d); 42.9 (s); 63.8 (t); 64.0 (d); 70.3 (s);
171.3 (s). MS: 212 (1, M+C), 170 (12), 152 (20), 137 (36), 124 (20), 109 (46), 81 (19), 67 (34), 55 (26), 43
(100).
2-[(1R)-2,2,3-Trimethylcyclopent-3-en-1-yl]ethyl 1,3-Dihydro-1,3-dioxo-isobenzofuran-5-carboxy-
late ((ꢀ)-15c). A mixture of trimellitic anhydride acid chloride (=1,3-dihydro-1,3-dioxoisobenzofuran-
5-caronyl chloride) (2.19 g, 10 mmol), alcohol (+)-15a (1.54g, 10 mmol), and AgCN (1.47 g, 11 mmol)
in toluene (20 ml) was heated under reflux for 5 h. The cold mixture was filtered, concentrated, and puri-
fied by CC (SiO2, toluene/AcOEt 9 :1 ! 1:1, then Et2
O): pure (ꢀ)-15c (29%). [a]2D0 =ꢀ0.5 (c=2.2,
N
CHCl3). IR: 2922, 2852, 1859, 1774, 1702, 1488, 1419, 1349, 1294, 1229, 1171, 1124, 1103, 1071, 919,
1
885. H-NMR: 0.81 (s, 3 H); 1.02 (s, 3 H); 1.38–1.58 (m, 1 H); 1.62 (s, 3 H); 1.75 (m, 1 H); 1.92 (m, 2
H); 2.36 (m, 1 H); 4.43 (m, 2 H); 5.25 (br. s, 1 H); 8.12 (dd, J=4, 10, 1 H); 8.6 (dd, J=4, 10, 1 H); 8.72
(s, 1 H). 13C-NMR: 12.6 (q); 19.7 (q); 25.7 (q); 29.1 (t); 35.5 (t); 47.0 (s); 47.0 (d); 66.4 (t); 121.5 (d);
125.8 (d); 127.5 (d); 131.8 (s); 136.6 (s); 137.2 (d); 137.6 (s); 148.6 (s); 161.5 (s); 164.0 (s); 168.1 (s).
MS: 328 (2, M+C), 175 (11), 136 (17), 121 (100), 108 (29), 103 (14), 93 (32), 75 (13).
(ꢀ)-(1R,3S,5S)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hexane-3-methanol Acetate ((ꢀ)-16a). MCPBA
(5.86 g, 34 mmol) was added in portions at 08 to a soln. of ketone (+)-4h (5.65 g, 34 mmol) in CH2Cl2
(100 ml). After 2 h at 208, MCPBA (5.86 g, 34 mmol) was added, and the mixture was refluxed for 24
h, while three successive portions of MCPBA (5.86 g, 34 mmol) were added after 24, 48, and 72 h. The
cold mixture was washed with H2O, 15% aq. NaOH soln., and H2O to neutrality, dried (MgSO4), concen-
trated, and purified by CC (SiO2, CH2Cl2): pure (ꢀ)-16a (33%). B.p. 1008/0.14 mbar. a2D0 =ꢀ4.0. IR: 2963,
1738, 1467, 1443, 1387, 1365, 1231, 1146, 1031, 971, 844. 1H-NMR: 0.82 (s, 3 H); 1.08 (s, 3 H); 1.12 (s, 3 H);
1.39 (dd, J=10, 12, 1 H); 1.85 (dd, J=7, 12, 1 H); 2.03 (s, 3 H); 2.09 (t, J=7, 1 H); 3.27 (s, 1 H); 3.99 (d,
J=7, 2 H). 13C-NMR: 12.8 (q); 18.7 (q); 20.9 (q); 21.6 (q); 30.0 (t); 40.9 (s); 41.7 (d); 62.2 (d); 64.8 (t); 68.9
(s); 171.0 (s). MS: 198 (0, M+C), 183 (1), 155 (9), 138 (38), 123 (65), 95 (41), 69 (36), 55 (26), 43 (100), 41
(32). Fruity, estery.
(+)-16a: a2D0 =+4.1. Cedar, camphor.
(ꢀ)-(1R,3S,5S)-1,2,2-Trimethyl-6-oxabicyclo[3.1.0]hexane-3-methanol ((ꢀ)-16b). A soln. of (ꢀ)-16a
(200 mg, 1.0 mmol) and LiOH·H2O (200 mg, 4.8 mmol) in THF (5 ml) and H2O (2 ml) was stirred for 24
h at 208. The mixture was saturated with NaCl and extracted with Et2O. The org. phase was washed to
G
neutral with brine, dried (Na2SO4), concentrated, and purified by CC (cyclohexane/AcOEt 9 :1): pure
(ꢀ)-16b (82%). B.p. 628/0.4 mbar. [a]2D0 =ꢀ4.2 (c=1.0, CHCl3). IR: 3411, 2959, 2932, 2872, 1466, 1442,
1375, 1364, 1144, 1075, 1024, 998, 926, 841, 806. 1H-NMR: 0.82 (s, 3 H); 1.08 (s, 3 H); 1.31 (s, 3 H);
1.39 (m, 1 H); 1.54 (br. s, 1 OH); 1.73 (dd, J=7.5, 10.2, 1 H); 2.11 (dd, J=6.6, 13.3, 1 H); 3.27 (s, 1 H);
3.53 (dd, J=7.5, 10.2, 1 H); 3.64 (dd, J=6.6, 10.2, 1 H). 13C-NMR: 12.85 (q); 18.6 (q); 21.9 (q); 30.1
(t); 40.9 (s); 45.3 (d); 62.4 (d); 63.5 (t); 69.3 (s). MS: 156 (1, M+C), 141 (56), 125 (66), 113 (43), 95 (39),
85 (32), 71 (60), 55 (83), 43 (100).
Alternatively, MCPBA (123 mg, 0.7 mmol) was added at 208 to a soln. of alcohol (ꢀ)-19b (100 mg,
0.7 mmol). After 1 h, the mixture was washed to neutral with H2O, dried (Na2SO4), and concentrated to
afford in 72% yield a 1:1 mixture of 16b and 4,4,5-trimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol. Puri-
fication by CC (SiO2, heptane/AcOEt 3 :1) afforded 4,4,5-trimethyl-6-oxabicyclo[3.1.0]hexane-1-metha-
nol (27%). IR: 3419, 2958, 2869, 1575, 1467, 1441, 1377, 1363, 1281, 1259, 1124, 1081, 1016, 901, 824. 1H-
NMR: 0.92 (s, 3 H); 1.07 (s, 3 H); 1.27 (m, 2 H); 1.29 (s, 3 H); 1.32 (br. s, 1 OH); 1.78 (m, 1 H); 2.02 (dd,
J=7, 12, 1 H); 3.78 (d, J=12, 1 H); 3.86 (d, J=12, 1 H). 13C-NMR: 10.6 (q); 22.1 (q); 24.2 (q); 26.7 (t);
34.2 (t); 41.3 (s); 62.4 (t); 71.3 (s); 73.2 (s). MS: 156 (3, M+C), 141 (11), 125 (33), 107 (23), 95 (51), 83 (100),
69 (28), 55 (69), 43 (78).

Helvetica Chimica Acta – Vol. 89 (2006)
2649
(ꢀ)-(1R,3S,5S)-3-{{[(tert-Butyl)dimethylsilyl]oxy}methyl}-1,2,2-trimethyl-6-oxabicyclo[3.1.0]hexane
(=(ꢀ)-(tert-Butyl)dimethyl{[(1R,3S,5S)-1,2,2-trimethyl-6-oxabicyclo[3.1.0]hex-3-yl]methoxy}silane;
t
((ꢀ)-16c). Me2 BuSiCl (41.7 mg, 0.28 mmol) was added to a soln. of (ꢀ)-16b (36 mg, 0.23 mmol) in DMF
(3 ml) at ꢀ308, followed by 1H-imidazole (19 mg, 0.28 mmol). After 2 h at 208, the reaction mixture was
diluted with Et2O and extracted with brine to neutral. The org. phase was dried (Na2SO4), concentrated,
A
and purified by CC (SiO2, cyclohexane/AcOEt 95 :5): pure (ꢀ)-16c (71%). [a]2D0 =ꢀ8.0 (c=0.6, CCl4).
IR: 2956, 2929, 2856, 1471, 1442, 1387, 1361, 1252, 1145, 1114, 1085, 1059, 1004, 833, 772. 1H-NMR:
0.0 (s, 3 H); 0.023 (s, 3 H); 0.82 (s, 3 H); 0.88 (s, 9 H); 1.08 (s, 3 H); 1.3 (s, 3 H); 1.33 (m, 1 H); 1.71
(m, 1 H); 2.0 (dd, J=7, 14, 1 H); 3.23 (s, 1 H); 3.53 (m, 2 H). 13C-NMR: ꢀ5.5 (q); ꢀ5.4 (q); 12.9 (q);
18.2 (s); 18.6 (q); 22.0 (q); 25.9 (3q); 29.8 (t); 40.9 (s); 44.9 (d); 62.5 (d); 63.2 (t); 69.4 (s). MS: 270 (1,
M+C), 213 (95); 183 (13); 171 (8); 157 (13), 143 (33), 125 (21), 121 (34), 75 (100), 73 (30).
(ꢀ)-(2R,4S)-4-{{[(tert-Butyl)dimethylsilyl]
17a). A soln. of alcohol (+)-20c (700 mg, 2.57 mmol) in CH2Cl2 (5 ml) was added to a suspension of
PCC (858 mg, 3.98 mmol) and Celiteꢃ (850 mg) in CH2Cl2 (20 ml). After 2.5 h, Et2
O was added, and
the mixture was filtered through a short SiO2 column to afford (+)-(2S,4S)-4-{{[(tert-butyl)dimethylsilyl]-
oxy}methyl}-2,3,3-trimethylcyclopentanone [27] ((ꢀ)-
AHCTREUNG
A
2856, 1740, 1463, 1388, 1362, 1251, 1088, 833, 773. 1H-NMR: 0.04 (s, 6 H); 0.66 (s, 3 H); 0.89 (s, 9 H); 0.92
(d, J=7, 3 H); 1.20 (s, 3 H); 1.9 (dd, J=9, 14, 1 H); 2.02 (q, J=7, 1 H); 2.12 (m, 1 H); 2.43 (dd, J=7, 14, 1
H); 3.63 (dd, J=7, 12, 1 H); 3.78 (dd, J=7, 12, 1 H). 13C-NMR: ꢀ5.4 (2q); 7.0 (q); 16.0 (q); 18.3 (s); 26.0
(3q); 27.2 (q); 39.3 (t); 40.9 (s); 47.3 (d); 57.5 (d); 63.1 (t); 219.1 (s). MS: 270 (0, M+C), 213 (30), 183 (17),
157 (15), 121 (48), 93 (22), 75 (100), 69 (30), 41 (30).
A soln. of pure cis-17a (90 mg, 0.333 mmol) in MeOH (2 ml) was treated at 658 for 2 h with a 30%
MeONa/MeOH soln. (66 mg, 0.366 mmol) to afford in 87% yield trans/cis-17a 3 :7. Purification by CC
(SiO2, CH2Cl2) gave a trans/cis-17a 65 :35 (22%). Analyses for trans-17a (=(ꢀ)-17a) were deduced
1
from the mixture: H-NMR: 0.04 (s, 6 H); 0.66 (s, 3 H); 0.87 (s, 9 H); 0.89 (d, J=7, 3 H); 1.10 (s, 3 H);
1.9 (dd, J=9, 14, 1 H); 2.02 (q, J=7, 1 H); 2.12 (m, 1 H); 2.38 (dd, J=7, 14, 1 H); 3.68 (dd, J=7, 12, 1
H); 3.73 (dd, J=7, 12, 1 H). 13C-NMR: ꢀ5.4 (2q); 8.6 (q); 15.9 (q); 18.2(s); 24.6 (3q); 29.8 (q); 39.2
(t); 40.9 (s); 45.5 (d); 53.5 (d); 63.9 (t); 221.3 (s). MS: 270 (0, M+C), 213 (32), 183 (17), 157 (16), 121
(48), 93 (20), 75 (100), 69 (23), 41 (25).
(+)-(tert-Butyl)dimethyl{[(1S,3S)-2,2,3-trimethyl-4-methylenecyclopentyl]methoxy}silane ((+)-17b).
TiCl4 (1.13 ml, 10.3 mmol) was added at ꢀ408 to a suspension of Zn dust (2.87 g, 44 mmol) and
CH2Br2 (1.01 ml, 14.4 mmol) in THF (25 ml). After 3 days at 58, the resulting slurry (7.5 ml, ca 2.58
mmol) was added at 58 to a soln. of ketone (ꢀ)-17a (350 mg, 1.3 mmol; ca. 65 :35 trans/cis) in CH2Cl2
(6 ml), and after 2 h at 58, the mixture was diluted with CH2Cl2, poured into a cold sat. aq. NaHCO3
soln. and extracted with Et2
ACHTREUNG
trated, and purified by CC (SiO2, cyclohexane/Et2O
N
[a]2D0 =+11.8 (c=0.7, CCl4). IR: 2957, 2928, 2857, 1656, 1471, 1463, 1388, 1362, 1253, 1101, 1087, 1065,
1006, 939, 873, 833, 773. 1H-NMR: 0.04 (s, 3 H); 0.05 (s, 3 H); 0.80 (s, 3 H); 0.89 (s, 9 H); 0.92 (d, J=7,
3 H); 0.93 (s, 3 H); 1.81 (m, 1 H); 2.18 (m, 1 H); 2.27 (m, 1 H); 2.52 (ddq, J=2, 7, 14, 1 H); 3.46 (dd,
J=7, 10, 1 H); 3.67 (dd, J=5, 10, 1 H); 4.76 (br. s, 1 H); 4.82 (br. s, 1 H). 13C-NMR: ꢀ5.4 (2q); 13.5
(q); 18.3 (s); 23.0 (q); 23.9 (q); 25.9 (3q); 33.9 (t); 42.1 (s); 48.5 (d); 48.6 (d); 64.2 (t); 104.4 (t); 156.8
(s). MS: 268 (0, M+C), 211 (62), 135 (51), 121 (38), 75 (100), 73 (28).
The pure cis-isomer (+)-cis-17b was also obtained (23%) after CC for anal. purposes. [a]2D0 =+39.2
(c=1.1, CCl4). IR: 2956, 2928, 2899, 2857, 1657, 1471, 1388, 1366, 1253, 1098, 1074, 1025, 1006, 874, 834,
814, 773, 663. 1H-NMR: 0.05 (s, 6 H); 0.52 (s, 3 H); 0.90 (s, 9 H); 0.91 (d, J=7, 3 H); 1.05 (s, 3 H); 1.81 (m,
1 H); 1.98 (m, 1 H); 2.07 (m, 1 H); 2.58 (ddq, J=1, 7, 14, 1 H); 3.51 (dd, J=7, 10, 1 H); 3.69 (dd, J=5, 10,
1 H); 4.72 (br. s, 1 H); 4.82 (br. s, 1 H). 13C-NMR: ꢀ5.4 (2q); 10.4 (q); 14.8 (q); 18.3 (s); 26.0 (3q); 26.6
(q); 34.3 (t); 42.1 (s); 50.0 (d); 50.8 (d); 64.1 (t); 103.9 (t); 155.5 (s). MS: 268 (0, M+C), 211 (88), 181 (82),
135 (28), 121 (30), 89 (70), 75 (100), 73 (58).
(+)-b-Necrodol (=(+)-(1S,3S)-2,2,3-Trimethyl-4-methylenecyclopentanemethanol; (+)-17c). A mix-
ture of (+)-17b (100 mg, 0.373 mmol), 1M Bu4
ACHTREUNG
was stirred for 24 h at 208. The mixture was diluted with brine and extracted with Et
AHCTREUNG

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Helvetica Chimica Acta – Vol. 89 (2006)
was washed to neutral with brine, dried (Na2SO4), concentrated, and purified by bulb-to bulb distillation:
pure (+)-17c (93%). B.p. 1208/0.1 mbar. [a]2D0 =+15.9 (c=1.0, CHCl3). For analyses and olfactive proper-
ties, see [16].
(+)-(1S)-2,2,3-Trimethylcyclopent-3-ene-1-carboxaldehyde ((+)-19a). A soln. of (ꢀ)-epoxyverbe-
none (ꢀ)-2e (10.0 g, 65 mmol; a2D0 =ꢀ112.5) in toluene (40 ml) was added dropwise to a refluxing
soln. of dry ZnBr2 (1.82g, 8 mmol) in toluene (10 ml). After 1.5 h. a second quantity of ZnBr2 (1.82 g,
8 mmol) was added. After 2.25 h, the temp. was equilibrated to 208, and H2O (20 ml) and then AcOH
(2 ml) were added. The mixture was extracted with Et
ACHTREUNG
and H2O to neutrality, dried (Na2SO4), and concentrated to remove Et2
AHCTREUNG
uene was purified by CC (SiO2, toluene/AcOEt 97:3): (+)-19a (47%).
In a 5-l Pyrex reactor, a mixture of enamine (+)-18a (300 g, 1.35 mol), MeOH (4275 ml), H2O (225
ml), Rose Bengal (4.5 g) and AcONa (4.5 g, 54.9 mmol) were irradiated at 188 with a Philips-Hoki lamp
(1200 W) for 6 h under O2. After absorption of O2 (31 l, 1.24 mol), DMS (300 ml, 4.09 mol) was added,
and after 18 h at 208, the mixture was concentrated and then distilled to afford a yellow oil (160 g, b.p.
29–618/2.5 Torr), which was fractionated with a 1.0-m spinning band apparatus: pure 19a (35%). B.p.
1
658/13 Torr. [a]2D0 =+7.5 (c=1.8, CHCl3). IR: 2956, 2850, 2700, 1717, 1450, 1355, 1125, 1008, 795. H-
NMR: 1.00 (s, 3 H); 1.22 (s, 3 H); 1.62 (br. s, 3 H); 2.36 (ddt, J=3, 7, 16, 1 H); 2.58 (m, 1 H); 2.70 (dt,
J=3, 7, 1 H); 5.26 (br. s, 1 H); 9.76 (d, J=2.5, 1 H). 13C-NMR: 11.8 (q); 21.5 (q); 27.1 (q); 29.4 (t);
49.0 (s); 61.6 (d); 121.1 (d); 146.9 (s); 204.6 (d). MS: 138 (18, M+C), 123 (56), 95 (100), 67 (65), 55 (27),
41 (32). Vaguely mint, green.
(ꢀ)-19a: Obtained from (+)-epoxyverbenone (a2D0 =+119.2). aD20 =ꢀ6.8. Almond, pharmacy.
(ꢀ)-(1S)-2,2,3-Trimethylcyclopent-3-ene-1-methanol ((ꢀ)-19b). As described in the General Proce-
dure I of [3]: (ꢀ)-19b (94%). B.p. 1008/8.5 mbar. a2D0 =ꢀ18.4. IR: 3427, 2957, 1716, 1464, 1360, 1270.
1H-NMR: 0.88 (s, 3 H); 1.08 (s, 3 H); 1.60 (br. s, 3 H); 1.85 (br. s, 1 OH); 1.96 (m, 1 H); 2.07 (m, 1 H);
2.37 (m, 1 H); 3.65 (dd, J=7, 9, 1 H); 3.80 (dd, J=7, 9, 1 H); 5.22 (br. s, 1 H). 13C-NMR: 12.2 (q); 19.9
(q); 26.9 (q); 33.4 (t); 46.5 (s); 51.9 (d); 64.3 (t); 121.3 (d); 148.3 (s). MS: 140 (19, M+C), 125 (37), 107
(100), 95 (28), 91 (36), 79 (33), 67 (23), 55 (21), 41 (27). Camphor, celluloid.
(ꢀ)-(4S)-{{[(tert-Butyl)dimethylsilyl]oxy}methyl}-1,5,5-trimethylcyclopent-1-ene
(=(ꢀ)-(tert-
Butyl)dimethyl{[(1S)-2,2,3-trimethylcyclopent-3-en-1-yl]methoxy}silane; (ꢀ)-19c). As described for (ꢀ)-
16c: (ꢀ)-19c (40%). B.p. 758/1.0 mbar. [a]2D0 =ꢀ4.1 (c=1.9, CHCl3). IR: 2954, 2928, 2857, 1471, 1463,
1
1387, 1360, 1252, 1102, 1068, 1006, 824, 772. H-NMR: 0.05 (s, 6 H); 0.85 (s, 3 H); 0.9 (s, 9 H); 1.08 (s,
3 H); 1.58 (s, 3 H); 1.88 (m, 1 H); 2.05 (quint., J=7, 1 H); 2.25 (m, 1 H); 3.60 (dd, J=7, 10, 1 H); 3.74
(dd, J=7, 10, 1 H); 5.20 (br. s, 1 H). 13C-NMR: ꢀ5.3 (2q); 12.3 (q); 18.4 (s); 19.8 (q); 26.0 (3q); 27.0
(q); 33.3 (t); 46.5 (s); 51.8 (d); 64.2 (t); 121.4 (d); 148.5 (s). MS: 254 (0, M+C), 197 (100), 121 (74), 107
(57), 89 (74), 75 (70), 73 (28).
(+)-(1S,3S,4S)-4-Hydroxy-2,2,3-trimethylcyclopentanemethanol ((+)-20a). As described for (+)-9b,
from (+)-19a with 2.0 mol-equiv. of BH3·Me2S complex: (+)-20a (72%). B.p. 1508/0.2 mbar.
G
[a]2D0 =+31.0 (c=1.0, EtOH). IR: 3333, 2958, 1456, 1367, 1064. 1H-NMR: 0.61 (s, 3 H); 0.94 (d, J=7, 3
H); 1.02 (s, 3 H); 1.49 (quint., J=7, 1 H); 1.72 (br. s, 2 OH); 1.82 (m, 2 H); 2.01 (m, 1 H); 3.49 (dd,
J=7, 9, 1 H); 3.72 (dd, J=4, 7, 1 H); 3.85 (dt, J=4, 7, 1 H). 13C-NMR: 11.0 (q); 16.1 (q); 27.0 (q);
36.9 (t); 42.1 (s); 50.3 (d); 54.5 (d); 64.1 (t); 77.9 (d). MS: 158 (1, M+C), 140 (5), 125 (13), 109 (44), 71
(51), 70 (100), 67 (32), 55 (55), 43 (53), 41 (57).
(ꢀ)-20a: [a]2D0 =ꢀ30.6 (c=1.0, EtOH), obtained analogously in 78% yield from (ꢀ)-19a.
(+)-[(1S,3S,4S)-4-Hydroxy-2,2,3-trimethylcyclopentyl]methyl 2,2-Dimethylpropanoate ((+)-20b). A
mixture of (+)-20a (490 mg, 3.1 mmol), pivalic acid (=2,2-dimethylpropanoic acid; 400 mg, 3.92
mmol), DCC (800 mg, 3.88 mmol), and DMAP (5 mg) in CH2Cl2 (10 ml) was stirred at 208 for 3.5 h.
After filtration, the mixture was extracted with pentane/H2O. The org. phase was washed with sat. aq.
NaHCO3 soln. and H2O to neutrality, dried (Na2SO4), concentrated, and purified by CC (SiO2, tolu-
ene/AcOEt 8 :2 ! 7:3): pure (+)-20b (74%). B.p. 1808/0.27 mbar. [a]2D0 =+7.5 (c=0.3, EtOH). IR:
1
3404, 2960, 1729, 1481, 1368, 1286, 1163, 1033. H-NMR: 0.63 (s, 3 H); 0.96 (d, J=7, 3 H); 1.03 (s, 3
H); 1.19 (s, 9 H); 1.51 (quint., J=7, 1 H); 1.72 (br. s, 1 OH); 1.77 (m, 1 H); 1.85 (m, 1 H); 2.17 (m, 1

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H); 3.84 (dt, J=4, 7, 1 H); 3.96 (dd, J=7, 9, 1 H); 4.08 (dd, J=7, 10, 1 H). 13C-NMR: 11.1 (q); 16.2 (q);
26.9 (q); 27.2 (3q); 36.5 (t); 38.8 (s); 42.2 (s); 46.6 (d); 54.3 (d); 65.4 (t); 77.7 (d); 178.8 (s). MS: 242 (0,
M+C), 224 (2), 140 (10), 122 (22), 107 (40), 103 (25), 85 (27), 70 (54), 57 (100), 41 (60).
Data of By-product (10%) 4-(2,2-Dimethyl-1-oxopropoxy)-2,2,3-trimethylcyclopentyl 2,2-Dimethyl-
1
propanoate. IR: 2960, 1730, 1480, 1370, 1285, 1165, 1035. H-NMR: 0.69 (s, 3 H); 0.90 (d, J=7, 3 H);
1.06 (s, 3 H); 1.20 (s, 18 H); 1.59–1.80 (m, 2 H); 1.90–2.18 (m, 2 H); 3.95 (dd, J=8, 10, 1 H); 4.10 (dd,
J=8, 10, 1 H); 4.71 (dt, J=4, 8, 1 H). 13C-NMR: 11.1 (q); 16.0 (q); 26.7 (q); 27.1 (3q); 27.2 (3q); 33.9
(t); 38.6 (s); 38.8 (s); 41.7 (s); 46.8 (d); 50.8 (d); 65.2 (t); 79.6 (d); 178.7 (s); 178.8 (s). MS: 326 (0,
M+C), 241 (1), 225 (8), 123 (58), 107 (27), 57 (100).
(+)-(1S,2S,4S)-4-{{[(tert-Butyl)dimethylsilyl]oxy}methyl}-2,3,3-trimethylcyclopentanol
((+)-20c).
The diprotected material (+)-(tert-butyl){{(1S,2S,4S)-4-{{[(tert-butyl)dimethylsilyl]oxy}methyl}-2,3,3-tri-
methylcyclopentyl}oxy}dimethylsilane was obtained in quantitative yield according to [27]. B.p. 908/0.8
mbar. [a]2D0 =+15.3 (c=1.0, EtOH). IR: 3334, 2955, 2928, 2857, 1462, 1388. 1362, 1252, 1094, 1076,
1030, 1005, 833, 772, 665. 1H-NMR: 0.02 (s, 12 H); 0.59 (s, 3 H); 0.85 (d, J=7, 3 H); 0.88 (s, 18 H);
0.98 (s, 3 H); 1.49 (dq, J=1.5, 7, 1 H); 1.65 (m, 2 H); 2.0 (m, 1 H); 3.45 (dd, J=7, 10, 1 H); 3.61 (dd,
J=7, 10, 1 H); 3.73 (m, 1 H). 13C-NMR: ꢀ4.4 (q); ꢀ4.6 (q); ꢀ5.3 (2q); 11.1 (q); 16.2 (q); 18.2 (s);
18.3 (s); 26.0 (6q); 27.5 (q); 36.9 (t); 41.3 (s); 49.8 (d); 54.2 (d); 64.4 (t); 78.4 (d). MS: 386 (0, M+C),
329 (67), 253 (23), 211 (67), 147 (18), 121 (21), 89 (22), 75 (100), 73 (62).
A soln. of this diprotected material (140 mg, 0.362 mmol) in THF (2 ml) was treated overnight at 208
with Bu
A
Et2O (3”10 ml). The org. phase was dried (Na2SO4) and concentrated: (+)-20c (97%). B.p. 1008/0.4
E
mbar. [a]2D0 =+15.9 (c=0.8, CHCl3). IR: 3334, 2955, 2928, 2896, 2857, 1462, 1388, 1362, 1252, 1094,
1
1076, 1030, 1005, 960, 938, 897, 833, 814, 772, 665. H-NMR: 0.7 (s, 6 H); 0.83 (s, 9 H); 0.88 (s, 3 H);
0.90 (s, 3 H); 0.98 (d, J=7, 3 H); 1.46 (sext., J=7, 1 H); 1.76 (m, 2 H); 1.99 (m, 1 H); 2.21 (br. s, 1
OH); 3.45 (m, 1 H); 3.70 (m, 1 H); 3.81 (m, 1 H). 13C-NMR: ꢀ2.6 (2q); 11.3 (q); 16.4 (q); 18.5 (s);
26.1 (3q); 26.3 (q); 37.8 (t); 41.6 (s); 50.7 (d); 54.4 (d); 64.8 (t); 78.7 (d). MS: 272 (0, M+C), 189 (24),
147 (100), 133 (6), 117 (5), 73 (14).
Cyclopropanol (+)-20c was also obtained in 95% yield from (+)-20a as described for (ꢀ)-16c, or in
22% yield (after CC (SiO2, heptane/AcOEt 9 :1)) by oxidative hydroboration of silyl ether (ꢀ)-19c with
1.0 mol-equiv. of BH3·Me2S according to the procedure used for (+)-9b.
G
(+)-(1R,3R)-2,2,3-Trimethylcyclopentaneacetaldehyde ((+)-21). As described in the General Proce-
dure K of [3] from (+)-22a: (+)-21 (98%). B.p. 1008/0.2 mbar. [a]2D0 =+6.4 (c=3.1, CHCl3). IR: 2953,
1
2870, 2714, 1724, 1467, 1409, 1387, 1367, 1316, 1268, 1227, 1185, 1128, 1076, 1034, 915. H-NMR: 0.51
(s, 3 H); 0.86 (d, J=7, 3 H); 0.89 (s, 3 H); 1.2 (m, 2 H); 1.55 (m, 1 H); 1.8 (m, 1 H); 1.9 (m, 2 H); 2.2
(m, 1 H); 2.49 (m, 1 H); 9.75 (d, J=4, 1 H). 13C-NMR: 13.9 (q); 14.6 (q); 25.4 (q); 28.2 (t); 30.2 (t);
42.4 (s); 44.6 (d); 44.8 (d); 45.5 (t); 203.2 (d). MS: 154 (1, M+C), 139 (56), 110 (16), 97 (76), 95 (48), 84
(49), 69 (100), 55 (33), 41 (35). Aldehydic, green, camphoraceous.
(ꢀ)-21: a2D0 =ꢀ4.8. Disgusting.
(+)-(1R,3R)-2,2,3-Trimethylcyclopentaneethanol ((+)-22a). Alcohol (+)-15a (23g, 0.13 mol) in
AcOEt (250 ml) was hydrogenated over 10% Pd/C (500 mg). After absorption of H2 (3.4 l) the soln.
was filtered, concentrated, and distilled: pure (+)-22a (90%). B.p. 1008/0.15 mbar. [a]2D0 =+26.9
1
(c=3.1, CHCl3). IR: 3380, 2910, 1480, 1070. H-NMR: 0.52 (s, 3 H); 0.83 (d, J=7, 3 H); 0.88 (s, 3 H);
1.19 (m, 2 H); 1.33 (m, 1 H); 1.48 (m, 2 H); 1.78 (m, 3 H); 1.9 (br. s, 1 OH); 3.59 (m, 1 H); 3.69 (m, 1
H). 13C-NMR: 13.9 (q); 14.4 (q); 25.5 (q); 28.2 (t); 30.3 (t); 33.9 (t); 42.3 (s); 45.0 (d); 47.2 (d); 62.6
(d). MS: 156 (8, M+C), 123 (23), 113 (25), 109 (19), 100 (19), 95 (41), 84 (62), 81 (37), 69 (100), 55 (45),
41 (45). Very vague.
(+)-(1R,3R)-2,2,3-Trimethylcyclopentaneethanol Acetate ((+)-22b). A mixture of alcohol (+)-22a
(120 mg, 0.77 mmol) and Ac2O (0.14 ml, 1.48 mmol) in pyridine (1.4 ml) was stirred at 208 for 1h. The
mixture was concentrated under vacuum and purified by bulb-to-bulb distillation: (+)-22b (74%). B.p.
1208/0.1 mbar. aD20 =+22.9. IR: 2952, 2869, 1739, 1468, 1387, 1365, 1229, 1064, 1029, 966. 1H-NMR:
0.52 (s, 3 H); 0.84 (d, J=7, 3 H); 0.88 (s, 3 H); 1.19 (m, 2 H); 1.35 (m, 1 H); 1.41 (m, 1 H); 1.50 (m, 1

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Helvetica Chimica Acta – Vol. 89 (2006)
H); 1.78 (m, 3 H); 2.06 (s, 3 H); 4.03 (m, 1 H); 4.09 (m, 1 H). 13C-NMR: 13.9 (q); 14.4 (q); 21.1 (q); 25.5
(q); 28.0 (t); 29.7 (t); 30.2 (t); 42.4 (s); 45.0 (d); 47.4 (d); 64.5 (t); 171.2 (s). MS: 198 (0, M+C), 155 (1), 138
(12), 123 (68), 110 (100), 95 (82), 84 (60), 81 (77), 69 (97), 55 (51), 43 (68).
rac-cis-2,3,3-Trimethylcyclopentaneethanol (rac-23a). A mixture of b-campholenol [31] (250 mg, 1.6
mmol) and Raney Ni (25 mg) in EtOH (5 ml) was hydrogenated (90 bars) for 18 h at 208. The mixture was
then filtered, concentrated, and purified by bulb-to-bulb distillation: pure rac-23a (53%). B.p. 1008/0.2
1
mbar. IR: 3321, 2936, 2866, 1462, 1375, 1178, 1055, 1007, 966, 859. H-NMR: 0.75 (d, J=7, 3 H); 0.88
(s, 3 H); 0.98 (s, 3 H); 1.28 (m, 2 H); 1.43 (m, 2 H); 1.57 (q, J=7, 1 H); 1.65 (br. s, OH); 1.66 (m, 1 H);
1.80 (m, 1 H); 2.19 (m, 1 H); 3.61 (m, 2 H). 13C-NMR: 10.6 (q); 24.6 (q); 29.5 (t); 30.2 (q); 35.6 (t);
37.8 (d); 39.0 (t); 41.4 (s); 45.8 (d); 62.6 (t). MS: 156 (0.5, M+C), 141 (3), 138 (4), 127 (20), 123 (39),
110 (60), 95 (78), 82 (85), 69 (100), 67 (70), 55 (76), 41 (53).
rac-cis-2,3,3-Trimethylcyclopentaneethanol Acetate (rac-23b). As described for (+)-22b: rac-23b
1
(56%). B.p. 908/0.2 mbar. IR: 2949, 2868, 1740, 1462, 1386, 1364, 1230, 1033. H-NMR: 0.75 (d, J=7, 3
H); 0.88 (s, 3 H); 0.98 (s, 3 H); 1.35 (m, 2 H); 1.49 (m, 2 H); 1.59 (quint., J=7, 1 H); 1.75 (m, 1 H);
1.83 (m, 1 H); 2.05 (s, 3 H); 2.17 (m, 1 H); 4.06 (m, 2 H). 13C-NMR: 10.5 (q); 21.1 (q); 24.6 (q); 29.4
(t); 30.1 (q); 31.3 (t); 38.2 (d); 38.9 (t); 41.4 (s); 45.8 (d); 64.4 (t); 171.2 (s). MS: 198 (0, M+C), 123 (33),
110 (97), 95 (100), 82 (52), 69 (49), 67 (35), 55 (32), 43 (45).
rac-cis-2,3,3-Trimethylcyclopentaneacetaldehyde (rac-24). As described for (ꢀ)-17a: rac-24 (quant.).
B.p. 908/0.25 mbar. IR: 2921, 2853, 1729, 1535, 1458, 1377, 1260, 1142, 1074, 721. 1H-NMR: 0.75 (d, J=7, 3
H); 0.87 (s, 3 H); 0.99 (s, 3 H); 1.3 (m, 1 H); 1.4 (m, 1 H); 1.5 (m, 1 H); 1.69 (quint., J=7, 1 H); 1.92 (tq,
J=4.6, 8.1, 1 H); 2.31 (ddd, J=2, 9.2, 15.9, 1 H); 2.52 (dd, J=2, 15.9, 1 H); 2.66 (m, 1 H); 9.75 (t, J=2, 1
H). 13C-NMR: 10.9 (q); 24.4 (q); 29.6 (t); 30.0 (q); 35.8 (d); 39.1 (t); 41.4 (s); 45.5 (d); 47.2 (t); 203.2 (d).
MS: 154 (3, M+C), 110 (62), 95 (100), 83 (68), 69 (47), 55 (46), 41 (30).
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Received May 31, 2006