Internal nucleophilic termination in acid-mediated polyene cyclizations: Part 5. Synthetic access to didehydro analogues of (±)-Ambrox and diastereoisomers

Article abstract of DOI:10.1002/hlca.200690276

Treatment of the acyclic tetraenols (E)- and (Z)-2 with an excess of ClSO₃H in 2-nitropropane at - 80° stereoselectively afforded in 30 and 43% yield, respectively, diastereoisomer mixtures of the racemic, tricyclic ethers 1c,d and 1a,b, together with 20 (Table). Under identical conditions, but with the acyclic pentaenol 10 (1:1 diastereoisomer mixture) as substrate, the tricyclic ethers 22a/22b (10:1) were isolated in 27% yield. These kinetically controlled stereospecific transformations are thought to proceed via non-concerted pathways (see Schemes 5 and 7), fully consistent with our earlier work. In contrast, another set of reaction conditions (CF ₃CO₂H, CH₂Cl₂, -15° to -10°) was used for the cyclization of the monocyclic dienols (E)-3 and (Z)-3, which resulted in the non-stereoselective formation of the major products 1c,d and 1a,b, respectively, in 35-37% yield. Representing novel didehydro analogues of the known ambergris odorant (±)-Ambrox and its diastereoisomers, the qualitative organoleptic properties of 1a-d and of the 10:1 diastereoisomer mixture of the novel tetradehydro analogues 22a/ 22b are briefly described.

Full text of DOI:10.1002/hlca.200690276

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Internal Nucleophilic Termination in Acid-Mediated Polyene Cyclizations
Part 51)
Synthetic Access to Didehydro Analogues of (Æ)-Ambroxꢀ and Diastereoisomers
by Roger L. Snowden* and Simon Linder
Firmenich SA, Corporate R&D Division, P. O. Box 239, CH-1211 Geneva 8
(phone: +41-22-7803608; fax: +41-22-7803334; e-mail: roger.snowden@firmenich.com)
Dedicated to Professor Georg Frµter on the occasion of his 65th birthday
Treatment of the acyclic tetraenols (E)-and ( Z)-2 with an excess of ClSO3H in 2-nitropropane at
À808 stereoselectively afforded in 30 and 43% yield, respectively, diastereoisomer mixtures of the race-
mic, tricyclic ethers 1c,d and 1a,b, together with 20 (Table). Under identical conditions, but with the acy-
clic pentaenol 10 (1:1 diastereoisomer mixture) as substrate, the tricyclic ethers 22a/22b (10 :1) were iso-
lated in 27% yield. These kinetically controlled stereospecific transformations are thought to proceed via
non-concerted pathways (see Schemes 5 and 7), fully consistent with our earlier work. In contrast,
another set of reaction conditions (CF3CO2H, CH2Cl2, À158 to À108) was used for the cyclization of
the monocyclic dienols (E)-3 and (Z)-3, which resulted in the non-stereoselective formation of the
major products 1c,d and 1a,b, respectively, in 35–37% yield. Representing novel didehydro analogues
of the known ambergris odorant (Æ)-Ambroxꢀ and its diastereoisomers, the qualitative organoleptic
properties of 1a–d and of the 10 :1 diastereoisomer mixture of the novel tetradehydro analogues 22a/
22b are briefly described.
1. Introduction. – As part of a project designed to discover organoleptically active
analogues of the labdane tricyclic ether Ambroxꢀ, a commercially important, naturally
occurring odorant [2], Escher and co-workers [3] synthesized in the 1980s the novel
didehydro analogue (À)-1d, starting from either (+)-larixyl acetate or (+)-sclareolide,
which itself is a precursor of Ambroxꢀ and derived from the oxidative degradation of
(À)-sclareol (Scheme 1)2). Because (À)-1d, aptly named Superambrox by Firmenich
perfumers, exhibits an extremely powerful ambergris tonality, it was decided to develop
a synthesis of the unknown racemate (Æ)-1d3), a potential odorant whose accessibility
would not be dependent on a natural source. As a matter of fact, this strategy has been
successfully used before for (Æ)-Ambrox, commercialized by Firmenich SA under the
trade name Cetaloxꢀ [2].
1
)
)
For Parts 1–4, see [1b–e].
2
For later, independent work by de Groot and co-workers, who also described the preparation of (À)-
1d from (+)-larixyl acetate, see [4].
3
)
For a stereoselective synthesis of (Æ)-1d, see [5].
ꢁ 2006 Verlag Helvetica Chimica Acta AG, Zürich

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Scheme 1
A retrosynthetic analysis for the preparation of 1d is shown in Scheme 2. Starting
from the homoallylic alcohols (E)-2 and (E)-3 as direct precursors, 1d should be acces-
sible via acid-mediated cyclization. Thus, site-selective protonation of (E)-2 or solvol-
ysis of the allylic CÀO bond of (E)-34) would afford a diastereoisomer mixture of the
cyclohexane-based allylic cations (E,Z)-l and (E,E)-l, of which only the latter, (E)-con-
figured cation was expected to undergo further cyclization to 1d. Although interconver-
sion of (E,Z)-I and (E,E)-I under the reaction conditions cannot be completely dis-
counted, this would necessarily involve quenching by an external nucleophile, followed
by regeneration of the allylic cation (for a precedent of such an allyl-cation interconver-
sion, involving a putative internal quenching, see [1d]).
Based on analogous previous work [1], we were confident that both (E)-2 and (E)-3
would form the desired trans-fused tetrahydrofuran ring via trans addition across the
C(3)=C(4) bond. However, we were less sure about the stereoselectivity with respect
to the C(9a)ÀMe group. Nevertheless, from inspection of models, it did not seem
unreasonable to suppose that pseudoequatorial CÀC bond formation opposite to the
axially orientated C(6)ÀMe group would be kinetically favored. Notably, in related sys-
tems, a kinetic preference for equatorial CÀC bond formation is generally observed for
the cyclization of a cyclohexyl cation with an adjacent equatorial side chain [1].
4
)
The putative conversion of (E)-2 to 1 represents another example of an acid-mediated polyene cyc-
lization in which the initiating group is an alkene and where termination is effected internally by an
OH group [1]. In contrast, the transformation of (E)-3 to 1 is analogous to the stereoselective cyc-
lization of i to ii [6].

Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 2. Retrosynthetic Analysis
3073
2. Results and Discussion. – 2.1. Preparation of the Homoallylic Alcohols (E)-2 and
(Z)-2. The synthetic approach towards 2 is outlined in Scheme 3. Following a reported
procedure [7], dehydrolinalool (=3,7-dimethyloct-6-en-1-yn-3-ol; 4) was converted to
the trienone 5 via Claisen rearrangement in 78% yield. Low-temperature metalation of
3-[(trimethylsilyl)oxy]prop-1-yne with BuLi, followed by addition of 5 to the subse-
quent alkynyllithio species, afforded, after hydrolytic deprotection of the Me3Si
group, the trienynediol 6 in 78% overall yield. Next, the primary OH group was esteri-
fied to afford the acetate 7 in 85% yield, whose tertiary OH group was further pro-
tected as an acetal to afford 8. The latter was immediately reduced with LiAlH4 in
THF at 208 to smoothly afford a 1.3 :1 mixture of (E)-9 and 10, which, after chromato-
graphic separation, were obtained in 54 and 43% yield, respectively. Reprotection of
the primary OH group of 9 furnished the acetate 11 in 97% yield, which, on treatment
with LiAlH4 in THF/toluene at reflux, afforded in 87% yield a 1.4 :1 mixture of (E)-
and (Z)-2 after chromatographic separation.
2.2. Synthesis of the Homoallylic Alcohols (E)-3 and (Z)-3. As shown in Scheme 4,
treatment of b-cyclocitral (=2,6,6-trimethylcyclohex-1-ene-1-carbaldehyde; 12) with
ꢂmethallyl chlorideꢃ (=3-chloro-2-methylprop-1-ene) and Mg in Et2O at reflux under
Barbier conditions gave the alcohol 13 (84% yield), which was protected as the t-
Bu(Me)2Si (TBDMS) ether 14 under standard conditions in 83% yield. Hydroboration
of the latter with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF, followed by oxidative
hydrolysis, afforded the primary alcohol 15 as a 1.4 :1 diastereoisomer mixture in
78% yield. Subsequent Swern oxidation cleanly gave the aldehyde 16 (1.4 :1 diaster-
eoisomer mixture), which then underwent a Wadsworth–Emmons reaction to furnish
the a,b-unsaturated ester 17 as a 81:19 (E/Z) mixture (four diastereoisomers). Base-
assisted isomerization of 17 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at
95–988 resulted in the formation of an equilibrium mixture of 17 ((E/Z) 3 :1; 24%)
and the b,g-unsaturated ester 18 ((E/Z) 1.9 :1; 72%). This mixture was treated with
LiAlH4 in THF at reflux to afford, after chromatography, the alcohol 19 as an (E/Z)

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2.5 :1 mixture in 88% yield. Hydrolysis of the TBDMS group with tetrabutylammo-
nium fluoride trihydrate (TBAF) finally afforded the desired diol 3 as an (E/Z)
2.5 :1 mixture in 87% yield. The diasteroisomers of 3 were readily separable by chro-
matography.
Scheme 4
t
a) 3-Chloro-2-methylprop-1-ene, Mg, Et2O, reflux. b) NaH, Bu(Me)2SiCl, THF, reflux. c) 1. 9-Borabi-
cyclo[3.3.1]nonane (9-BBN), THF, r.t.; 2. 3N aq. NaOH soln., 35% aq. H2O2 soln., 458. d) Oxalyl chlo-
ride, DMSO, Et3N, CH2Cl2, À558 to r.t. e) (MeO)2P(O)CH2CO2Me, MeONa/MeOH, toluene, r.t. f)
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 95–988. g) LiAlH4, THF, reflux. h) Bu4NF·3 H2O, THF,
reflux.
2.3. Acid-Mediated Cyclization of (E)-2 and (Z)-2 to the Tricyclic Ethers 1a–1d. The
acid-mediated cyclizations of (E)-and ( Z)-2 were effected by treatment of each sub-
strate with an excess of chlorosulfonic acid (ClSO3H; 6 mol-equiv.) in 2-nitropropane
at À808 during 15 min. Subsequent neutralization with aqueous Na2CO3 solution,
extractive workup, and distillation in vacuo afforded the product mixtures in 30%
and 43% yield, respectively. Pure samples of 1c, 1d, and 20 were obtained by column
chromatography, and fully characterized spectroscopically. The 9 :1 mixture of 1a/1b
was inseparable by chromatography. Nevertheless, structure assignment of each isomer
was possible by in-depth NMR experiments.
The observed results are rationalized by kinetically controlled cyclizations, in anal-
ogy to our previous work [1]. A likely mechanistic rationale is presented in Scheme 5.

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Thus, in a first step, protonation of the terminal trisubstituted C=C bond of (E)-2 and
(Z)-2, followed by cyclization, generates the cyclohexyl cations (E,Z)-I and (E,E)-I in
the former case, and (Z,Z)-I and (Z,E)-I in the latter. Further cyclization of (E,E)-I and
(Z,E)-I, considered to be concerted via simultaneous CÀC and CÀO bond formation,
then occurs with good stereoselectivity to afford the tricyclic ethers 1c/1d (3.8 :1) and
1a/1b (9 :1), respectively. It is interesting to note that, in both cases, the MM2 energies
of 1c and 1d (39.2 and 39.4 kcal/mol), and of 1a and 1b (35.3 and 36.8 kcal/mol) qual-
itatively reflect the observed selectivities. The cation (Z,E)-I also undergoes a concom-
itant cyclization/[1,2]-H shift to the cyclohexenyl cation II, energetically favored by the
adjacent pseudoaxial H-atom, which then cyclizes to the tricyclic ether 20. The struc-
ture of 20 was confirmed by NMR spectroscopy, where a marked NOE was observed
between HÀC(9) and MeÀC(1). The low isolated yields of the products of these two
cyclizations suggests that there is no rapid interconversion between (E,Z)-I and
(E,E)-I, and between (Z,Z)-I and (Z,E)-I, respectively. It would thus appear likely
that (E,Z)-I and (Z,Z)-I both lead to polymeric products under the highly acidic reac-
tion conditions.
2.4. Acid-Mediated Cyclization of (E)-3 and (Z)-3 to the Tricyclic Ethers 1a–d. In
contrast, the acid-mediated cyclizations of (E)-and ( Z)-3 using ClSO3H in 2-nitropro-
pane at À808 afforded complex product mixtures containing only small amounts (ca.
5%) of the tricyclic ethers 1a–1d, and were best conducted with a large excess of tri-
fluoroacetic acid (TFA; 32 mol-equiv.) in CH2Cl2 at À108 (Scheme 6). Subsequent neu-
tralization with aqueous Na2CO3 solution, extractive workup, and distillation in vacuo
afforded the product mixtures in 35% and 37% yield, respectively. The product distri-
bution was determined by analytical gas chromatography (Table). The compounds
1a–1d were identified by comparison with authentic samples, and the tetrahydrofuran
21 was isolated by column chromatography, and characterized by mass spectrometry
and NMR spectroscopy5).
The observed results are consistent with a mechanism first involving heterolysis of
the allylic CÀO bond in (E)-and ( Z)-3 to afford the same allylic cations, (E,Z)-l/(E,E)-l
and (Z,Z)-l/(Z,E)-l, respectively, as proposed for the cyclizations of (E)-2 and (Z)-2
(vide supra). Not surprisingly, in view of the harsher reaction conditions, subsequent
cyclization proceeds with lower stereoselectivity with respect to CÀC bond formation.
In the former case, 1c/1d (1.3 :1; 27% yield) and 1b (<1% yield) were formed, whereas
in the latter case 1a/1b (1.4 :1; 32% yield) and 1d (<0.5% yield) were obtained. In both
cases, small amounts (7 and 5%, resp.) of 21 were isolated, a product resulting from CÀ
O bond formation via protonation at C(3) (see Scheme 6).
2.5. Acid-Mediated Cyclization of 10 to the Tricyclic Ethers 22a,b. Acid-mediated
cyclization of 10 (1:1 diastereoisomer mixture), under conditions identical to those
employed for (E)-and ( Z)-2 (excess of ClSO3H at À808), furnished 22a/22b 10 :1 in
27% yield (Scheme 7). Once again, this result may be rationalized by a kinetically con-
trolled, stepwise process. In a first step, 10 cyclizes non-stereoselectively to the cyclo-
hexyl cations (E/Z)-III, whereupon the former cation then undergoes a second cycliza-
tion to afford the allylic cation IV as a ꢂsynꢃ/ꢂantiꢃ diastereoisomer mixture. Only ꢂsynꢃ-
5
)
Structure determinations were greatly facilitated by comparison with the NMR spectra of analogous
tricyclic ethers from earlier work [1].

Helvetica Chimica Acta – Vol. 89 (2006)
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Scheme 5. Acid-Mediated Cyclizations of (E)- and (Z)-2, and Mechanistic Rationale for the Formation
of 1a–d and 20

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Table. Results of Acid-Mediated Cyclizations of Compounds 2 and 3. For details, see Exper. Part.
Substrate
Conditiona)
Product distribution [%]b)
Yield [%]
1a
1b
1c
1d
20
21
(E)-2
(Z)-2
(E)-3
(Z)-3
A
A
B
B
–
57
–
6
2
79
–
45
–
21
–
34
1
–
37
–
–
–
19
13
30
43
35
37
50
36
–
a) A: Substrate (0.3 g), ClSO3H (0.5 ml), 2-nitropropane (15 ml), À808; B: substrate (0.4 g), CF3CO2H (4
b
ml), CH2Cl2 (40 ml), À158 to À108. ) According to GC analysis of the distilled product after workup.
IV can undergo subsequent CÀO bond formation and ring closure to 22, but a prece-
dent in a closely analogous system [1d] indicated that ꢂantiꢃ-IV also leads to the same
product mixture via rapid interconversion of the ꢂsynꢃ and ꢂantiꢃ diastereoisomers. In
analogy with the cyclizations of (E)-2 and (Z)-2 (vide supra), it is noteworthy that
the MM2 energies of 22a and 22b (33.7 and 36.1 kcal/mol, resp.) qualitatively mirror
the observed selectivity for the former diastereoisomer.
Scheme 7. Acid-Mediated Cyclization of 10 (1 :1 diastereoisomer mixture) and Mechanistic Rationale
for the Formation of 22a,b
2.6. Organoleptic Properties of 1a–1d, 20, and 22a,b. Due to the small amounts of
compounds available, qualitative rather than quantitative odor evaluations were
effected. Thus, in comparison with racemic Ambrox, the didehydro analogues 1a–1d
were all perceived as amber and woody, though 1d clearly stood out as being the
most powerful of the four diastereoisomers. In contrast, the tetrahydropyran 20 only
exhibited weak woody notes. Finally, the tetradehydro analogues 22a/22b (10 :1) also
possessed strong ambery-woody tonalities.

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3. Conclusions. – Synthetic access to racemic didehydro and tetradehydro analogues
of the labdane tricyclic ether Ambrox was achieved, and their organoleptic properties
have been qualitatively evaluated. The described results provide further examples of
Brønsted acid-mediated polyene cyclizations, in which the initiating group is an alkene
and the terminating group is an alcohol. Although these cyclizations do not always
occur with high stereoselectivity, and proceed in only fair yields, the methodology is
suited to access tricyclic ethers from readily available starting materials, ethers that
would be difficult to prepare by other methods.
We thank Mr. W. Thommen and Mr. R. Brauchli for the measurement and interpretation of NMR
spectra. Dr. B. Winter and Dr. J.-Y. de Saint Laumer are kindly acknowledged for performing MM2 cal-
culations.
Experimental Part
General. See [1d]. GC Retention times (tR, in min) refer to the following conditions: SPB1 column
(15 m; i.d. 0.25 mm), 150–2208 at 108/min, He flow at 10 ml/min.
6,10-Dimethylundeca-4,5,9-trien-2-one (5). A mixture of 3,7-dimethyloct-6-en-1-yn-3-ol (4; 20 g, 0.13
mol), 2-methoxypropene (28 g, 0.39 mol), hydroquinone (60 mg), and TsOH·H2O (20 mg) in petroleum
ether (b.p. 80–1008, 50 ml) was heated at reflux under N2 during 16 h. After cooling to 258, a soln. of
AcONa (20 mg) in MeOH (2 ml) was added, and the mixture was evaporated and fractionally distilled
in vacuo to afford 5 (19.5 g, 78%). Pale-yellow oil. B.p. 57–598/0.05 mbar. Rf 0.65 (cyclohexane/
AcOEt 7:3). IR: 2916, 1719, 1443, 1356, 1222, 1156. 1H-NMR: 1.60 (s, 3 H); 1.69 (s, 3 H); 1.69 (d,
J=3, 3 H); 1.97 (2 H); 2.09 (2 H); 2.18 (s, 3 H); 3.05 (d, J=7, 2 H); 5.05–5.17 (m, 1 H); 5.10–5.20 (m,
1 H). 13C-NMR: 17.7 (q); 18.9 (q); 25.7 (q); 26.3 (t); 29.1 (q); 34.1 (t); 44.7 (t); 83.5 (d); 100.4 (s);
124.2 (d); 131.7 (s); 203.2 (s); 206.7 (s). MS: 192 (1, M+), 134 (9), 119 (11), 109 (100), 81 (34), 69 (48).
3-[(Trimethylsilyl)oxy]prop-1-yne. Me3SiCl (21.7 g, 0.2 mol) was added dropwise during 15 min to a
stirred soln. of prop-2-yn-1-ol (11.2 g, 0.2 mol) and 1H-imidazole (15 g, 0.22 mol) in DMF (100 ml) at 108
under N2. The mixture was allowed to attain 208 during 14 h, and then poured into sat. aq. NaHCO3 soln.
Extraction with pentane, workup, evaporation at 760 mbar, and fractional distillation afforded the title
1
compound (18.5 g, 72%). B.p. 85–888/760 mbar. H-NMR: 0.12 (s, 9 H); 2.34 (t, J=2.5, 1 H); 4.22 (d,
J=2.5, 2 H). MS: 128 (<0.5, M+), 113 (85), 83 (100).
4,8,12-Trimethyltrideca-6,7,11-trien-2-yne-1,4-diol (6). A 1.6M hexane soln. of BuLi (38 ml) was
added dropwise during 30 min to a stirred soln. of 3-[(trimethylsilyl)oxy]prop-1-yne (13 g, 70 mmol) in
THF (75 ml) at À908 under N2. After a further 30 min at À908, a soln. of 5 (10 g, 052 mmol) in THF
(25 ml) was added dropwise during 25 min, and, after a further 2 h, the mixture was poured into sat.
aq. NH4Cl soln. (300 ml). Extraction with Et2O was followed by vigorous stirring of the org. phase
with 5% aq. HCl (80 ml) at 208 during 2 h. Separation of the org. phase was followed by washing to neu-
trality with sat. aq. NaHCO3 soln. and brine. Workup, CC (cyclohexane/AcOEt 4 :1), and evaporation at
58/0.05 mbar afforded 6 as a 1:1 diastereoisomer mixture (9.2 g, 78%). Rf 0.14 (cyclohexane/AcOEt 7:3).
1H-NMR (after exchange with D2O): 1.51 (s, 3 H); 1.61 (s, 3 H); 1.69 (s, 3 H); 1.70 (d, J=3, 3 H); 1.97 (2
H); 2.11 (2 H); 2.30 (ddd, J=14, 8, 2.5, 1 H); 2.38 (dd, J=14, 8, 1 H); 4.29 (s, 2 H); 5.13 (2 H). 13C-NMR:
17.7 (q); 19.1, 19.3 (2q); 25.7 (q); 26.3 (t); 29.0 (q); 34.1, 34.2 (2t); 44.3 (t); 50.9 (t); 67.6 (s); 81.8 (s); 85.0
(d); 89.3 (s); 99.3, 99.4 (2s); 124.1, 124.2 (2d); 131.8, 131.9 (2s); 203.9 (s). MS: 248 (<0.5, M+), 230 (3), 212
(12), 197 (16), 169 (20), 129 (35), 91 (47), 69 (59), 41 (100).
4-Hydroxy-4,8,12-trimethyldeca-6,7,11-trien-2-yn-1-yl Acetate (7). Et3N (6.6 ml, 47 mmol) was added
dropwise during 15 min to a stirred soln. of 6 (9 g, 36 mmol) and Ac2O (4.2 ml, 44 mmol) in CH2Cl2 (10
ml) at 0–28. After a further 90 min (conversion almost complete by TLC analysis), 4-(dimethylamino)-
pyridine (DMAP; 15 mg) was added and, 30 min later, the mixture was poured into cold 10% aq. HCl.
Extraction with Et2O, workup, CC (cyclohexane/AcOEt 4 :1), and evaporation at 508/0.05 mbar afforded
7 as a 1:1 diastereoisomer mixture (9.9 g, 85%). Attempted distillation in vacuo resulted in extensive

Helvetica Chimica Acta – Vol. 89 (2006)
3081
1
decomposition. Rf 0.40 (cyclohexane/AcOEt 7:3). H-NMR (after exchange with D2O): 1.51 (s, 3 H);
1.60 (s, 3 H); 1.69 (s, 3 H); 1.70 (d, J=3, 3 H); 1.98 (2 H); 2.10 (s, 3 H); 2.11 (2 H); 2.29 (br. d, J=14,
8, 1 H); 2.38 (dd, J=14, 8, 1 H); 4.70 (s, 2 H); 5.06–5.18 (2 H). MS (more-volatile diastereoisomer):
290 (<0.5, M+), 212 (28), 197 (30), 187 (21), 169 (36), 144 (35), 129 (38), 69 (46), 43 (100). MS (less-vol-
atile diastereoisomer): 290 (<0.5, M+), 212 (27), 197 (25), 187 (12), 169 (37), 144 (38), 128 (37), 69 (48), 43
(100).
(2E)-4-[(1-Ethoxyethyl)oxy]-4,8,12-trimethyltrideca-2,6,7,11-tetraen-1-ol (9) and 4,8,12-Trimethyltri-
deca-2,3,5,6,11-pentaen-1-ol (10). A soln. of ethyl vinyl ether (3 g, 42 mmol) in toluene (5 ml) was
added dropwise during 10 min to a stirred soln. of 7 (5.6 g, 19 mmol) and TsOH·H2O (40 mg) in toluene
(25 ml) at À108 under N2. After 2 h at 08, the mixture was poured into sat. aq. NaHCO3 soln. and
extracted with Et2O. Workup, CC (cyclohexane/AcOEt 9 :1), and evaporation at 608/0.05 mbar afforded
crude 4-[(1-ethoxyethyl)oxy]-4,8,12-trimethyltrideca-6,7,11-trien-2-yn-1-yl acetate (8) as
a diaster-
eoisomer mixture (6.1 g, 87%; Rf 0.48 (cyclohexane/AcOEt 4 :1)), which was used without further puri-
fication. Thus, a soln. of 8 (5.5 g, 15 mmol) in THF (25 ml) was added dropwise during 30 min to a stirred
suspension of LiAlH4 (0.68 g, 18 mmol) in THF (15 ml) at 208 under N2. After a further 30 min, the mix-
ture was cooled to 108, and H2O (0.68 ml), 15% aq. NaOH soln. (0.68 ml), and H2O (2 ml) were succes-
sively added dropwise under vigorous stirring. After 30 min at 208, the mixture was filtered (Hyflo) and
the filtrate was evaporated in vacuo to afford a residual oil (4.9 g). CC (cyclohexane/AcOEt 4 :1) and
evaporation at 408/0.05 mbar furnished the more polar product 9 as a 1:1:1:1 diastereoisomer mixture
(2.6 g, 54%), and the less polar product 10 as a 1:1 diastereoisomer mixture (1.5 g, 43%). Attempted dis-
tillation in vacuo resulted in extensive decomposition.
Data of 9. Rf 0.15 (cyclohexane/AcOEt 4 :1). 1H-NMR (after exchange with D2O): 1.16 (t, J=7, 3 H);
1.27, 1.28 (2d, J=7, 3 H); 1.31, 1.37 (2s, 3 H); 1.60 (s, 3 H); 1.66, 1.67 (2d, J=2, 3 H); 1.69 (s, 3 H); 1.93 (2
H); 2.08 (br. dt, J=7, 7, 2 H); 2.24 (2 H); 3.42–3.59 (m, 2 H); 4.13–4.19 (2 H); 4.81 (q, J=6, 1 H);
4.94–5.02 (m, 1 H); 5.12 (br. t, J=7, 1 H); 5.70–5.85 (m, 2 H). 13C-NMR: 15.4, 15.5 (2q); 17.7 (q);
19.1 (q); 21.5, 21.9 (2q); 23.1, 23.2 (2q); 25.7, 26.3 (2q); 34.1 (t); 41.9, 42.1, 42.2 (3t); 58.3, 59.1 (2t);
63.3 (t); 85.6, 85.7 (2d); 94.4, 94.6 (2d); 98.4 (s); 124.3 (d); 129.2, 129.5 (2d); 131.6 (s); 136.2, 136.5
(2d); 203.1 (s). MS: 322 (<0.5, M+), 145 (14), 73 (100),
1
Data of 10. Rf 0.45 (cyclohexane/AcOEt 4 :1). H-NMR (after exchange with D2O): 1.60 (s, 3 H);
1.68 (6 H); 1.75, 1.76 (2s, 3 H); 1.95 (2 H); 2.09 (br. dt, J=7, 7, 2 H); 2.65 (d, J=7, 2 H); 4.07 (d, J=6,
2 H); 5.00 (m, 1 H); 5.13 (br. t, J=7, 1 H); 5.27 (m, 1 H). 13C-NMR: 17.7 (q); 18.6 (q); 19.2, 19.3 (2q);
25.7 (q); 26.3 (t); 34.2 (t); 35.0 (t); 60.8, 60.9 (2t); 87.8 (d); 91.3 (d); 99.7 (s); 102.2 (s); 124.2 (d); 131.6
(s); 200.4 (s); 201.9 (s). MS: 232 (1, M+), 189 (46), 145 (69), 105 (36), 91 (41), 69 (62), 43 (100).
(2E)-4-[(1-Ethoxyethyl)oxy]-4,8,12-trimethyltrideca-2,6,7,11-tetraen-1-yl Acetate (11). Et3N (1.35 ml,
9.6 mmol) was added dropwise during 10 min to a stirred mixture of 9 (2.5 g, 7.7 mmol), Ac2O (0.9 ml, 9.4
mmol), and DMAP (10 mg) in toluene (12 ml) at r.t. under N2. After a further 2 h at 35–408, the cooled
mixture was poured into cold 5% aq. HCl soln. (15 ml) and extracted with Et2O. Workup, filtration
through silica gel (cyclohexane/AcOEt 9 :1), and evaporation at 508/0.04 mbar afforded 11 as a
1
1:1:1:1 diastereoisomer mixture (2.75 g, 97%). Rf 0.26 (cyclohexane/AcOEt 9 :1). H-NMR: 1.17 (2t,
J=7, 3 H); 1.27, 1.29 (2d, J=7, 3 H); 1.31, 1.37 (2s, 3 H); 1.60 (s, 3 H); 1.66, 1.67 (2d, J=2, 3 H); 1.69
(s, 3 H); 1.90–1.96 (m, 2 H); 2.07 (s, 3 H); 2.03–2.13 (m, 2 H); 2.20–2.30 (m, 2 H); 3.37–3.57 (2 H);
4.58 (d, J=6, 2 H); 4.73–4.81 (m, 1 H); 4.92–5.02 (m, 1 H); 5.11 (br. t, J=7, 1 H); 5.65–5.92 (m, 2
H). 13C-NMR: 15.4 (q); 17.7 (q); 19.1 (q); 20.9 (q); 21.5, 22.0 (2q); 23.0, 23.1 (2 q); 25.7 (q); 26.3 (t);
34.1 (t); 41.8, 42.1 (2t); 59.8 (t); 64.7 (t); 85.4 (d); 94.7 (d); 98.4 (s); 123.8, 124.3 (2d); 131.5 (s); 139.4,
139.6 (2d); 170.7 (s); 203.1 (s). MS: 364 (<0.5, M+), 145 (9), 91 (11), 73 (100).
4,8,12-Trimethyltrideca-3,6,7,11-tetraen-1-ol (2). A soln. of 11 (2.6 g, 7.1 mmol) in THF (12 ml) was
added dropwise during 20 min to a stirred slurry of LiAlH4 (0.33 g, 8.7 mmol) in THF (8 ml) at 508
under N2, and the mixture was then heated at reflux for 5 d. Toluene was added, and the mixture was
heated at reflux for a further 24 h. The mixture was cooled at 108, and successively treated dropwise
with H2O (0.33 ml), 15% aq. NaOH soln. (0.33 ml), THF (20 ml), and H2O (1 ml). Filtration (Hyflo), con-
centration of the filtrate in vacuo, CC (toluene, AcOEt 9 :1), and evaporation at 508/0.04 mbar afforded 2
as a 1.4 :1 (E/Z)-mixture (1.45 g, 87%). Further purification by CC led to the isolation of (E)-2 (0.51 g)
and (Z)-2 (0.44 g).

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Helvetica Chimica Acta – Vol. 89 (2006)
1
Data of (E)-2. Rf 0.58 (toluene/AcOEt 85 :15). H-NMR (after exchange with D2O): 1.60 (s, 3 H);
1.68 (s, 3 H); 1.69 (s, 3 H); 1.75 (s, 3 H); 1.91–1.99 (m, 2 H); 2.09 (br. dt, J=7, 7, 2 H); 2.30 (dt, J=7,
7, 2 H); 2.71 (d, J=7, 2 H); 3.61 (br. t, J=6, 2 H); 4.93–5.01 (m, 1 H); 5.10–5.16 (m, 1 H); 5.18 (br. t,
J=7, 1 H). 13C-NMR: 16.2 (q); 17.7 (q); 19.2 (q); 25.7 (q); 26.4 (t); 31.6 (t); 34.2 (t); 40.2 (t); 62.2 (t);
88.8 (d); 99.3 (s); 120.6 (d); 124.3 (d); 131.5 (s); 138.0 (s); 202.0 (s). MS: 234 (<0.5, M+), 219 (4), 191
(17), 173 (18), 147 (34), 135 (39), 119 (59), 105 (65), 91 (48), 69 (53), 41 (100).
1
Data of (Z)-2. Rf 0.63 (toluene/AcOEt 85 :15). H-NMR (after exchange with D2O): 1.60 (s, 3 H);
1.68 (s, 3 H); 1.69 (2s, 6 H); 1.92–1.97 (m, 2 H); 2.08 (br. dt, J=7, 7, 2 H); 2.30 (dt, J=7, 7, 2 H); 2.67
(d, J=7, 2 H); 3.61 (br. t, J=6, 2 H); 4.94–5.02 (m, 1 H); 5.10–5.16 (m, 1 H); 5.20 (br. t, J=7, 1 H).
13C-NMR: 17.7 (q); 19.2 (q); 23.6 (q); 25.7 (q); 26.4 (t); 31.4 (t); 32.4 (t); 34.3 (t); 62.4 (t); 88.2 (d);
99.7 (s); 121.0 (d); 124.3 (d); 131.6 (s); 137.8 (s); 201.8 (s). MS: 234 (<0.5, M+), 219 (3), 191 (18), 173
(18), 147 (32), 135 (37), 119 (55), 105 (61), 93 (50), 69 (53), 41 (100).
Acid-Mediated Cyclization of (E)-2. A soln. of (E)-2 (0.3 g, 1.28 mmol) in 2 nitropropane (6 ml) was
added dropwise during 20 min to a mechanically stirred soln. of ClSO3H (0.5 ml, 7.5 mmol) in 2-nitropro-
pane (9 ml) at À808 under N2. After 15 min at À808, sat. aq. Na2CO3 soln. (6 ml) was added to the orange
mixture, which was then allowed to attain 208 over 1 h. Extraction with Et2O, workup, CC (cyclohexane/
AcOEt 19 :1), and bulb-to-bulb distillation in vacuo (140–1508/0.04 mbar) afforded a 79 :21 mixture of
1c/1d (90 mg, 30%) as a pale-yellow oil. Repeated CC (cyclohexane/AcOEt 19 :1) afforded anal. pure
samples (ca. 10–15 mg) of each diastereoisomer.
Data of (3aRS,9aSR,9bRS)-1,2,3a,4,6,7,8,9,9a,9b-Decahydro-3a,6,6,9a-tetramethylnaphtho[2,1-
b]furan (1c). Rf 0.26 (cyclohexane/AcOEt 9 :1). GC: tR 3.72. IR (CHCl3): 2966, 1465, 1363, 1290, 1143,
1
1087, 1044, 995. H-NMR: 1.04 (s, 3 H); 1.09 (s, 3 H); 1.19 (s, 3 H); 1.26 (s, 3 H); 3.82–3.92 (m, 1 H);
3.94–4.01 (m, 1 H); 5.49 (dd, J=6, 3, 1 H). 13C-NMR: 19.3 (t, C(8)); 19.4 (q, MeÀC(3a)); 23.2 (t,
C(1)); 28.2 (q, MeaÀC(6)); 29.8 (q, C(9a)); 32.5 (t, C(9)); 33.8 (q, MebÀC(6)); 37.1 (s, C(6)); 39.6 (s,
C(9a)); 40.5 (t, C(4)); 42.0 (t, C(7)); 56.4 (d, C(9b)); 65.6 (t, C(2)); 79.4 (s, C(3a)); 118.1 (d, C(5));
150.4 (s, C(5a)). MS: 234 (2, M+), 219 (3), 150 (63), 135 (99), 105 (26), 84 (100).
Data of (3aRS,9aRS,9bRS)-1,2,3a,4,6,7,8,9,9a,9b-Decahydro-3a,6,6,9a-tetramethylnaphtho[2,1-
b]furan (1d). Rf 0.30 (cyclohexane/AcOEt 9 :1). GC: tR 3.86. IR (CHCl3): 2929, 1472, 1378, 1142, 1046,
1
993. H-NMR: 1.06 (s, 3 H); 1.09 (s, 3 H); 1.13 (s, 3 H); 1.14 (s, 3 H); 1.20–1.30 (m, 1 H); 2.20–2.28
(m, 2 H); 3.85 (ddd, J=8, 8, 8, 1 H); 3.98 (ddd, J=9, 8, 3, 1 H); 5.44 (dd, J=4, 4, 1 H). 13C-NMR: 18.3
(t, C(8)); 19.5 (q, MeÀC(9a)); 21.8 (q, MeÀC(3a)); 23.5 (t, C(1)); 29.0 (q, MebÀC(6)); 33.2 (q, MeaÀ
C(6)); 36.3 (s, C(6)); 38.4 (s, C(9a)); 41.5 (t, C(4)); 42.0 (t, C(7)); 42.3 (t, C(9)); 57.3 (d, C(9b)); 65.4
(t, C(2)); 78.3 (s, C(3a)); 117.6 (d, C(5)); 149.9 (s, C(5a)). MS: 234 (1, M+), 219 (9), 150 (59), 135 (82),
105 (21), 84 (100).
Acid-Mediated Cyclization of (Z)-2. Using the same procedure as described above, (Z)-2 (0.3 g, 1.28
mmol) was treated with ClSO3H (0.5, l, 7.5 mmol) to afford, after CC (cyclohexane/AcOEt 19 :1) and
bulb-to-bulb distillation (140–1508/0.04 mbar), a 57:6 :37 mixture of 1a/1b/20 (130 mg, 43%). Repeated
CC (cyclohexane/toluene/AcOEt 10 :9 :1) afforded an inseparable 9 :1 mixture of 1a/1b (ca. 20 mg) and
20 (20 mg).
Data of (3aRS,9aRS,9bSR)-1,2,3a,4,6,7,8,9,9a,9b-Decahydro-3a,6,6,9a-tetramethylnaphtho[2,1-
b]furan (1a). Rf 0.33 (cyclohexane/AcOEt 9 :1). GC: tR 3.28. 1H-NMR: 1.07 (s, 3 H); 1.11 (s, 3 H); 1.14
(s, 3 H); 1.36 (s, 3 H); 1.20–1.80 (8 H); 1.92–1.99 (m, 1 H); 2.09 (dd, J=18, 3, 1 H); 2.39 (dd, J=18, 6,
1 H); 3.49–3.55 (m, 1 H); 3.71 (ddd, J=6, 6, 2, 1 H); 5.58 (dd, J=6, 3, 1 H). 13C-NMR: 17.7 (t, C(8));
25.8 (q, MeÀC(9a)); 30.1 (q, MeÀC(3a)); 31.4 (q, MeaÀC(6)); 32.2 (q, MebÀC(6)); 33.1 (t, C(1)); 34.8
(s, C(6)); 37.1 (t, C(4)); 37.2 (t, C(9)); 37.9 (s, C(9a)); 40.1 (t, C(7)); 57.9 (d, C(9b)); 64.1 (t, C(2));
80.8 (s, C(3a)); 117.9 (d, C(5)); 148.7 (s, C(5a)). MS: 234 (14, M+), 150 (33), 135 (100), 107 (14), 84 (61).
Data of (3aRS,9aSR,9bSR)-1,2,3a,4,6,7,8,9,9a,9b-Decahydro-3a,6,6,9a-tetramethylnaphtho[2.1-
b]furan (1b). Rf 0.33 (cyclohexane/AcOEt 9 :1). GC: tR 3.53. 1H-NMR: 1.01 (s, 3 H); 1.10 (s, 3 H);
1.11 (s, 3 H); 1.13 (s, 3 H); 0.80–1.80 (7 H); 1.81–1.90 (m, 1 H); 1.95–2.02 (m, 1 H); 2.25–2.35 (m, 2
H); 3.79–3.87 (m, 2 H); 5.63 (dd, J=7, 3.5, 1 H). 13C-NMR: 18.2 (t, C(8)); 19.9 (q, MeÀC(9a)); 26.7
(t, C(1)); 29.4 (q, MeaÀC(6)); 32.2 (q, MeÀC(3a)); 32.4 (q, MebÀC(6)); 35.2 (s, C(6)); 36.5 (t, C(4));
37.8 (t, C(9a)); 39.9 (s, C(7) or C(9)); 40.0 (t, C(9) or C(7)); 57.3 (d, C(9b)); 65.9 (t, C(2)); 77.9 (s,
C(3a)); 118.3 (d, C(5)); 152.7 (s, C(5a)). MS: 234 (6, M+), 150 (56), 135 (100), 107 (12), 84 (76).

Helvetica Chimica Acta – Vol. 89 (2006)
3083
Data of (2SR,6RS,6aRS,11SR)-4,5,6,6a,7,8,9,10-Octahydro-6a,10,10,11-tetramethyl-2,6-methano-2H-
3-benzoxocin (20). Rf 0.40 (cyclohexane/AcOEt 9 :1). GC: tR 3.87. 1H-NMR: 1.13 (s, 3 H); 1.14 (s, 3 H);
1.24 (d, J=7, 3 H); 1.26 (s, 3 H); 1.20–1.70 (7 H); 1.82–1.96 (m, 2 H); 2.03–2.11 (m, 1 H); 3.43 (dd,
J=11, 7, 1 H); 3.68–3.77 (m, 1 H); 3.84 (br. d, J=6, 1 H); 5.50 (d, J=6, 1 H). 13C-NMR: 16.6 (q); 18.8
(t); 21.6 (t); 27.6 (q); 29.8 (q); 30.0 (d); 33.1 (q); 36.2 (s); 37.3 (t); 39.7 (s); 42.1 (t); 45.9 (d); 57.3 (t); 71.0
(d); 116.7 (d); 157.0 (s). MS: 234 (14, M+), 175 (46), 135 (39), 119 (41), 105 (88), 91 (56), 55 (55), 41 (100).
3-Methyl-1-(2,6,6-trimethylcyclohex-1-en-1-yl)but-3-en-1-ol (13). A soln. of b-cyclocitral (12; 10 g, 67
mmol) and 3-chloro-2-methylprop-1-ene (8.2 g, 91 mmol) in Et2O (130 ml) was added dropwise during 75
min to a stirred slurry of Mg turnings (2.3 g, 95 mmol) in Et2O (20 ml) containing MeI (50 mg) at reflux
under N2. After 2 h at reflux, the mixture was cooled to 58, and sat. aq. NH4Cl soln. (50 ml) was added
dropwise. Extraction with Et2O, workup, CC (cyclohexane/AcOEt 19 :1), and bulb-to-bulb distillation in
vacuo afforded 13 (12.7 g, 84%). Colorless oil. B.p. 120–1308/0.03 mbar. Rf 0.32 (cyclohexane/AcOEt
1
9 :1). H-NMR (after exchange with D2O): 0.99 (s, 3 H); 1.12 (s, 3 H); 1.38–1.48 (m, 2 H); 1.50–1.61
(m, 2 H); 1.82 (s, 3 H); 1.85 (s, 3 H); 1.92–1.96 (m, 2 H); 2.17 (br. d, J=14, 1 H); 2.64 (dd, J=14, 11,
1 H); 4.40 (dd, J=11, 3, 1 H); 4.86 (s, 1 H); 4.90 (s, 1 H). 13C-NMR: 19.4 (t); 21.1 (q); 22.3 (q); 28.1
(q); 28.7 (q); 34.1 (t); 34.8 (s); 40.1 (t); 45.2 (t); 68.3 (d); 113.1 (t); 131.5 (s); 139.1 (s); 143.7 (s). MS:
208 (<0.5, M+), 153 (100), 119 (22), 109 (79), 95 (43), 69 (38).
4-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-1-ene
(14)6). A soln. of 13 (12.6 g, 55 mmol) in THF (20 ml) was added dropwise to a stirred slurry of NaH (60%
suspension in oil; 2.8 g, 70 mmol) in THF (80 ml) at r.t. under N2. The mixture was stirred at reflux during
7 h. Then, a soln. of t-Bu(Me2)SiCl (TBDMSCl) (10.9 g, 70 mmol) in THF (20 ml) was added dropwise.
After reflux for 2 h, the cooled mixture was poured into sat. aq. NaHCO3 soln. and extracted with Et2O.
Workup, CC (cyclohexane/AcOEt 98 :2), and distillation in vacuo afforded 14 (19.6 g, 83%). Colorless
oil. B.p. 81–828/0.02 Torr. Rf 0.74 (cyclohexane/AcOEt 9 :1). IR (CHCl3): 2930, 1472, 1375, 1082, 938,
1
835. H-NMR: À0.04 (s, 3 H); 0.04 (s, 3 H); 0.85 (s, 9 H); 0.98 (s, 3 H); 1.13 (s, 3 H); 1.32–1.47 (m, 2
H); 1.50–1.60 (m, 2 H); 1.76 (s, 3 H); 1.83 (s, 3 H); 1.91 (m, 2 H); 2.15 (br. d, J=14, 1 H); 2.54 (dd,
J=14, 11, 1 H); 4.37 (br. d, J=11, 1 H); 4.74 (br. s, 1 H); 4.76 (br. s, 1 H). 13C-NMR: À4.8 (q); À4.3 (q);
18.4 (s); 19.4 (t); 21.5 (q); 22.5 (q); 26.0 (3q); 28.6 (q); 29.7 (q); 34.2 (t); 34.6 (s); 40.5 (t); 46.8 (t); 69.9
(d); 112.4 (t); 131.0 (s); 139.0 (s); 143.6 (s). MS: 322 (<0.5, M+), 267 (27), 209 (3), 107 (8), 93 (9), 73 (100).
4-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-1-ol
(15). A soln. of 9-borabicyclo[3.3.1]nonane (9-BBN; 70 mmol) in THF (140 ml) was added dropwise dur-
ing 1 h to a stirred soln. of 14 (19.5 g, 45 mmol) in THF (80 ml) at r.t. under N2. After 5 h, the mixture was
cooled to À58, and 3N aq. NaOH soln. (32 ml) was added dropwise, followed by 35% aq. H2O2 soln. (32
ml). The mixture was stirred at 458 over 45 min, poured into H2O, and extracted with Et2O. The org. phase
was washed with 5% aq. HCl soln. and brine. Workup, CC (cyclohexane/AcOEt 9 :1), and bulb-to-bulb
distillation in vacuo afforded 15 as a 1.4 :1 diastereoisomer mixture (13.0 g, 78%). Colorless oil. B.p.
200–2108/0.04 mbar. Samples of the pure diastereoisomers were obtained by repeated CC (cyclohex-
ane/AcOEt 94 :6).
Data of Major Diastereoisomer of 15. Rf 0.26 (cyclohexane/AcOEt 9 :1). IR (CHCl3): 3620, 3500
1
(br.), 2930, 1472, 1255, 1076, 836. H-NMR (after exchange with D2O): 0.00 (s, 3 H); 0.10 (s, 3 H); 0.91
(s, 9 H); 0.96 (s, 3 H); 1.00 (d, J=7, 3 H); 1.13 (s, 3 H); 1.30–1.60 (m, 6 H); 1.83 (s, 3 H); 1.78–2.05
(m, 3 H); 3.49 (dd, J=11, 7, 1 H); 3.65 (dd, J=11, 4, 1 H); 4.33 (dd, J=11, 7, 1 H). 13C-NMR: À4.9
(q); À4.1 (q); 18.3 (q); 18.3 (s); 19.4 (t); 21.7 (q); 26.0 (3q); 28.5 (q); 29.7 (q); 32.8 (d); 34.2 (t); 34.5
(s); 40.5 (t); 42.0 (t); 66.9 (t); 69.7 (d); 131.0 (s); 139.1 (s). MS: 340 (<0.5, M+), 267 (18), 227 (49), 135
(20), 107 (27), 93 (28).
Data of Minor Diastereoisomer of 15. Rf 0.22 (cyclohexane/AcOEt 9 :1). IR (CHCl3): 3620, 3480
1
(br.), 2930, 1472, 1256, 1074, 836. H-NMR (after exchange with D2O): 0.00 (s, 3 H); 0.11 (s, 3 H); 0.90
(s, 9 H); 0.95 (s, 3 H); 0.97 (d, J=7, 3 H); 1.14 (s, 3 H); 1.14–1.24 (m, 1 H); 1.33–1.48 (m, 2 H);
1.52–1.60 (m, 2 H); 1.82 (s, 3 H); 1.85–2.05 (m, 4 H); 3.43–3.53 (m, 2 H); 4.34 (br. d, J=11, 1 H).
6
)
Systematic name: (1,1-dimethylethyl)(dimethyl){[3-methyl-1-(2,6,6-trimethylcyclohex-1-en-1-yl)-
but-3-en-1-yl]oxy}silane.
AHCTREUNG

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Helvetica Chimica Acta – Vol. 89 (2006)
13C-NMR: À5.0 (q); À4.1 (q); 15.7 (q); 18.4 (s); 19.4 (t); 21.7 (q); 26.0 (3q); 28.5 (q); 29.8 (q); 33.1 (d);
34.2 (t); 34.6 (s); 40.5 (t); 41.9 (t); 69.2 (t); 69.2 (d); 131.1 (s); 138.9 (s). MS: 340 (<0.5, M+), 267 (15), 227
(48), 135 (20), 107 (25), 93 (29), 75 (100).
4-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butanal
(16). DMSO (7.4 ml, 45 mmol) in CH2Cl2 (25 ml) was added dropwise to a stirred soln. of oxalyl chloride
(4.4 ml, 51 mmol) in CH2Cl2 (100 ml) at À558 under N2. After 2 min, a soln. of 15 (1.4 :1 diastereoisomer
mixture; 12.9 g, 35 mmol) in CH2Cl2 (20 ml) was added dropwise over 15 min at À558. After a further 15
min, CH2Cl2 (60 ml) was added, followed by Et3N (12.5 ml, 90 mmol). After 5 min, the mixture was
allowed to attain r.t. over 1 h. Brine was added, and the mixture was extracted with CH2Cl2. The org.
phase was washed successively with cold 5% aq. HCl and brine. Workup, CC (cyclohexane/AcOEt
19 :1), and bulb-to-bulb distillation in vacuo afforded 16 as a 1.4 :1 diastereoisomer mixture (10.2 g,
85%). Colorless oil. B.p. 190–2008/0.04 mbar. Samples of the pure diastereoisomers were obtained by
CC (cyclohexane/AcOEt 98 :2).
Data of Major Diastereoisomer of 16. Rf 0.47 (cyclohexane/AcOEt 19 :1). IR (CHCl3): 2931, 1721,
1
1256. H-NMR: À0.03 (s, 3 H); 0.05 (s, 3 H); 0.89 (s, 9 H); 0.99 (s, 3 H); 1.10 (s, 3 H); 1.13 (d, J=7, 3
H); 1.32–1.48 (m, 2 H); 1.50–1.59 (2 H); 1.82 (s, 3 H); 1.80–2.00 (m, 4 H); 2.67–2.79 (m, 1 H); 4.29
(dd, J=11, 3, 1 H); 9.70 (d, J=3, 3 H). 13C-NMR: À5.0 (q); À4.1 (q); 14.6 (q); 18.4 (s); 19.3 (t); 21.6
(q); 26.0 (3 q); 28.4 (q); 29.8 (q); 34.2 (t); 34.5 (s); 40.0 (t); 40.5 (t); 43.7 (d); 69.2 (d); 131.4 (s); 138.7
(s); 205.2 (d). MS: 338 (<0.5, M+), 281 (7), 149 (6), 119 (25), 107 (23), 93 (23), 75 (100).
Data of Minor Diastereoisomer of 16. Rf 0.33 (cyclohexane/AcOEt 19 :1). IR (CHCl3): 2931, 1719,
1
1719, 1472, 1217, 1085, 836. H-NMR: 0.00 (s, 3 H); 0.10 (s, 3 H); 0.89 (s, 9 H); 0.94 (s, 3 H); 1.12 (d,
J=7, 3 H); 1.14 (s, 3 H); 1.27–1.49 (m, 3 H); 1.50–1.61 (m, 2 H); 1.84 (s, 3 H); 1.87–2.01 (m, 2 H);
2.31–2.41 (m, 1 H); 2.64–2.76 (m, 1 H); 4.33 (dd, J=11, 3, 1 H); 9.69 (d, J=1.5, 1 H). 13C-NMR: À5.0
(q); À4.2 (q); 12.1 (q); 18.4 (s); 19.3 (t); 21.7 (q); 26.0 (3 q); 28.5 (q); 29.8 (q); 34.2 (t); 34.6 (s); 38.4
(t); 40.4 (t); 44.2 (d); 68.5 (d); 132.0 (s); 138.1 (s); 205.2 (d). MS: 338 (<0.5, M+), 281 (7), 149 (20),
119 (30), 107 (28), 93 (27), 75 (100).
Methyl 6-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)ACHTREhUNG ex-
2-enoate (17). A soln. of MeONa (ca. 5.4M in MeOH; 5.1 ml, 28 mmol) in MeOH (10 ml) was added drop-
wise during 15 min to a stirred mixture of 16 (7.7 g, 22 mmol) and trimethylphosphonoacetate (5.8 g, 32
mmol) in toluene (40 ml) at 3 to 68 under N2. The mixture was allowed to attain r.t. during 30 min, stirred
for a further 1 h, and then poured into cold 10% aq. NH4Cl soln. Extraction with (Et2O), workup, and con-
centration in vacuo afforded crude 17 (9.5 g, 93%) as a pale-yellow oil consisting of an (E/Z) 81:19 mixture.
An anal. sample (160 mg) was subjected to CC (cyclohexane/AcOEt 98 :2), which afforded the more-polar
(E)-17 and the less-polar (Z)-17 isomers, both as 1.2 :1 diastereoisomer mixtures.
Data of (E)-17 (1.2 :1 diastereoisomer mixture). 1H-NMR: À0.05, À0.02 (2s, 3 H); 0.05, 0.08 (2s, 3
H); 0.89, 0.88 (2s, 9 H); 0.87, 0.92 (2s, 3 H); 1.06 (2d, J=7, 3 H); 1.06, 1.12 (2s, 3 H); 1.78 (2s, 3 H);
2.61–2.73 (m, 1 H); 3.74, 3.71 (2s, 3 H); 4.10, 4.31 (2 br. d, J=9, 1 H); 5.84, 5.78 (2d, J=15, 1 H); 6.84,
6.97 (2dd, J=15, 6, 1 H). 13C-NMR: À5.0, À4.9 (2q); À4.1, À4.0 (2q); 16.8 (2d); 18.4 (2s); 19.4 (2t);
21.1, 21.7 (2q); 26.0, 26.1 (2q); 28.4, 28.5 (2q); 29.8, 29.9 (2q); 33.0, 34.2 (2d); 34.2 (2t); 34.6, 34.7 (2s);
40.4, 40.5 (2t); 43.9, 45.3 (2t); 51.5 (2q); 68.4, 69.4 (2d); 118.3, 120.4 (2d); 131.2, 131.6 (2s); 138.4, 138.7
(2s); 154.5, 155.8 (2d); 167.4, 167.6 (2s). MS: 394 (<0.55, M+), 337 (66), 267 (100), 199 (15), 75 (76).
Data of (Z)-17 (1.2 :1 diastereoisomer mixture). 1H-NMR: À0.07, À0.02 (2s, 3 H); À0.02, 0.08 (2s, 3
H); 0.87, 0.90 (2s, 9 H); 0.95 (2s, 3 H); 1.06, 1.03 (2d, J=7, 3 H); 1.08, 1.11 (2s, 3 H); 1.79 (2s, 3 H);
3.57–3.67 (m, 1 H); 3.69, 3.70 (2s, 3 H); 4.08, 4.31 (2 br. d, J=9, 1 H); 5.65, 5.78 (2d, J=10, 1 H); 6.03,
6.07 (2dd, J=10, 8, 1 H). 13C-NMR: À5.2, À4.9 (2q); À4.1, À4.0 (2q); 18.3 (2s); 18.7 (2d); 19.4 (2t);
21.2, 21.7 (2q); 26.1, 26.2 (2q); 28.4, 28.5 (2q); 29.8, 30.0 (2q); 30.7, 31.3 (2d); 34.2 (2t); 34.7 (2s); 40.5
(2t); 45.0, 46.7 (2t); 51.1, 51.2 (2q); 69.0, 70.1 (2d); 117.5, 119.3 (2d); 131.0, 131.2 (2s); 138.9, 139.0
(2s); 155.8, 156.0 (2d); 166.6, 166.9 (2s). MS: 394 (<0.5, M+), 337 (76), 267 (100), 199 (12), 75 (72).
Methyl 6-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)-
hex-3-enoate (18). A soln. of 17 ((E/Z) 81:19; 9.3 g, 20 mmol) in 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU; 50 ml) was heated at 95–988 during 5 h under N2. The cooled mixture was poured into cold
aq. HCl soln. (120 ml) and extracted with Et2O. Workup and concentration in vacuo afforded a pale-yel-
low oil (8.8 g), which, according to GC analysis, contained a mixture of 17 ((E/Z) 3 :1; 24%) and 18 ((E/

Helvetica Chimica Acta – Vol. 89 (2006)
3085
Z) 1.9 :1; 72%). Purification of an aliquot (200 mg) by CC (cyclohexane/AcOEt 98.5 :1.5) afforded pure
samples of the more polar (E)-and the less polar ( Z)-isomer of 18.
Data of (E)-18. 1H-NMR: À0.05 (s, 3 H); À0.01 (s, 3 H); 0.82 (s, 9 H); 0.97 (s, 3 H); 1.11 (s, 3 H); 1.67
(s, 3 H); 1.81 (s, 3 H); 2.19 (br. d, J=12, 1 H); 2.52 (dd, J=12, 8, 1 H); 2.96–3.13 (m, 2 H); 3.67 (s, 3 H);
4.30–4.40 (m, 1 H); 5.39 (br. t, J=6, 1 H). 13C-NMR: À4.9 (q); À4.3 (q); 16.4 (q); 18.3 (s); 19.4 (t); 21.6
(q); 25.9 (3q); 28.6 (q); 29.7 (q); 33.8 (t); 34.2 (t); 34.6 (s); 40.5 (t); 48.2 (t); 51.6 (q); 69.6 (d); 118.1 (d);
131.2 (s); 136.9 (s); 138.8 (s); 172.7 (s). MS: 394 (<0.5, M+), 267 (100), 185 (11), 75 (17), 73 (27).
Data of (Z)-18. 1H-NMR: À0.03 (s, 3 H); À0.01 (s, 3 H); 0.81 (s, 9 H); 0.97 (s, 3 H); 1.11 (s, 3 H); 1.79
(s, 3 H); 1.87 (s, 3 H); 2.77 (dd, J=12, 9, 1 H); 3.03–3.11 (m, 1 H); 3.18–3.26 (m, 1 H); 3.68 (s, 3 H);
4.39–4.43 (m, 1 H); 5.40 (br. t, J=6, 1 H). 13C-NMR: À4.8 (q); À4.3 (q); 18.4 (s); 19.4 (t); 21.7 (q);
23.3 (q); 25.9 (3q); 28.7 (q); 29.7 (q); 33.7 (t); 34.2 (t); 34.6 (s); 40.5 (t); 40.7 (t); 51.8 (q); 69.2 (d);
118.3 (d); 131.4 (s); 137.0 (s); 138.9 (s); 173.1 (s). MS: 394 (<0.5, M+), 267 (100), 185 (4), 75 (17), 73 (23).
6-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)hex-3-en-
1-ol (19). A soln. of 18 ((E/Z) 1.9 :1; 8.6 g, 15 mmol) in THF (40 ml) was added dropwise during 10 min to
a stirred slurry of LiAlH4 (0.6 g, 15 mmol) in THF (20 ml) at 25–408 under N2. After reflux for 1 h, the
cooled mixture was treated with H2O (0.6 ml), and further THF (20 ml) was added. Subsequently, 15%
aq. NaOH soln. (0.6 ml) was added cautiously, and, after stirring for a further 10 min, more H2O (1.6 ml)
was added. Stirring at r.t. for 45 min was followed by filtration through Celite. Concentration in vacuo
gave a yellow viscous oil (7.6 g), which was purified by CC (cyclohexane/AcOEt 95 :5) and bulb-to-
bulb distillation (200–2108/0.05 mbar) to afford 19 ((E/Z) 2.5 :1) as a pale-yellow oil (5.7 g, 88%). An
aliquot (200 mg) was subjected to CC (cyclohexane/AcOEt 9 :1), which afforded pure (E)-and ( Z)-19.
Data of (E)-19. Rf 0.21 (cyclohexane/AcOEt 9 :1). IR (CHCl3): 3640, 2930, 1472, 1255, 1081, 837. 1H-
NMR (after exchange with D2O): À0.05 (s, 3 H); 0.00 (s, 3 H); 0.84 (s, 9 H); 0.97 (s, 3 H); 1.11 (s, 3 H);
1.32–1.46 (m, 2 H); 1.49–1.60 (m, 2 H); 1.68 (s, 3 H); 1.82 (s, 3 H); 1.78–1.88 (m, 2 H); 2.17 (br. d, J=14,
1 H); 2.15–2.40 (m, 2 H); 2.50 (dd, J=14, 11, 1 H); 3.57–3.69 (m, 2 H); 4.35 (br. d, J=11, 1 H); 5.18 (br. t,
J=7, 1 H). 13C-NMR: À4.8 (q); À4.2 (q); 16.4 (q); 18.3 (s); 19.4 (t); 21.6 (q); 26.0 (3q); 28.7 (q); 29.7 (q);
31.8 (t); 34.2 (t); 34.6 (s); 40.6 (t); 48.6 (t); 62.5 (t); 69.8 (d); 122.3 (d); 131.1 (s); 136.6 (s); 139.0 (s). MS:
366 (<0.5, M+), 267 (13), 135 (14), 93 (9), 73 (100).
Data of (Z)-19. Rf 0.25 (cyclohexane/AcOEt 9 :1). IR (CHCl3): 3620, 3460 (br.), 2930, 1472, 1377,
1
1255, 1078, 937. H-NMR (after exchange with D2O): À0.02 (s, 3 H); 0.03 (s, 3 H); 0.83 (s, 9 H); 0.98
(s, 3 H); 1.12 (s, 3 H); 1.33–1.46 (m, 2 H); 1.50–1.60 (m, 2 H); 1.78 (s, 3 H); 1.87 (s, 3 H); 1.80–2.02
(m, 2 H); 1.98 (br. d, J=14, 1 H); 2.23–2.47 (m, 2 H); 2.86 (dd, J=14, 11, 1 H); 3.56–3.67 (m, 2 H);
4.44 (dd, J=11, 3, 1 H); 5.20 (br. t, J=7, 1 H). 13C-NMR: À4.7 (q); À4.3 (q); 18.4 (s); 19.4 (t); 21.7
(q); 23.4 (q); 26.0 (3q); 28.7 (q); 29.7 (q); 31.7 (t); 34.3 (t); 34.5 (s); 40.4 (t); 40.6 (t); 62.7 (t); 69.4 (d);
122.7 (d); 131.4 (s); 136.7 (s); 139.1 (s). MS: 366 (<0.5, M+), 267 (28), 135 (4), 93 (10), 73 (100).
4-Methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)hex-3-en-1,6-diol (3). A mixture of 19 ((E/Z) 2.5 :1; 5.5
g, 13 mmol) and tetrabutylammonium fluoride trihydrate (TBAF; 8.5 g, 27 mmol) in THF (60 ml) was
heated at reflux during 3 d under N2. The cooled mixture was poured into H2O and extracted with
Et2O. Workup and concentration in vacuo afforded crude 3 (3.9 g, 87%; (E/Z) 2.5 :1) as a yellow oil. Puri-
fication by CC (cyclohexane/AcOEt 60 :40) and recrystallization (pentane/Et2O 9 :1) afforded the pure,
more polar (E)-3 (2 g) and the less-polar (Z)-3 (0.9 g) isomers.
Data of (E)-3. M.p. 94–958. IR (CHCl3): 3422 (br.), 2932, 1385, 1047. 1H-NMR (after exchange with
D2O): 0.99 (s, 3 H); 1.11 (s, 3 H); 1.38–1.46 (m, 2 H); 1.51–1.61 (m, 2 H); 1.74 (s, 3 H); 1.84 (s, 3 H);
1.90–1.98 (m, 2 H); 2.19 (br. d, J=14, 1 H); 2.25–2.43 (m, 2 H); 2.60 (dd, J=14, 11, 1 H); 3.60–3.70
(m, 2 H); 4.37 (dd, J=11, 3, 1 H); 5.30 (br. t, J=7, 1 H). 13C-NMR: 16.2 (q); 19.4 (t); 21.2 (q); 28.2
(q); 28.7 (q); 31.5 (t); 34.2 (t); 34.8 (s); 40.1 (t); 46.9 (t); 62.1 (t); 68.1 (d); 123.8 (d); 131.5 (s); 136.3
(s); 139.3 (s). MS: 252 (<0.5, M+), 153 (100), 109 (71), 95 (44), 69 (42).
Data of (Z)-3. M.p. 72–738. 1H-NMR (after exchange with D2O): 1.00 (s, 3 H); 1.11 (s, 3 H);
1.88–2.00 (m, 2 H); 1.52–1.60 (m, 2 H); 1.73 (s, 3 H); 1.91 (2s, 6 H); 2.18–2.27 (m, 1 H); 2.45–2.56
(m, 1 H); 3.05 (dd, J=12, 10, 1 H); 3.55–3.61 (m, 1 H); 3.69–3.74 (m, 1 H); 4.44 (dd, J=10, 2, 1 H);
5.30–5.37 (m, 1 H). 13C-NMR: 19.3 (t); 21.2 (q); 23.6 (q); 28.1 (q); 28.7 (q); 31.4 (t); 34.1 (t); 34.8 (s);
38.6 (t); 40.0 (t); 62.0 (t); 68.3 (d); 124.8 (d); 131.5 (s); 135.7 (s); 139.6 (s). MS: 252 (<0.5, M+), 234
(17), 153 (100), 109 (49).

3086
Helvetica Chimica Acta – Vol. 89 (2006)
Acid-Mediated Cyclization of (E)-3. A soln. of (E)-3 (0.4 g, 1.57 mmol) in CH2Cl2ACHTRE(UNG 5 ml) was added to
a mechanically stirred soln. of CF3CO2H (4 ml, 51 mmol) in CH2Cl2 (35 ml) at À158 under N2. The color
gradually changed to yellow and then to orange. After a further 45 min at À108, sat. aq. Na2CO3 soln. (40
ml) was rapidly added dropwise (temperature rise to 108). Extraction with Et2O, workup, and concentra-
tion in vacuo gave a yellow viscous oil (390 mg), which was filtered over silica gel, eluting with cyclohex-
ane/AcOEt 95 :5, to afford, after bulb-to-bulb distillation (160–1708/0.03 mbar), a colorless oil (142 mg,
35%). The oil was shown by GC analysis to consist of four major products: 1c (45%), 1d (34%), 1b (2%),
and 2-methyl-2-[(E)-2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethenyl]tetrahydrofuran (21; 19%). The latter
compound was isolated by CC (cyclohexane/AcOEt 98 :2).
Data of 21. IR (CHCl3): 2968, 1458, 1029. 1H-NMR: 0.98 (s, 6 H); 1.36 (s, 3 H); 1.42–1.47 (m, 2 H);
1.55–1.75 (m, 4 H); 1.65 (s, 3 H); 1.90–2.00 (m, 4 H); 3.85–3.95 (m, 2 H); 5.40 (d, J=16, 1 H); 6.00 (br. d,
J=16, 1 H). MS: 234 (22, M+), 219 (43), 119 (41), 105 (69), 98 (58), 85 (61), 71 (66), 43 (100).
Acid-Mediated Cyclization of (Z)-3. A soln. of (Z)-3 (0.4 g, 1.57 mmol) in CH2Cl2 ACHTRE(UNG 5 ml) was submit-
ted to the same cyclization conditions and workup as described above to afford a colorless oil (150 mg,
37%) consisting of 1a (50%), 1b (36%), 1d (1%), and 21 (13%), which were identical to authentic sam-
ples (vide supra).
Acid-Mediated Cyclization of 10. Using the same procedure as described for the cyclizations of (E)-2
and (Z)-2 (vide supra), compound 10 (1:1 diastereoisomer mixture; 1.3 g, 5.3 mmol) was treated with
ClSO3H (2 ml, 30 mmol) at À808 to afford, after CC (cyclohexane/AcOEt 19 :1) and bulb-to-bulb distil-
lation in vacuo (140–1508/0.04 mbar), a 10 :1 mixture of 22a and 22b (330 mg, 27%). Repeated CC (cy-
clohexane/AcOEt 19 :1) allowed the isolation of samples (ca. 40 mg) of 22a and 22a/22b (ca. 1:1).
Data of (3aRS,9aRS)-2,3a,4,6,7,8,9,9a-Octahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan (22a). Rf
0.36 (cyclohexane/AcOEt 9 :1). GC: tR 3.22. IR: 2926, 1464, 1363, 1296, 1206, 1139, 1084, 1060, 1040,
1
1025. H-NMR: 1.07 (s, 3 H); 1.15 (s, 3 H); 1.38 (s, 3 H); 1.43 (s, 3 H); 1.20–1.70 (4 H); 1.77–1.92 (m,
2 H); 2.20–2.38 (m, 2 H); 4.56 (dd, J=12, 2, 1 H); 4.66 (br. d, J=12, 1 H); 5.46 (br. s, 1 H); 5.59 (dd,
J=7, 3.5, 1 H). 13C-NMR: 19.4 (t, C(8)); 24.4 (q, MeÀC(3a)); 28.4 (q, MeÀC(9a)); 29.3 (q, MebÀ
C(6)); 33.7 (q, MeaÀC(6)); 35.9 (s, C(6)); 39.3 (t, C(4)); 40.1 (s, C(9a)); 40.3 (t, C(9)); 41.2 (t, C(7));
73.0 (t, C(2)); 86.9 (s, C(3a)); 116.1 (d, C(1)); 118.4 (d, C(5)); 148.8 (s, C(5a)); 155.2 (s, C(9b)). MS:
232 (11, M+), 217 (100), 175 (8), 147 (23), 119 (12), 91 (14), 43 (32).
Data of (3aRS,9aSR)-2,3a,4,6,7,8,9,9a-Octahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan (22b). Rf
0.37 (cyclohexane/AcOEt 9 :1). GC: tR 3.53. 1H-NMR: 1.12 (s, 3 H); 1.18 (s, 3 H); 1.30 (s, 3 H); 1.40 (s, 3
H); 1.20–1.70 (4 H); 1.82–1.96 (m, 2 H); 2.31–2.41 (m, 2 H); 4.53 (dd, J=12, 2, 1 H); 4.66 (br. d, J=12, 1
H); 5.28 (br. s, 1 H); 5.43 (dd, J=6, 3.5, 1 H). 13C-NMR: 18.5 (t, C(8)); 27.2 (q, MeÀC(9a)); 27.4 (q, MeÀ
C(3a)); 28.8 (q, MebÀC(6)); 33.0 (q, MeaÀC(6)); 36.5 (s, C(6)); 38.8 (s, C(9a)); 39.1 (s, C(9)); 41.8 (t,
C(7)); 42.0 (t, C(4)); 72.8 (t, C(2)); 85.4 (s, C(3a)); 112.8 (d, C(1)); 117.4 (d, C(5)); 147.4 (s, C(5a));
154.3 (s, C(9b)). MS: 232 (10, M+), 217 (100), 175 (9), 147 (22), 119 (11), 91 (13), 43 (27).
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Received September 28, 2006