Enantioselective access to (-)-Ambrox starting from β-farnesene

Article abstract of DOI:10.1002/hlca.201300286

Starting from inexpensive (E)-β-farnesene (1), an eight-step enantioselective synthesis of the olfactively precious Ambrox ((-)-2a) has been performed. The crucial step is the catalytic asymmetric isomerization of (2E,6E)-N,N-diethylfarnesylamine (3) to t

Full text of DOI:10.1002/hlca.201300286

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Enantioselective Access to (ꢀ)-Ambroxꢀ Starting from b-Farnesene1)
by Christian Chapuis
Firmenich SA, Corporate R & D Division, P.O. Box 239, CH-1211 Geneva 8
(phone: þ 41-22-7803610; fax: þ 41-22-7803334; e-mail: christian.chapuis@firmenich.com)
Dedicated to the memory of Dr. G. Bernardinelli (University of Geneva)
Starting from inexpensive (E)-b-farnesene (1), an eight-step enantioselective synthesis of the
olfactively precious Ambroxꢀ ((ꢀ)-2a) has been performed. The crucial step is the catalytic asymmetric
isomerization of (2E,6E)-N,N-diethylfarnesylamine (3) to the corresponding enamine (ꢀ)-(R,E)-4a,
applying Takasagoꢁs well-known industrial methodology. The resulting dihydrofarnesal ((þ)-(R)-5)
(90% yield, 96% ee), obtained after in situ hydrolysis (AcOH, H2O), was then cyclized under catalytic
SnCl4 conditions, via its corresponding unreported enol acetate (ꢀ)-(R)-4b, to afford trans-decalenic
aldehyde (þ)-6a. Subsequent transformations furnished bicyclic ketone (ꢀ)-8a and unsaturated nitrile
(þ)-11, both reported as intermediates to access to (ꢀ)-2a.
Introduction. – (E)-b-Farnesene (1), a precursor of farnesane biodiesel [1], is
readily obtained by biotechnology from Brazilian sugar cane syrop [2] and has recently
received particular attention as an extremely inexpensive starting material [3]. In a
previous work, we succeeded in circumventing the patented BINAP/RhI Takasago
industrial asymmetric isomerization process to access to optically active (þ)-(R)-
citronellal and (ꢀ)-isopulegol, and thus (ꢀ)-l-menthol, from myrcene [4]. In analogy,
farnesene 1 was submitted to our modified conditions [5a], with Ambroxꢀ ((ꢀ)-2a) as
the potential target (Scheme).
Results and Discussion. – By analogy to myrcene [6], neat (E)-b-farnesene (1) was
treated at 508 with Et2NH in the presence of either metallic Li (75% yield) or BuLi
(87% yield) to afford (2E,6E)-N,N-diethylfarnesylamine (3) stereoselectively [7].
Further treatment with 0.01 mol-equiv. of both [Rh(COD)2]CF3SO3 (COD ¼ cy-
cloocta-1,5-diene) and (S,R)-(tBu)josiphos (¼di(tert-butyl){(R)-1-[(S)-2-diphenyl-
phosphinoferrocenyl]ethyl}phosphine) in refluxing THF for 18 h readily furnished
the so far unreported (1E)-enamine (ꢀ)-(R)-4a, which was hydrolyzed in situ (AcOH/
1
)
Work presented at the University of Geneva (12th June and 18th September 2012, as well as 12th
June 2013, course 14C031 Perfume and Flavor Chemistry), and discussed at the IChOPAN Warsaw
(6th September 2012).
ꢂ 2014 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Scheme
i) HNEt2, Li, 75%, or HNEt2, BuLi, 87%. ii) [Rh(COD)2]CF3SO3, THF, 668, (S,R)-(tBu)josiphos; 90%
yield, 92% ee; or (S)-BINAP; 93% yield, 96% ee. iii) AcOH, H2O, 668, > 98%. iv) Ac2O, AcOK, Et3N;
87%, 7:3 ((1E)/(1Z)). v) 0.6 mol-equiv. SnCl4, CH2Cl2, 208, 52%. vi) mCPBA, CH2Cl2; 71%. vii) KOH,
MeOH, H2O, 658; 88%. viii) PCC, CH2Cl2, 84 – 86%. ix) HCꢁCLi(H2NCH2)2, THF, ꢀ 208 to 258, 84%.
x) [V2O6SiPh2]n, xylene, 1458; 85%; or SOCl2, py, ꢀ 408 to 208; 78%, then tBuOK, tBuOH, 828; 94%. xi)
LiAlH4, THF; > 98% for (þ)-12a; CrO3 · H2SO4, acetone, 60% for (þ)-12b. xii) FeCl3, ClCH2CH2Cl,
258, 77%; or TsOH, MeNO2, 1008; 36% from (þ)-12a; Amberlyst-15, toluene, 1108, or HI, CHCl3;

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73 – 75% from (þ)-12b. xiii) NaCN, NaHSO3, THF, H2O; 36%. xiv) P2O5, xylene, 1408; or Li3PO4 290 –
3408; 4 – 16% from (þ)-10a; or toluylboronic acid, Pd(OAc)2; 8 – 10% from (ꢀ)-10b or (ꢀ)-10c. xv)
H2NOH · HCl, EtOH, Pr3P3O6, 84% from (þ)-9a; or H2NOH · HCl, EtOH, py, then Ac2O, 1008; 75% via
i
(þ)-9b. xvi) DIBAL-H, toluene, ꢀ 788, then NaBH4, PrOH, 208, (þ)-12a; 78%; or excess KOH,
ethylene glycol, 1508 4 h, (þ)-12c, or 12 h, (þ)-12b; 14 – 82%; or glycerol, 2008, 5 h, (þ)-12b; 82 – 83%.
xvii) Me2S, Me2SO, Me2SO4, NaOH; 70 – 78%. xviii) Al(OiPr)3, AlCl3, toluene 1108; 25%. xix) HIO3,
DMSO, 46%. xx) H2NOH · HCl, EtOH, py; > 98%. xxi) SO2Cl2, CH2Cl2, 408, then LiCl, DMF, 1508; 3 –
6%. xxii) O2, Et2O; 60%. xxiii) MeLi, Et2O, ꢀ 788 to 258; 91%. xxiv) (EtO)2P(O)CH2CN, tBuOK, THF,
828; 98%. xxv) (CF3SO2)2O, 2,6-lutidine, CH2Cl2; 94%; or MeSO2Cl, Et3N, CH2Cl2; 97%. xxvi) LDA,
HMPA, MeCOOtBu, ꢀ 788; 89%. xxvii) SOCl2, DMAP, pyridine, ꢀ 408 to 208; 40 – 97%. xxviii)
Ph3(Me)PI, NaH, DMSO, 40 – 1858; 39%.
H2O) to give the known dihydrofarnesal ((þ)-(R)-5) [8a] in 90% yield and 92% ee2).
When performed under the same conditions, but with (S)-BINAP (BINAP ¼ (1,1’-
binaphthalene-2,2’-diyl)bis(diphenylphosphine)) as ligand, (þ)-(R)-5 was isolated in
93% yield and 96% ee. Aldehyde (þ)-(R)-5 was then converted quantitatively to the so
far unreported corresponding (1E)/(1Z)-enol acetate (ꢀ)-(R)-4b (Ac2O, AcOK, Et3N
[11][[12]). We were particularly interested in submitting this acyclic intermediate to
the catalytic SnCl4 cyclization conditions that we had earlier reported for the
corresponding monocyclic analog [12], and were gratified to isolate the trans-decalenic
aldehyde (þ)-(1S,2R,4aS,8aS)-6a as a 75 :25 (1S)/(1R) mixture in 52% yield3). This
aldehyde mixture could be quantitatively epimerized (0.01 mol-equiv. EtONa, EtOH,
788) to a 95 :5 (1S)/(1R) mixture. Recognizing (þ)-6a as a possible intermediate for
access to the olfactively precious (ꢀ)-2a4), we decided to synthesize, via different
routes, known precursors. The first route involved a BaeyerꢀVilliger oxidation,
performed according to the conditions reported by Margot et al. on cyclocitronellal
(mCPBA (meta-chloroperbenzoic acid), CH2Cl2, [17]), and delivered the so far
unreported formate (ꢀ)-7a in 71% yield. Either simple saponification (KOH, MeOH,
H2O, 88% yield) or reduction (LiAlH4, Et2O, 98% yield) afforded the secondary
bicyclic alcohol (ꢀ)-7b5). Further oxidation (PCC (¼ pyridinium chlorochromate),
CH2Cl2, 84% yield) gave the corresponding ketone (ꢀ)-8a [13d][19], earlier used by
Fehr, via Li acetylide addition of the ethylenediamine complex6) and MeyerꢀSchuster
rearrangement to (þ)-9a7), towards the synthesis of Ambroxꢀ ((ꢀ)-2a) [24]. A second
2
)
For rac-5, see [8b – 8d]. Under our previously reported asymmetric hydrogenation conditions ((þ)-
(R,R)-chiraphos, (¼(þ)-(2R,3R)-2,3-bis(diphenylphosphino)butane), 0.01 mol-equiv. Rh4(CO)12,
H2, [5]), recently developed and exploited on an industrial scale by BASF chemists to access to (ꢀ)-
l-menthol [9], via continuous dynamic distillation of neral from citral, resulting from the elegant
cascade ClaisenꢀCope methodology, earlier reported by Thomas and Ozainne [10], (ꢀ)-(S)-5 was
also obtained from (2E,6E)-farnesal [10c], in 96% yield and 41% ee.
For rac-6a, see [12][13].
3
4
)
)
For reviews, and recent syntheses of Ambroxꢀ ((ꢀ)-2a) and analogs, see [14][15] and [16],
respectively.
5
6
7
)
)
)
For rac-7b, see [18].
For Li acetylide addition to (ꢀ)-8a under non-chelated conditions (55% yield), see [20].
The chiroptical properties of this natural product, isolated by Demole and Engist from Oriental
tobacco, were never reported [21][22]. For rac-9a, see [23a], for telescoped MeyerꢀSchuster and
reduction conditions (PhCO2H, VO(OSiPh3)3, xylene, 1408, then directly MeOH, NaBH4), see
[23b].

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route comprised treatment of aldehyde (þ)-6a with NaCN and NaHSO3 in THF/H2O
[25], followed by dehydration (P2O5, xylene, 1408, 16% yield [26a]) of the resulting
56 :44 cyanohydrin mixture (þ)-10a to afford the unsaturated nitrile (þ)-11 [27]8).
Saponification under basic conditions (excess KOH, ethylene glycol, 1508, or glycerol,
2008, 5 h, 82 – 83% yield [30][31b]) furnished the corresponding acid (þ)-12b [32a]9),
a known precursor of either (þ)-sclareolide ((þ)-2b) [31a]10) or b-ambrol ((þ)-12a)
[24]11). One synthetic step may be saved by performing the reported one-pot tandem
DIBAL-H (¼diisobutylaluminium hydride)/NaBH4 reduction of (þ)-11 to (þ)-12a
[27], the final cyclization to (ꢀ)-2a having also been reported [24][35]12). To avoid the
linear approach via (ꢀ)-8a, we also searched for an alternative route from (þ)-6a,
which is based on a C1 homologation, using a CoreyꢀChaykovsky reaction under the
conditions we had reported earlier (Me2S, Me2SO, Me2SO4, NaOH, [36]). Accordingly,
the equatorial epoxy derivative (þ)-13 could be cleanly isolated in 78% yield as a 56 :44
mixture of stereoisomers13). It is noteworthy that, under these conditions, we could
also start directly from the 75 :25 (1S)/(1R) mixture of non-epimerized aldehyde14).
Opening of the epoxy ring under basic conditions in order to access a positional isomer
8
)
For other dehydration conditions, see [26b – 26e]. Alternatively, pyrolysis (2908 – 3408, 4% yield), or
b-elimination (toluylboronic acid, Pd(OAc)2, 8 – 10% yield, [26f]) from the corresponding triflate
(ꢀ)-10b (Tf2O, 2,6-lutidine, CH2Cl2, 94% from 10a), or methanesulfonate 10c (MsCl, Et3N, CH2Cl2,
97% from 10a), were less efficient. Nitrile (þ)-11 was also obtained in a single step from (þ)-9a
(H2NOH · HCl, EtOH, Pr3P3O6, 84% yield) by analogy to [28]. When this reaction was performed
according to the usual two-step procedure (H2NOH · HCl, EtOH, py (¼pyridine), then Ac2O, 1008,
75% yield), the intermediate oxime (þ)-9b was isolated quantitatively. A quantitative short cut
from (ꢀ)-8a to (þ)-11 was performed by addition of an excess of (EtO)2P(O)CH2CN and tBuOK in
THF at 668 as described in [29]. It is noteworthy that the NMR analyses reported for 11 in [27] are
incomplete and quite different, in addition to the erroneous chiroptical properties of the starting
material used by the Spanish authors (see Footnote 19). We were unable to obtain a copy of their
analyses.
9
)
For rac-12b, see [32b – 32f]. Alternatively, by analogy to [32g], (þ)-12b was also obtained in 60%
yield by Jones oxidation of (þ)-9a. For analytical purpose, we also isolated the intermediate
acetamide (þ)-12c after a few hours at 1508. The known and fully characterized ester (þ)-12d,
previously obtained from (ꢀ)-8a (LDA (¼LiN(iPr)2), HMPA (¼hexamethylphosporamide),
MeCOOtBu, ꢀ 788, 89%, then SOCl2, DMAP, pyridine, 208, 97%), was quantitatively reduced to
(þ)-12a (LiAlH4, Et2O) by Hagiwara et al. [34].
10
11
12
)
)
)
For Amberlyst-15, toluene, 1108, or HI, CHCl3 lactonization conditions, see [31b][31c], respectively.
[a]2D0 ¼ 83.3 (c ¼ 0.2, CHCl3), [33]: [a]2D0 ¼ 110 (c ¼ 2.4, CHCl3); [34]: [a]2D0 ¼ ꢀ41.8 (c ¼ 1.0, MeOH).
The TsOH, MeNO2 cyclization conditions of (þ)-12a to (ꢀ)-2a were initially discovered by Dr. S. D.
Escher (Firmenich SA, unreported results, 1984).
13
14
)
)
For alternative oxiranylation conditions using either ClCH2Br, CH2Br2; or CH2I2, with BuLi or
metallic Li, see [37][38].
t
Under non-reversible conditions for the generation of the sulfur ylide (tBuOK, BuOH, Me3SOI,
20% yield; or NaH, DMSO, Me3SOI, 54% yield) [38a][39], the oxiranylation took place prior to
epimerization, and the signals of the minor axial ethylene oxides were detectable at 3.05, 2.90, and
1
2.37 ppm in the H-NMR spectrum. Furthermore, these conditions were less efficient, as heavier
uncharacterized material, resulting from ylide double addition, was also observed.

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of (þ)-12a was unsuccessful under a variety of conditions, due to the extreme steric
crowding of the axial H-atom at C(1)15). We eventually found that treatment of (þ)-13
with Al(OiPr)3 in refluxing toluene in the presence of AlCl3 gave the so far unreported
saturated aldehyde (ꢀ)-14a in 25% yield16). An oxidative elimination (SO2Cl2,
CH2Cl2, 40817), then LiCl, DMF, 1008 [42f][43d]) allowed us to access again to
intermediate (þ)-9a, albeit in a miserable 3% yield. Additionally, reduction of
aldehyde (ꢀ)-14a18) (LiAlH4, THF, 94% yield) occurred readily to give the
corresponding alcohol (þ)-15a. Finally, the oxidation of aldehyde (þ)-6a to b-
bicyclofarnesal ((þ)-16a), a natural compound first isolated by Demole and Engist
from Oriental tobacco [21], then by Toyota et al. from liverwort Diplophyllum
serrulatum [45], was also performed with SO2Cl2, CH2Cl2, 408, then LiCl, DMF at 1508
in 6% yield19). Further autoxidation (O2, Et2O, [36], 60% yield) afforded the known
acid (þ)-16b20) [46a]. Finally, treatement with MeLi in Et2O from ꢀ 788 to 258, as
reported for the fully characterized racemate [52], allowed us to determine the
15
)
Epoxide (þ)-13 remained unchanged when treated with either LDA, tBuOK, or NaNH2 in refluxing
THF, toluene, or xylene, even in the presence of additional LiBF4 or LiClO4. A similar inertness
t
was observed, either with BuOK in refluxing tBuOH, even in the presence of the same Li salts, or
with Li/(H2NCH2)2 at 115 8. For alternative non-attempted conditions via pyrolysis on Li3PO4, see
[40].
16
17
)
)
Besides (þ)-15a (18% yield). For stereoisomers of 15, see [41].
MS of the intermediate a-chloroaldehyde: 270 (5, Mþ), 257 (12), 255 (30), 221 (10), 192 (28), 177
(25), 137 (12), 123 (100), 121 (15), 109 (37), 107 (20), 97 (12), 95 (43), 93 (18), 81 (40), 79 (17), 69
(50), 67 (22), 55 (28), 41 (28), 32 (18), 28 (31).
18
)
Identical reduction of the reported aldehyde (ꢀ)-14b [13b – 13d] ([a]2D0 ¼ ꢀ11.2 (c ¼ 1.2, CHCl3))
afforded in 95% yield the corresponding weakly amber-like alcohol (þ)-15b, earlier delivered to
our perfumers by Mr. C. Vial (Firmenich SA, 1980, unpublished results), who obtained it by using an
independent approach. The reverse oxidation of (þ)-15b to (ꢀ)-14b was performed in 86% yield
with PCC in CH2Cl2. The potential C1 homologation of (þ)-6a via Wittig/epoxidation was not
attempted [44].
19
)
Enal (þ)-16a (0.37%) was also isolated by B. Maurer from longoza concrete, extracted from
Hedychium flavum (Zingiberaceae), a flower growing in Madagascar (Firmenich SA, unpublished
results, 1987). The chiroptical properties of the natural product were not reported in the original
papers, but astonishingly, b-drimenal (4aS,8aS)-16a was reported as exhibiting either dextrorotatory
[46] or laevorotatory [27][47] chiroptical properties. For a report, in which laevorotatory properties
were mentioned in the discussion and dextrorotatory properties in the experimental part, see [48].
For the enantiomer, see [46f]. The chemical yield of the intermediate a-chloroaldehyde (20%) was
66% based on the recovered pure unreacted stereoisomer (þ)-6a. Addition/elimination of Br2 in
dioxane according to [42] was unsuccessful on diastereoisomerically pure (þ)-6a, while treatment
with HIO3 in DMSO [49] afforded the saturated acid (þ)-6b in 46% yield. Attempted addition of
MeNO2 to (ꢀ)-8a failed (either NaOH, EtOH, 258 – 808; or DBU (¼1,8-diazabicyclo[5.4.0]undec-7-
ene), 208 – 1008; or (H2NCH2)2, 0.15 – 1.0 mol-equiv., 1008) [50]. Treatments of (ꢀ)-8a with either
t
(EtO)2P(O)CH2NO2 [51], BuOK, THF, 668; or MeCN, deprotonated with either (Me3Si)2NLi,
s
CeCl3, or BuLi, in THF, ꢀ 788, were not attempted.
20
)
Also found in Oriental tobacco, although not reported in [21].

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chiroptical properties of the methyl ketone (þ)-16c (90% yield)21). Alternatively, the
key intermediate ketone (ꢀ)-8a was also submitted to the CoreyꢀChaykovsky
oxiranylation conditions (Me2S, Me2SO, Me2SO4, NaOH, 70% yield [36]) to afford a
85 :15 mixture of epoxides (þ)-18a/18b22).
Conclusions. – We have described, via (þ)-10a and (þ)-11, an eight-step
enantioselective access to Ambroxꢀ ((ꢀ)-2a) from the inexpensive and industrially
available b-farnesene (1), comprising the in situ hydrolysis of (ꢀ)-(R)-4a23). This
methodology, based on Takasagoꢁs industrial process, may also give access to other
members of the labdane/podocarpane family24), starting from either intermediates
(þ)-6a and (ꢀ)-14a, or the natural products (þ)-9a and (þ)-16a, all possessing an
aldehyde functionality for suitable chemical modifications.
´
I am indebted to my apprentices Mayeul Cretignier and Tim Vernet for their experimental skills.
Experimental Part
General. See [5a].
(2E,6E)-N,N-Diethyl-3,7,11-trimethyldodeca-2,6,10-trien-1-amine ((2E,6E)-3). In a Schlenk flask
with a magnetic bar were placed (E)-b-farnesene (1; 2.04 g, 9.98 mmol), Et2NH (1.39 g, 18.97 mmol), and
Li (25 mg, 3.60 mmol) under N2. The sealed Schlenk flask was heated to 508 and was stirred for 5 h. The
cold mixture was poured into ice-water, the upper org. layer was separated, and the aq. layer was
extracted with Et2O. The combined org. layer was washed with brine, dried (Na2SO4), and concentrated.
Bulb-to-bulb distillation afforded the desired material in 75% yield. When BuLi (18.97 mmol) was used
instead of Li, (2E,6E)-3 was isolated in 87% yield. B.p. 1358/0.2. IR: 2967, 2922, 1668, 1447, 1381, 1288,
21
)
For an alternative direct conversion or analogous addition of MeLi to an enal, followed by
DessꢀMartin oxidation, see [53]. Alternatively, the Rupe rearrangement of a 56:44 mixture of (1R/
S,2R,4aS,8aS)-1-ethynylperhydro-2,5,5,8a-tetramethyl-4aH-naphthalenol [20][24] (HCO2H [54],
79% yield) also afforded (þ)-16c. The inverse sequence (þ)-16c ! (þ)-16b ! (þ)-16a may
eventually be performed by analogy to [54b], followed by LiAlH4/THF [55], then MnO2/CH2Cl2
[55] or PCC/CH2Cl2 treatment [47], since the haloform oxidative degradation (NaOH, Br2, 1,4-
dioxane, 208, or NaOH, NaOCl, 1,4-dioxane, 508) was totally inefficient. Dehydration of the
intermediate mixture of propargyl alcohols (CuSO4, toluene 1108, or xylene 1408) was unsuccessful,
while (SOCl2, py, ꢀ 408 [19i][20][34], 40% yield) furnished the so far unreported (þ)-17. Further
direct one-pot reduction via hydroboration/NaBH4 reduction, using either 9-borabicyclo[3.3.1]no-
nane [56], or the less hindered BH3 · THF complex [34], THF, from ꢀ 108 to 208, then K2CO3, 3%
H2O2, and then H2O, MeOH, NaBH4 was inefficient.
22
)
For analytical purposes, ketone (ꢀ)-8a was treated with Ph3PCH3I, NaH, DMSO, THF, 668 [57a],
and the Wittig adduct (ꢀ)-8b [19b][57b] (39% yield) was epoxidized (AcO2H, AcONa, CH2Cl2) to
afford a 55:45 mixture of (þ)-18a/18b in 91% yield. This mixture remained unchanged when
treated with either LiNiPr2, or LiNEt2, or NaNH2, THF, ꢀ 788 to 08, in an unsuccessful attempt to
obtain the desired allylic alcohol [27][46e], as a known precursor of (þ)-16a [47]. Further additions
of MeNO2, 1,3-dithiane, or KCN to (þ)-18a/18b, were not attempted.
23
24
)
)
Alternatively, a nine-step sequence, via (ꢀ)-8a, (þ)-12d, and (þ)-12a, comprising in situ
saponification of (ꢀ)-7a to (ꢀ)-7b. The direct oxidation of ( þ )-6a to ( ꢀ )-8a under the new
conditions presented by Baldovini et al. (30% H2O2, DMSO, MeOH, KOH, 708) at Flavors &
Fragrances 2013 (11 – 13 Sept., Leipzig) were not attempted.
We initially performed the beginning of this sequence in the enantiomeric series, using the first
available optically active ligand we had.

Helvetica Chimica Acta – Vol. 97 (2014)
203
1200, 1166, 1108, 1068, 1054, 984, 834, 763. 1H-NMR: 5.27 (qt, J ¼ 1.3, 6.8, 1 H); 5.11 (qt, J ¼ 1.3, 6.8, 1 H);
5.09 (qt, J ¼ 1.3, 7.1, 1 H); 3.06 (d, J ¼ 7.1, 2 H); 2.51 (q, J ¼ 7.1, 4 H); 2.14 – 1.95 (m, 8 H); 1.68 (br. d, J ¼
1.3, 3 H); 1.64 (s, 3 H); 1.60 (s, 6 H); 1.03 (t, J ¼ 7.1, 6 H ) . 13C-NMR: 137.7 (s); 135.1 (s); 131.3 (s); 124.4
(d); 124.1 (d); 121.7 (d); 50.5 (t); 46.7 (2t); 39.8 (t); 39.7(t); 26.8 (t); 26.4 (t); 25.7 (q); 17.7 (q); 16.3 (q);
16.0 (q); 11.8 (2q). MS: 277 (9, Mþ), 262 (7), 208 (39), 140 (78), 126 (54), 124 (16), 110 (15), 93 (14), 86
(58), 81 (48), 73 (36), 69 (98), 67 (22), 58 (100), 56 (17), 41 (53).
(ꢀ)-(1E,3R,6E)-N,N-Diethyl-3,7,11-trimethyldodeca-1,6,10-trien-1-amine ((ꢀ)-(3R)-4a). Isolated
quantitatively by simple concentration and bulb-to-bulb distillation of the reaction mixture after
isomerization of (2E,6E)-3, as described for (þ)-(3R,6E)-5. B.p. 1008/0.07 mbar. [a]2D0 ¼ ꢀ8.0 (c ¼ 3.5,
CHCl3). IR: 2965, 2917, 2853, 1650, 1449, 1375, 1244, 1197, 1095, 935, 834, 807, 783. 1H-NMR: 5.80 (d, J ¼
13.8, 1 H); 5.06 – 5.14 (m, 2 H); 4.04 (dd, J ¼ 8, 13.8, 1 H); 2.93 (q, J ¼ 7, 4 H); 2.04 – 2.10 (m, 2 H); 1.95 –
2.01 (m, 4 H); 1.68 (s, 3 H); 1.60 (s, 3 H); 1.58 (s, 3 H); 1.18 – 1.36 (m, 3 H); 1.04 (t, J ¼ 7, 6 H); 0.97 (t, J ¼
6.7, 3 H). 13C-NMR: 135.8 (d); 134.4 (s); 131.2 (s); 125.8 (d); 124.5 (d); 105.1 (d); 44.5 (t); 39.8 (t); 38.9
(t); 35.0 (d); 26.8 (t); 26.0 (t); 25.7 (q); 22.8 (q); 17.7 (q); 16.0 (q); 12.2 (q). MS: 277 (4, Mþ), 262 (4), 208
(57), 126 (100), 112 (5), 110 (6).
(ꢀ)-(1E,3R,6E)-3,7,11-Trimethyldodeca-1,6,10-trien-1-yl Acetate ((ꢀ)-(3R)-4b). (þ)-(3R,6E)-Dihy-
drofarnesal (5; 17.65 g, 79 mmol) was added to a soln. of Et3N (17.13g, 168 mmol) and AcOK (1.25 g,
12.61 mmol) in Ac2O (125 ml). The soln. was heated at 1208 for 5 h, cooled to 208, poured into H2O, and
extracted with hexane. The org. phase was washed with sat. aq. NaHCO3, brine, dried (Na2SO4),
concentrated, and bulb-to-bulb distilled to afford the desired material in 87% yield as a 29 :71 (1Z/1E)
mixture. tR (Silicon DB1, 1008, 1 min, then 108/min to 2208, 0.32 mm, 50 m, He) 12.62 and 12.9 min,
resp.25). B.p. 1558/0.1 mbar. [a]D20 ¼ ꢀ7.0 (c ¼ 2.4, CHCl3). IR: 2961, 2917, 2870, 2855, 1756, 1672, 1452,
1369, 1216, 1104, 1087, 1043, 933. 1H-NMR ((1E,3R,6E)-isomer): 7.06 (dd, J ¼ 1, 12.5, 1 H); 5.30 (dd, J ¼
8.7, 12.5, 1 H); 5.10 – 5.06 (m, 2 H); 2.69 (q, J ¼ 6.4, 1 H); 2.22 – 1.94 (m, 7 H); 1.68 (s, 3 H); 1.60 (s, 6 H);
1.37 – 1.23 (m, 4 H); 1.02 (d, J ¼ 6.4, 3 H). 13C-NMR: 168.3 (s); 135.2 (s); 134.6 (d); 131.3 (s); 124.4 (d);
124.2 (d); 120.6 (d); 39.8 (t); 37.2 (t); 32.0 (d); 26.7 (t); 25.7 (q); 25.6 (t); 20.9 (q); 20.7 (q); 17.7 (q); 16.0
(q). MS: 264 (0, Mþ), 161 (13), 135 (19); 123 (11), 109 (40), 107 (23), 93 (23), 84 (19), 81 (17), 71 (32), 69
(92), 67 (18), 43 (100), 41 (47). Deduced from the mixture, 1H-NMR ((1Z,3R,6E)-isomer): 6.99 (dd, J ¼
1, 6.4, 1 H); 5.10 – 5.06 (m, 2 H); 4.68 (dd, J ¼ 6.4, 9.6, 1 H); 2.69 (q, J ¼ 6.4, 1 H); 2.22 – 1.94 (m, 7 H);
2.13 (s, 3 H); 1.68 (s, 3 H); 1.58 (s, 6 H); 1.37 – 1.23 (m, 4 H); 0.99 (d, J ¼ 6.4, 3 H). 13C-NMR: 168.2 (s);
135.1 (s); 133.1 (d); 131.2 (s); 124.4 (d); 124.2 (d); 120.2 (d); 39.8 (t); 37.3 (t); 32.2 (d); 26.7 (t); 25.7 (q);
25.6 (t); 20.9 (q); 20.7 (q); 17.7 (q); 16.0 (q). MS: 264 (0, Mþ), 161 (14), 135 (15), 123 (11), 109 (38), 107
(22), 93 (25), 84 (16), 81 (17), 71 (28), 69 (92), 67 (20), 43 (100), 41 (47).
(þ)-(3R,6E)-3,7,11-Trimethyldodeca-6,10-dienal (¼( þ )-(3R,6E)-Dihydrofarnesal; 5). In a glove-
box, a soln. of [Rh(cod)2]CF3SO3 in THF (0.01m; 2.5 ml, 0.025 mmol) was added to (S,R)-(tBu)josiphos
(13.6 mg, 0.025 mmol; 25 ml flask with a key stopper). After stirring for 1 h, (2E,6E)-3 (1.0m/THF, 10 ml,
10 mmol) was added and the key stopper-closed flask, equipped with a condenser, was connected to a
Schlenk line. The condenser was purged with Ar, then the key stopper was opened, and the clear soln. was
refluxed for 20 h. To the soln. cooled to 08, AcOH/H2O 1:4 (5 ml) was added, and after 5 min at 08, and
then 30 min at 208, the soln. was extracted with Et2O, the extract was washed with H2O (10 ml), 15%
NaOH soln. (2 ꢂ 10 ml), H2O to neutral, dried (MgSO4), concentrated, and then bulb-to-bulb distilled
25
)
For GC identification purpose, (6Z)-5 [8d] was similarly transformed to (1Z,6Z)-4b (tR (Silicon
DB1): 12.2 min. MS: 264 (1, Mþ), 189 (8), 161 (18), 148 (6), 135 (21), 122 (17), 113 (11), 109 (42), 107
(23), 95 (16), 93 (22), 84 (15), 81 (19), 79 (9), 71 (32), 69 (100), 67 (16), 43 (70), 41 (38)), and
(1E,6Z)-4b (tR (Silicon DB1): 12.5 min. MS: 264 (1, Mþ), 204 (7), 189 (10), 161 (26), 135 (25), 126
(8), 123 (20), 113 (16), 109 (56), 107 (32), 105 (10), 97 (10), 95 (17), 93 (32), 84 (20), 81 (21), 71 (43),
69 (100), 67 (20), 55 (12), 53 (10), 43 (94), 41 (45)).

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Helvetica Chimica Acta – Vol. 97 (2014)
(1108/0.01 mbar): pure (þ)-(3R,6E)-5 (90% yield). [a]2D0 ¼ þ12.94 (c ¼ 3.4 CHCl3), 92% ee; [a]D20 þ 13.0
(c ¼ 4.0, CHCl3), 93% yield, 96% ee using (S)-BINAP26). IR: 2957, 2923, 2871, 1725, 1453, 1377, 1107,
1080, 1019, 983, 870, 834, 741. 1H-NMR: 9.75 (t, J ¼ 2.4, 1 H); 5.12 – 5.06 (m, 2 H); 2.41 (ddd, J ¼ 2.1, 5.7,
16, 1 H); 2.22 (ddd, J ¼ 2.7, 7.8, 16, 1 H); 2.11 – 1.96 (m, 6 H); 1.68 (d, J ¼ 1.0, 3 H); 1.60 (s, 6 H); 1.42 – 1.25
(m, 3 H); 0.97 (d, J ¼ 6.6, 3 H). 13C-NMR: 203.0 (d); 135.4 (s); 131.3 (s); 124.3 (d); 124.0 (d); 51.0 (t); 37.7
(t); 36.9 (t); 27.8 (d); 26.7 (t); 25.7 (q); 25.3 (t); 19.9 (q); 17.7 (q); 16.0 (q). MS: 222 (2, Mþ), 179 (25), 161
(11), 123 (22), 109 (30), 93 (12), 81 (14), 69 (100), 67 (19), 41 (39). Tallow, burnt candle, waxy. The odor
of the (ꢀ)-(3S,6E) enantiomer was aldehydic, watery, weak.
(þ)-(1S,2R,4aS,8aS)-Decahydro-2,5,5,8a-tetramethylnaphthalene-1-carbaldehyde ((þ)-6a). SnCl4
(1.0m in CH2Cl2, 3.6 ml, 3.6 mmol) was added to a stirred soln. of (ꢀ)-(3R)-4b (1.5 g, 5.67 mmol) in
CH2Cl2 (20 ml) at 208. After 18 h, the mixture was poured into H2O and extracted with Et2O. The org.
phase was washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), and concentrated. CC (SiO2;
cyclohexane/AcOEt 97:3 to 95 :5) and then bulb-to-bulb distillation afforded (þ)-6a in 52% yield as a
3 :1 mixture of trans/cis stereoisomers27). B.p. 1508/0.9 mbar. [a]D20 ¼ þ15.3 (c ¼ 0.83, CHCl3). IR: 2959,
2925, 2869, 2848, 1717, 1457, 1385, 1367, 1238, 1120, 1079, 1034, 975, 933, 784, 760. 1H-NMR (main
isomer): 9.69 (d, J ¼ 4, 1 H); 2.08 (m, 1 H); 1.90 (dq, J ¼ 13, 3, 1 H); 1.09 (s, 3 H); 0.86 (s, 3 H); 0.84 (s,
3 H); 0.78 (d, J ¼ 7, 3 H ) . 13C-NMR: 207.6 (d); 70.4 (d); 54.3 (d); 41.9 (t); 40.3 (t); 38.5 (s); 35.6 (t); 33.5
(q); 33.3 (s); 27.6 (d); 21.8 (q); 21.6 (t); 20.6 (q); 18.4 (t); 15.9 (q). MS: 222 (15, Mþ), 207 (15), 189 (12),
152 (10), 138 (67), 123 (100), 109 (62), 107 (19), 97 (26), 95 (66), 93 (22), 91 (17), 84 (92), 81 (66), 79
(25), 77 (15), 71 (37), 69 (87), 67 (38), 55 (57), 41 (53). Deduced from the mixture with the minor
unreported stereoisomer (1R,2R,4aS,8aS)-decahydro-2,5,5,8a-tetramethylnaphthalene-1-carbaldehyde:
1H-NMR: 9.91 (d, J ¼ 4, 1 H); 2.08 (m, 1 H); 1.90 (dq, J ¼ 13, 3, 1 H); 1.13 (s, 3 H); 0.89 (s, 3 H); 0.86 (s,
3 H); 0.78 (d, J ¼ 7, 3 H ) . 13C-NMR: 206.5 (d); 67.0 (d); 49.4 (d); 42.2 (t); 39.7 (s); 38.2 (t); 37.4 (t); 33.5
(q); 33.0 (s); 30.1 (t); 29.1 (d); 24.2 (q); 22.3 (q); 18.0 (t); 15.9 (q). MS: 222 (3, Mþ), 207 (7), 189 (6), 138
(64), 123 (74), 109 (37), 107 (14), 97 (17), 95 (48), 93 (19), 91 (17), 84 (100), 81 (48), 79 (21), 77 (12), 71
(27), 69 (58), 67 (28), 55 (38), 41 (43), 28 (48). Epimerization with 0.01 mol-equiv. EtONa in refluxing
EtOH afforded quantitatively a 95 :5 mixture. [a]2D0 ¼ þ33.9 (c ¼ 1.6, CHCl3), 96% ee; [a]D20 ¼ þ31.7 (c ¼
1.7, CHCl3), 92% ee 28).
(þ)-(1S,2R,4aS,8aS)-Decahydro-2,5,5,8a-tetramethylnaphthalene-1-carboxylic Acid ((þ)-6b). In a
flask protected from light, a soln. of HIO3 (112 mg, 0.632 mmol) in DMSO (4 ml) was heated at 808 for
1.5 h, then a soln.of (þ)-6a (47 mg, 0.21 mmol) in DMSO (4 ml) was added at 658. After 24 h at 658, the
cold soln. was poured into 10% aq. HCl at 08 and then extracted with Et2O. The org. phase was dried
(MgSO4), concentrated, and the residue was purified by CC (SiO2; cyclohexane/AcOEt 95 :5 to 9 :1) to
afford pure (þ)-6b (46% yield). [a]2D0 ¼ þ13.9 (c ¼ 0.6, CHCl3). IR: 2923, 2869, 2850, 1698, 1457, 1414,
1388, 1378, 1367, 1302, 1226, 1165, 1113, 1033, 979, 935, 693. 1H-NMR: 11.40 (br. s, OH); 1.92 – 1.74 (m,
4 H); 1.60 – 0.95 (m, 9 H); 1.05 (s, 3 H); 0.87 (d, J ¼ 7, 3 H); 0.86 (s, 3 H); 0.84 (s, 3 H). 13C-NMR: 179.8
(s); 64.7 (d); 54.2 (d); 42.0 (t); 40.0 (t); 37.2 (s); 35.3 (t); 33.5 (q); 33.2 (s); 29.7 (d); 21.8 (q); 21.6 (t); 20.8
(q); 18.6 (t); 14.5 (q). MS: 238 (30, Mþ), 223 (90), 182 (27), 137 (11), 123 (100), 109 (32), 95 (30), 87
(23), 81 (85), 69 (31), 67 (16), 55 (18), 41 (17).
26
)
The optical purity is based on chiral GC analysis of (þ)-(R)-5. RGB-174 Column, 30 m/0.25 mm/
0.25 mm; 908, 60 min; 0.58/min to 1408m 100 min; He, 1.5 ml/min. tR (minor) 145.69 min, tR (major)
146.35 min, baseline separated. Before to decide on these GC separation conditions, we also
reduced (þ)-(R)-5 (LiAlH4, Et2O, 97% yield) to the nearly odorless naturally occurring (þ)-(3R,
6E)-dihydrofarnesol [8e], [a]2D0 ¼ 4.0 (c ¼ 3.9, CHCl3) [8h – 8j], as intermediate for acylation to (þ)-
(3R,6E)-3,7,11-trimethyldodeca-6,10-dienyl acetate (Ac2O, py, 94%), another natural product
earlier isolated from Cyperus serotinus Rottb. [8k]; [a]2D0 ¼ 3.0 (c ¼ 3.2, CHCl3). 13C-NMR: 171.2 (s);
135.0 (s); 131.3 (s); 124.5 (d); 124.4 (d); 63.0 (t); 39.8 (t); 37.0 (t); 35.4 (t); 29.5 (d); 26.7 (t); 25.7 (q);
25.3 (t); 21.0 (q); 19.4 (q); 17.7 (q); 16.0 (q).
The reaction time could be reduced to 5 h by using an equimolar amount of SnCl4.
The optical purity is based on chiral GC analysis of (þ)-6a. RGB-174 Column, 30 m/0.25 mm/
0.25 mm; 908, 60 min; 0.58/min to 1408, 100 min; He, 1.5 ml/min. tR (minor) 130.06 min, tR (major)
131.65 min, baseline separated.
27
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Helvetica Chimica Acta – Vol. 97 (2014)
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(ꢀ)-(1S,2R,4aS,8aS)-Decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl Formate ((ꢀ)-7a). A soln. of
(þ)-6a (0.62g, 2.79 mmol) in CH2Cl2 (15 ml) was treated with mCPBA (70% pure, 1035 mg, 4.2 mmol) at
208 for 4 d. Upon complete conversion, the mixture was poured into H2O. The aq. phase was extracted
with CH2Cl2 (3 ꢂ 10 ml), and the combined org. phase was washed with brine, dried (Na2SO4),
concentrated, and purified by CC (SiO2; cyclohexane/AcOEt 97:3 to 85 :15) to afford pure (ꢀ)-7a (71%
yield29)). [a]D20 ¼ ꢀ30.1 (c ¼ 1.6, CHCl3). IR: 2994, 2957, 2932, 2919, 2868, 1711, 1462, 1447, 1387, 1379,
1
1354, 1189, 1175, 1158, 1120, 1091, 1053, 975, 950, 912, 888, 633. H-NMR: 8.23 (s, 1 H); 4.57 (s, 1 H);
2.01 – 1.94 (m, 1 H); 1.67 – 1.12 (m, 11 H); 1.00 (s, 3 H); 0.88 (s, 3 H); 0.81 (s, 3 H); 0.80 (d, J ¼ 6.7, 3 H).
13C-NMR: 161.2 (d); 82.7 (d); 45.6 (d); 42.1 (t); 38.5 (s); 35.3 (t); 33.0 (s); 33.0 (q); 30.4 (d); 30.1 (t); 21.8
(q); 21.5 (t); 19.2 (q); 18.4 (t); 18.4 (q). MS: 238 (4, Mþ), 223 (58), 192 (28), 177 (100), 149 (11), 136 (28),
123 (80), 121 (40), 109 (32), 107 (40), 95 (41), 93 (28), 81 (45), 79 (21), 69 (37), 67 (24), 55 (35), 43 (16),
41 (41). Medicinal, pungent, weakly woody, rooty.
(ꢀ)-(1S,2R,4aS,8aS)-Decahydro-2,5,5,8a-tetramethylnaphthalen-1-ol ((ꢀ)-7b). A soln. of (ꢀ)-7a
( 358 mg, 1.5 mmol) in MeOH (5 ml) was heated under reflux in the presence of KOH (0.25 g, 4.5 mmol)
in H2O (0.76 ml) for 1 h to complete conversion. The mixture was cooled to 208, extracted with Et2O (3 ꢂ
10 ml), and the aq. phase extracted twice with Et2O (10 ml). The dried (Na2SO4) combined org. phase
was concentrated and purified by CC (SiO2; cyclohexane/AcOEt 95 :5 to 80 :20) to afford (ꢀ)-7b (88%
yield30)). [a]D20 ¼ ꢀ10.8 (c ¼ 2.6, CHCl3). IR: 3342, 2995, 2956, 2937, 2920, 2904, 2865, 1457, 1442, 1386,
1
1378, 1340, 1308, 1295, 1182, 1134, 1095, 1057, 1046, 1009, 980, 943, 919, 654. H-NMR: 2.92 (d, J ¼ 2,
1 H); 1.90 – 1.84 (m, 1 H); 1.73 – 1.07 (m, 12 H); 0.92 (d, J ¼ 6, 3 H); 0.90 (s, 3 H); 0.87 (s, 3 H); 0.81 (s,
3 H). 13C-NMR: 81.5 (d); 44.6 (d); 42.3 (t); 39.1 (s); 35.3 (t); 33.0 (s); 33.0 (q); 31.0 (d); 29.2 (t); 21.9 (q);
21.6 (t); 19.5 (q); 18.9 (q); 18.6 (t). MS: 210 (8, Mþ), 195 (23), 192 (30), 177 (100), 149 (12), 136 (20), 125
(22), 123 (82), 121 (29), 109 (36), 107 (32), 95 (43), 93 (20), 81 (50), 79 (21), 69 (42), 67 (30), 55 (40), 41
(43). Woody, amber-like, weak.
(ꢀ)-(2R,4aS,8aS)-Octahydro-2,5,5,8a-tetramethylnaphthalen-1(2H)-one ((ꢀ)-8a). A soln. of (ꢀ)-7b
(210 mg, 1.0 mmol) in CH2Cl2 (10 ml) was oxidized with PCC (260 mg, 1.2 mmol). After full conversion,
the mixture was diluted with Et2O, filtered over a short path of SiO2, concentrated, and purified by bulb-
to-bulb distillation to afford (ꢀ)-8a (84% yield). [a]2D0 ¼ ꢀ30 (neat); [a]2D0 ¼ ꢀ30.5 (c ¼ 1.2, CHCl3). IR:
2981, 2957, 2927, 2896, 2869, 1690, 1460, 1447, 1383, 1372, 1361, 1158, 1134, 1000, 987, 979, 963, 858, 848,
1
808, 754, 731, 693. H-NMR: 2.68 (sept., J ¼ 7, 1 H); 2.13 (m, 1 H); 1.76 – 1.65 (m, 2 H); 1.57 – 1.51 (m,
4 H); 1.42 – 1.36 (m, 1 H); 1.26 – 1.09 (m, 3 H); 1.14 (s, 3 H); 0.97 (d, J ¼ 7, 3 H); 0.93 (s, 3 H); 0.88 (s,
3 H). 13C-NMR: 216.8 (s); 54.2 (d); 48.8 (s); 41.6 (t); 39.9 (d); 35.8 (t); 34.2 (s); 33.2 (t); 33.1 (q); 22.1 (q);
21.4 (t); 18.8 (q); 18.2 (t); 15.1 (q). MS: 208 (59, Mþ), 193 (30), 175 (27), 165 (22), 150 (55), 138 (22), 135
(31), 125 (42), 123 (100), 109 (58), 98 (21), 95 (87), 81 (64), 79 (30), 69 (70), 67 (71), 55 (63), 41 (90).
Ambery, woody, slightly liquorice and camphoraceous.
(ꢀ)-(4aS,6R,8aS)-Decahydro-1,1,4a,6-tetramethyl-5-methylidenenaphthalene ((ꢀ)-8b). A suspension
of NaH (503 mg, 55% in mineral oil, 11.52 mmol, washed 3 ꢂ with pentane) in DMSO (2 ml) was heated
at 408 for 3 h, then a soln. of Ph3(Me)PI (4.16 g, 10.3 mmol) in DMSO (6 ml) was added, followed, after
2 h at 408, by a soln. of (ꢀ)-8a (300 mg, 1.44 mmol) in THF (1 ml). After 3 h at 1858, the cold mixture was
diluted with H2O (100 ml) and extracted with Et2O (3 ꢂ 40 ml). The org. phase was washed with H2O
(2 ꢂ 100 ml), and then dried (MgSO4) and concentrated. The residue was crystallized in pentane, and the
filtrate was concentrated and then purified by CC (SiO2; cyclohexane/AcOEt 99 :1) to afford pure (ꢀ)-
8b (39% yield). [a]D20 ¼ ꢀ50.1 (c ¼ 0.8, CHCl3). IR: 2923, 2868, 2849, 1633, 1461, 1387, 1373, 1051, 986,
974, 893, 882, 861, 708, 650. 1H-NMR: 4.63 (br. s, 1 H); 4.50 (br. s, 1 H); 2.33 (dsept., J ¼ 1.6, 6.4, 1 H); 1.87
(dq, J ¼ 4.1, 12.4, 1 H); 1.66 (tt, J ¼ 3.3, 13.4, 2 H); 1.59 (dsext., J ¼ 1.9, 12.4, 1 H); 1.55 – 1.42 (m, 5 H); 1.40
(dsext., J ¼ 1.9, 13.4, 1 H); 1.16 (dt, J ¼ 3.9, 13.4, 1 H); 1.04 (s, 3 H); 1.00 (d, J ¼ 6.4, 3 H); 0.86 (s, 3 H);
0.84 (s, 3 H). 13C-NMR: 164.6 (s); 99.7 (t); 54.2 (d); 42.4 (t); 40.3 (s); 37.9 (t); 37.6 (t); 33.8 (s); 33.3 (d);
33.3 (q); 22.4 (t); 21.9 (q); 20.7 (q); 19.4 (q); 19.2 (t). MS: 206 (30, Mþ), 191 (44), 163 (18), 149 (12), 136
When a 75:25 mixture with the stereoisomer 6a was used as starting material, an [a]2D0 value of
ꢀ 12.4 (c ¼ 1.94, CHCl3) was obtained for the corresponding mixture of 7a.
Alternatively, reduction of 7a (65:35 mixture of stereoisomers at C(1)) with LiAlH4 in THF at 208
afforded quantitatively a mixture of 7b.
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Helvetica Chimica Acta – Vol. 97 (2014)
(100), 135 (31), 123 (29), 121 (50), 109 (51), 107 (40), 105 (12), 95 (55), 93 (37), 91 (24), 82 (41), 81 (41),
80 (40), 79 (26), 77 (16), 69 (28), 67 (28), 55 (27), 53 (13), 41 (28).
(þ)-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]acetaldehyde ((þ)-
9a). A soln. of (4aR,6R,8aS)-5-[(E)-2-chloroethenyl]decahydro-1,1,4a,6-tetramethylnaphthalene (3 :1
mixture of stereoisomers; see Exper. Part for (þ)-17; 120 mg, 0.475 mmol) in tBuOH (5 ml) was added to
a soln. of tBuOK (107 mg, 0.949 mmol) in tBuOH (5 ml). After 4 h at 828, the cold mixture was diluted
with H2O (25 ml) and then extracted with Et2O (3 ꢂ 40 ml). The org. phase was washed with H2O and
brine, dried (Na2SO4), concentrated, and purified by bulb-to-bulb distillation to afford pure (þ)-9a (94%
yield). B.p. 1008/0.01 mbar. [a]2D0 ¼ þ128.4 (c ¼ 3.7, CHCl3). IR: 2925, 2866, 2847, 1721, 1458, 1387, 1374,
1366, 1239, 1190, 1116, 1091, 1062, 1048, 991, 949, 914, 824. For NMR and MS data, see [22b][24].
N-Hydroxy-2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]ethanimine
((þ)-9b). Pyridine (3.4 ml) was added to a soln. of (þ)-9a (950 mg, 3.97 mmol) and NH2OH · HCl
(800 mg, 10.37 mmol) in EtOH (3.4 ml), then the mixture was heated to 908 for 2 h. The cold mixture was
diluted with Et2O (5 ml) and H2O (5 ml). The org. phase was washed with H2O, then brine, dried
(Na2SO4), and concentrated to afford quantitatively pure (þ)-9b as a 2 :1 (E)/(Z)-mixture after bulb-to-
bulb distillation. [a]2D0 ¼ þ99.3 (c ¼ 4.3, CHCl3). IR: 3220, 3080, 2924, 2865, 2847, 1592, 1457, 1440, 1387,
1374, 1032, 973, 932, 901, 753, 701, 665. Deduced from the mixture: 1H-NMR ((E)-isomer): 7.32 (t, J ¼ 4.1,
1 H); 7.30 (m, OH); 3.09 (t, J ¼ 4.1, 2 H); 2.07 – 1.97 (m, 2 H); 1.80 – 1.61 (m, 3 H); 1.54 (s, 3 H); 1.51 –
1.38 (m, 4 H); 1.18 – 1.01 (m, 4 H); 0.96 (s, 3 H); 0.90 (s, 3 H); 0.83 (s, 3 H). 1H-NMR ((Z)-isomer): 7.69
(m, OH); 6.54 (t, J ¼ 5.1, 1 H); 2.98, 2.85 (2dd, J ¼ 5.1, 15.1, each 1 H); 2.07 – 1.97 (m, 2 H); 1.80 – 1.61 (m,
3 H); 1.58 (s, 3 H); 1.51 – 1.38 (m, 4 H); 1.18 – 1.01 (m, 4 H); 0.96 (s, 3 H); 0.89 (s, 3 H); 0.83 (s, 3 H).
13C-NMR ((E)-isomer): 153.1 (d); 136.3 (s); 128.8 (s); 52.0 (d); 41.7 (t); 38.8 (s); 36.7 (t); 33.8 (t); 33.3
(s); 33.3 (q); 28.1 (t); 24.0 (t); 21.6 (q); 19.7 (q); 19.5 (q); 19.0 (t). 13C-NMR ((Z)-isomer): 151.7 (d);
134.9 (s); 129.6 (s); 51.7 (d); 41.6 (t); 38.8 (s); 37.1 (t); 33.8 (t); 33.3 (s); 33.3 (q); 28.1 (t); 24.0 (t); 21.6 (q);
19.9 (q); 19.5 (q); 19.0 (t). MS ((E)-isomer): 249 (18, Mþ), 234 (32), 216 (38), 191 (96), 175 (18), 164
(26), 146 (100), 138 (22), 134 (35), 123 (97), 120 (53), 109 (40), 107 (37), 105 (54), 95 (52), 93 (40), 91
(55), 81 (33), 79 (35), 69 (52), 67 (20), 55 (28), 41 (37). MS ((Z)-isomer): 249 (2, Mþ), 233 (13), 217
(41), 191 (40), 175 (30), 160 (12), 146 (100), 138 (8), 134 (32), 123 (94), 120 (43), 109 (24), 107 (27), 105
(50), 95 (30), 93 (33), 91 (40), 81 (23), 79 (25), 69 (45), 67 (14), 55 (22), 41 (30).
(þ)-2-[(1S,2R,4aS,8aS)-Decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]-2-hydroxyacetonitrile ((þ)-
10a). A soln. of (þ)-6a (250 mg, 0.787 mmol) in THF (3 ml) was added to a soln. of NaHSO3 (300 mg,
2.87 mmol) in H2O (10 ml) at 08. After 40 min at 08, NaCN (159 mg, 3.15 mmol) was added. After 24 h at
208, the mixture was treated with 10% HCl (under strong ventilation), then extracted with Et2O. The org
phase was washed with NaHCO3, then with brine to neutrality, dried (Na2SO4), and concentrated. For
anal. purposes, the residue was purified by CC (SiO2; cyclohexane/AcOEt 99 :1 to 8 :2) to afford pure
(þ)-10a as a 56 :44 mixture of stereoisomers (36% yield). [a]2D0 ¼ þ13.6 (c ¼ 1.0, CHCl3). IR: 3440, 2924,
2869, 2850, 2239, 1450, 1388, 1369, 1221, 1118, 1089, 1072, 1052, 977, 934, 896, 861, 819. 1H-NMR (major
isomer): 4.90 (s, 1 H); 2.4 (br. s, OH); 2.0 – 1.2 (m, 13 H); 1.20 (d, J ¼ 6.3, 3 H); 0.95 (s, 3 H); 0.86 (s, 3 H);
0.82 (s, 3 H). 13C-NMR (major isomer): 121.9 (s); 61.1 (d); 57.7 (d); 57.1 (d); 41.7 (t); 39.9 (t); 38.3 (s);
36.5 (t); 33.6 (q); 33.3 (s); 27.8 (d); 24.3 (q); 21.7 (q); 21.7 (t); 18.7 (t); 15.2 (q). MS (major isomer): 249
(0, Mþ), 222 (27), 207 (25), 189 (20), 152 (12), 138 (70), 123 (100), 109 (61), 107 (22), 97 (21), 95 (61); 93
(23), 91 (19), 84 (54), 81 (61), 79 (27), 71 (21), 69 (55), 67 (36), 55 (41), 41 (40). Minor stereoisomer
deduced from the mixture: 1H-NMR: 5.0 (d, J ¼ 1, 1 H); 2.12 (br. s, OH); 2.0 – 1.2 (m, 13 H); 1.23 (d, J ¼
7.5, 3 H); 1.13 (s, 3 H); 0.86 (s, 3 H); 0.83 (s, 3 H). 13C-NMR: 121.2 (s); 64.5 (d); 54.7 (d); 48.8 (d); 42.1
(t); 38.3 (t); 38.0 (s); 37.8 (s); 31.8 (t); 33.5 (q); 29.7 (d); 24.6 (q); 22.2 (q); 18.7 (t); 17.6 (t); 15.2 (q). MS:
249 (0, Mþ), 222 (8), 207 (14), 189 (15), 152 (18), 138 (85), 123 (100), 109 (51), 107 (22), 97 (16), 95 (60),
93 (23), 91 (21), 84 (88), 81 (59), 79 (27), 71 (21), 69 (50), 67 (34), 55 (37), 41 (41).
(ꢀ)-Cyano[(1S,2R,4aS,8aS)-decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]methyl Trifluorometha-
nesulfonate ((ꢀ)-10b). Trifluoromethanesulfonic anhydride (217 mg, 0.77 mmol) was added dropwise at
ꢀ 508 to a soln. of 10a (160 mg, 0.64 mmol) and 2,6-lutidine (84 mg, 0.77 mmol) in CH2Cl2 (3 ml). After
3 h at 08, the mixture was diluted with CH2Cl2 (7 ml), washed with H2O, dried (Na2SO4), and
concentrated to afford a 1:1 mixture 10a/10b. Purification by CC (SiO2; cyclohexane/AcOEt 98 :2)
afforded 10b as a main diastereoisomer (94% yield based on recovered 10a). [a]2D0 ¼ ꢀ2.9 (c ¼ 0.7,

Helvetica Chimica Acta – Vol. 97 (2014)
207
CHCl3). IR: 2928, 2872, 2851, 1741, 1459, 1422, 1390, 1369, 1244, 1208, 1139, 976, 924, 907, 849, 817.
1H-NMR: 5.71 (s, 1 H); 2.31 – 2.26 (m, 1 H); 2.08 – 2.00 (m, 1 H); 1.94 – 1.87 (m, 1 H); 1.83 – 1.79 (m,
1 H); 1.68 – 1.55 (m, 3 H); 1.47 – 1.13 (m, 6 H); 1.08 (d, J ¼ 7, 3 H); 1.00 (s, 3 H); 0.89 (s, 3 H); 0.84 (s,
3 H). 13C-NMR: 171.2 (s); 113.9 (s); 73.2 (d); 61.1 (d); 54.6 (d); 41.4 (t); 39.2 (t); 38.3 (s); 36.0 (t); 33.5
(d); 33.4 (s); 30.7 (q); 21.8 (q); 21.4 (t); 21.2 (q); 18.6 (t); 15.6 (q). MS: 381 (4, Mþ), 366 (18), 233 (13),
218 (100), 216 (17), 190 (9), 176 (13), 162 (13), 160 (11), 150 (15), 134 (10), 123 (98), 121 (25), 109 (38),
107 (17), 105 (11), 95 (35), 81 (34), 79 (20), 69 (57), 67 (21), 55 (28), 41 (25), 28 (32).
(ꢀ)-(RS)-Cyano[(1S,2R,4aS,8aS)-decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]methyl Methane-
sulfonate ((ꢀ)-10c). MsCl (88 mg, 0.77 mmol) was added dropwise at 08 to a soln. of 10a (160 mg,
0.64 mmol) and Et3N (139 mg, 1.28 mmol) in CH2Cl2 (2 ml). After 2 h at 208, the mixture was diluted
with CH2Cl2 (8 ml), washed with H2O, dried (Na2SO4), and concentrated to afford 10c as a 1:1 mixture
of diastereoisomers (97%). The crude material was used as such, or purified by CC (SiO2; cyclohexane/
AcOEt 95 :5) for anal. purposes. [a]2D0 ¼ ꢀ1.6 (c ¼ 0.6, CHCl3). IR: 2926, 2869, 2853, 2175, 1703, 1515,
1459, 1374, 1334, 1261, 1222, 1180, 1085, 1020, 950, 905, 837, 815, 800, 720. Deduced from a 2 :1 enriched
1
mixture. H-NMR: 5.58 (s, 1 H); 3.17 (s, 3 H); 2.15 – 2.10 (m, 1 H); 2.05 – 1.97 (m, 1 H); 1.90 – 1.83 (m,
1 H); 1.65 – 1.52 (m, 3 H); 1.44 – 1.41 (m, 1 H); 1.34 – 1.25 (m, 3 H); 1.21 – 1.11 (m, 3 H); 1.08 (d, J ¼ 7,
3 H); 0.98 (s, 3 H); 0.87 (s, 3 H); 0.83 (s, 3 H). 13C-NMR: 115.5 (s); 67.3 (d); 60.5 (d); 54.6 (d); 41.4 (t);
39.3 (q); 39.2 (t); 38.2 (s); 36.2 (t); 33.5 (q); 33.4 (s); 30.9 (d); 21.8 (q); 21.5 (t); 21.3 (q); 18.6 (t); 15.5 (q).
MS: 327 (4, Mþ), 312 (51), 248 (5), 232 (20), 218 (40), 216 (19), 190 (5), 176 (12), 162 (10), 160 (13), 150
(22), 137 (10), 123 (100), 121 (13), 109 (30), 107 (18), 95 (32), 91 (15), 81 (33), 79 (28), 69 (59), 67 (22),
55 (27), 41 (24), 32 (28), 28 (60). 1H-NMR: 5.60 (s, 1 H); 3.20 (s, 3 H); 2.15 – 2.10 (m, 1 H); 2.05 – 1.97 (m,
1 H); 1.90 – 1.83 (m, 1 H); 1.65 – 1.52 (m, 3 H); 1.44 – 1.41 (m, 1 H); 1.34 – 1.25 (m, 3 H); 1.21 – 1.11 (m,
3 H); 1.18 (d, J ¼ 7, 3 H); 0.97 (s, 3 H); 0.87 (s, 3 H); 0.83 (s, 3 H). 13C-NMR: 117.5 (s); 63.7 (d); 60.7 (d);
54.9 (d); 41.5 (t); 39.9 (t); 39.2 (q); 37.9 (s); 36.4 (t); 33.5 (q); 31.0 (s); 28.5 (d); 21.7 (q); 21.5 (t); 21.3 (q);
18.6 (t); 14.7 (q). MS: 327 (10, Mþ), 312 (76), 248 (4), 232 (18), 218 (28), 216 (12), 176 (11), 162 (8), 160
(9), 150 (19), 137 (8), 123 (100), 121 (10), 109 (21), 107 (16), 95 (27), 93 (14), 81 (29), 79 (27), 69 (55), 67
(20), 55 (27), 41 (22), 28 (15).
(þ)-2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]acetonitrile ((þ)-
11). Propane-1-phosphonic acid cyclic anhydride (50%/AcOEt, 1400 mg, 2.20 mmol) was added at 208
to a soln. of (þ)-9a (500 mg, 2.00 mmol), H2NOH · HCl (153 mg, 2.20 mmol) and Et3N (225 mg,
2.20 mmol) in DMF (2 ml). After 1.25 h at 1008, the cold soln. was poured into aq. sat. NaHCO3 and then
extracted with AcOEt. The org. phase was washed with H2O and brine, dried (Na2SO4), and
concentrated, to afford (þ)-11 in 84% yield after bulb-to-bulb distillation. Alternatively, a soln. of (þ)-9b
(250 mg, 1.0 mmol) in Ac2O (1 ml) was heated at 1008 for 1 h. The cold mixture was diluted with Et2O
(20 ml) and H2O (10 ml). The org. phase was washed with H2O and sat. aq. NaHCO3, dried (Na2SO4),
concentrated, and purified by CC (SiO2; cyclohexane/AcOEt 97:3) to afford (þ)-11 (75% yield).
t
Alternatively, a mixture of diethyl cyanomethylphosphonate (1116 mg, 6.05 mmol), BuOK (577 mg,
5.04 mmol), and (ꢀ)-8a (210 mg, 1.01 mmol) in THF (5 ml) was heated at 668 for 72 h. The cold mixture
was diluted with H2O and then extracted with Et2O. The org. phase was washed with brine, dried
(Na2SO4), concentrated, and bulb-to-bulb distilled to afford quantitatively (þ)-11, contaminated with
7% of a 6 :1 (E)/(Z)-mixture of the corresponding intermediate conjugated nitriles31). Alternatively,
crude (þ)-10a was treated with 2.0 mol-equiv. of P2O5 in refluxing xylene to afford (þ)-11 in 16% yield.
B.p. 1308/0.1 mbar. [a]2D0 ¼ þ144.0 (c ¼ 4.1, CHCl3). IR: 2925, 2866, 2243, 1458, 1441, 1428, 1388, 1377,
1367, 1240, 1198, 1130, 1042, 1018, 990, 974, 954, 937, 718. 1H-NMR: 3.02 (d, J ¼ 17.9, 1 H); 2.90 (d, J ¼ 17.9
1 H); 2.10 – 2.04 (m, 2 H); 1.75 (dt, J ¼ 3, 7, 2 H); 1.68 (s, 3 H); 1.71 – 1.52 (m, 3 H); 1.45 – 1.26 (m, 2 H);
1.21 – 1.13 (m, 2 H); 0.96 (s, 3 H); 0.90 (s, 3 H); 0.84 (s, 3 H). 13C-NMR: 132.3 (s); 130.6 (s); 119.2 (s); 51.6
31
)
The intermediate major conjugated isomer, tentatively attributed to the thermodynamically more
stable (E)-nitrile, exhibited the following MS data: 231 (6, Mþ), 216 (7), 191 (4), 160 (5), 146 (14),
134 (7), 124 (59), 109 (100), 105 (11), 93 (9), 91 (14), 81 (13), 79 (10), 69 (14), 55 (10), 41 (14), 32
(38), 28 (68). 1H-NMR: olefinic signal at 5.19. MS (minor conjugated (Z)-isomer): 231 (8, Mþ), 216
(20), 189 (6), 174 (8), 160 (6), 135 (10), 123 (20), 121 (10), 109 (33), 95 (16), 91 (13), 81 (18), 69 (13),
1
67 (10), 55 (8), 44 (6), 41 (11), 32 (64), 28 (100), H-NMR: 5.05.

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Helvetica Chimica Acta – Vol. 97 (2014)
(d); 41.3 (t); 38.7 (s); 36.7 (t); 33.8 (t); 33.2 (s); 33.1 (q); 21.5 (q); 19.8 (q); 19.5 (q); 18.8 (t); 18.7 (t); 15.2
(t). MS: 231 (12, Mþ), 216 (34), 191 (33), 160 (10), 146 (100), 134 (28), 123 (90), 120 (40), 105 (22), 91
(26), 81 (14), 79 (15), 77 (12), 69 (32), 67 (9), 55 (11), 41 (18).
(þ)-2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]acetic Acid ((þ)-
12b). A mixture of (þ)-11 (200 mg, 0.864 mmol) and KOH (85%, 1.15 g, 17.4 mmol) in ethylene glycol
(10 ml) was heated at 1508 for 12 h. The cold mixture was extracted with toluene, the org. phase was
discarded, and the aq. phase was acidified to pH 1 with conc. HCl at 08, then, after 30 min at 208,
extracted with toluene. This org. phase was dried (Na2SO4) and concentrated to afford pure (þ)-12b. The
reaction time could be reduced to 5 h in glycerol at 2008 (82 – 83% yield). Alternatively, a soln. of
aldehyde (þ)-9a (510 mg, 2.176 mmol) in acetone (20 ml) at 08 was treated with CrO3 · H2SO4 (2.7m,
1.6 ml, 4.352 mmol). After 1.5 h at 08, the mixture was poured into H2O and then extracted with Et2O.
The org. phase was washed with 5% aq. NaOH (2 ꢂ 25 ml). This aq. phase was acidified with 10% aq.
HCl and then extracted with Et2O. This org. phase was washed with H2O and brine, dried (Na2SO4),
concentrated, and purified by CC (SiO2; cyclohexane/AcOEt 85 :15) to afford (þ)-12b (60% yield).
[a]2D0 ¼ þ112.0 (c ¼ 3.4, CHCl3); [a]2D0 ¼ þ134.5 (c ¼ 8.93, benzene [32a]). IR: 3200, 2925, 2865, 1703,
1458, 1441, 1407, 1387, 1376, 1324, 1281, 1241, 1217, 1206, 1194, 1169, 1120, 1042, 1019, 974, 935, 842, 786,
1
762, 735, 683, 635. H-NMR: 11.0 (br. s, 1 H); 3.14 (d, J ¼ 17, 1 H); 3.01 (d, J ¼ 17, 1 H); 2.18 – 2.09 (m,
1 H); 2.02 (dd, J ¼ 6.2, 17, 1 H); 1.72 – 1.65 (m, 2 H); 1.58 (s, 3 H); 1.60 – 1.37 (m, 4 H); 1.26 – 1.12 (m,
3 H); 0.94 (s, 3 H); 0.89 (s, 3 H); 0.84 (s, 3 H)32). 13C-NMR: 179.2 (s); 133.4 (s); 130.7 (s); 51.4 (d); 41.5
(t); 38.6 (s); 36.3 (t); 33.6 (t); 33.3 (s); 33.1 (q); 33.0 (t); 21.6 (q); 20.1 (q); 19.7 (q); 18.9 (2t). MS: 250 (34,
Mþ), 235 (71), 204 (10), 190 (100), 175 (86), 165 (82), 163 (27), 161 (20), 153 (24), 147 (20), 139 (69), 135
(20), 133 (39), 123 (49), 121 (64), 119 (76), 109 (38), 107 (53), 105 (75), 97 (12), 95 (37), 93 (50), 91
(60), 83 (11), 81 (38), 79 (34), 77 (30), 69 (51), 67 (22), 65 (13), 55 (37), 53 (15), 43 (22), 41 (47), 39 (11),
32 (40), 28 (78). Vague odor.
(þ)-2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]acetamide ((þ)-
12c). Isolated after 4 h at 1508 during the preparation of (þ)-12b (<15% yield). [a]2D0 ¼ þ34.3 (c ¼
1
2.5, CHCl3). IR: 3500, 3347, 2922, 2853, 1670, 1458, 1375, 1215, 1042, 755. H-NMR: 5.84 (br. s, 2 H);
3.08 (d, J ¼ 17, 1 H); 2.90 (d, J ¼ 17, 1 H); 2.10 (dt, J ¼ 6.4, 17, 2 H); 1.78 – 1.09 (m, 9 H); 1.63 (s, 3 H); 0.96
(s, 3 H); 0.90 (s, 3 H); 0.85 (s, 3 H). 13C-NMR: 175.0 (s); 136.3 (s); 131.1 (s); 52.1 (d); 41.6 (t); 38.9 (s);
36.1 (t); 35.7 (t); 33.6 (t); 33.4 (s); 33.2 (q); 21.6 (q); 20.2 (q); 19.9 (q); 18.8 (2t). MS: 249 (18, Mþ), 234
(17), 190 (84), 175 (100), 163 (50), 147 (17), 138 (14), 133 (17), 123 (17), 121 (34), 119 (36), 109 (21),
107 (24), 105 (57), 95 (20), 91 (30), 81 (14), 79 (18), 77 (16), 69 (20), 60 (19), 55 (18), 41 (24).
(þ)-2-[(1S,2R,4aS,8aS)-Decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]oxirane ((þ)-13). Under
strong mechanical stirring (900 rpm) were added successively, in the reactor, DMSO (30 ml), Me2S
(0.5 ml, 6.74 mmol), and Me2SO4 (0.58 ml, 6.05 mmol). After 30 min at 208, NaOH (small beads,
diameter 1 – 2 mm, 1.6 g, 40 mmol) was added, followed by a soln. of (þ)-6 (1.6 g, 4.53 mmol) in DMSO
(5 ml). After 5 d, the mixture was poured onto ice and then extracted twice with AcOEt. The org. phase
was washed with brine to neutrality, dried (Na2SO4), concentrated, and then purified by CC (SiO2;
cyclohexane/AcOEt 99 :1) to afford (þ)-13 in 78% yield, as a 44 :56 mixture of stereoisomers33). [a]D20
¼
þ4.9 (c ¼ 1.83, CHCl3). IR: 3038, 2921, 2868, 2850, 1456, 1385, 1365, 1262, 1204, 1181, 1135, 1035, 976,
961, 947, 935, 889, 868, 857, 827, 818. 1H-NMR (major isomer): 2.98 (ddd, J ¼ 3, 4, 9.3, 1 H); 2.85 (dd, J ¼ 4,
5, 1 H); 2.55 (dd, J ¼ 4, 5, 1 H); 1.13 (d, J ¼ 7.5, 3 H); 1.06 (s, 3 H); 0.85 (s, 3 H); 0.84 (s, 3 H); 2.2 – 0.74
(m, 13 H). 1H-NMR (minor isomer): 2.73 (dd, J ¼ 4, 5, 1 H); 2.67 (dd, J ¼ 3, 4, 8.7, 1 H); 2.55 (dd, J ¼ 4, 5,
1 H); 1.02 (d, J ¼ 6.7, 3 H); 1.00 (s, 3 H); 0.84 (s, 3 H); 0.83 (s, 3 H); 2.2 – 0.74 (m, 13 H). 13C-NMR (major
isomer): 56.8 (d); 56.2 (d); 51.6 (d); 50.0 (t); 42.1 (t); 40.5 (t); 38.0 (s); 34.2 (t); 33.5 (q); 33.2 (s); 30.1 (d);
21.7 (q); 18.3 (t); 17.3 (t); 17.2 (q); 16.4 (q). 13C-NMR (minor isomer): 60.1 (d); 54.6 (d); 53.2 (d); 46.8 (t);
42.1 (t); 40.7 (t); 38.4 (s); 36.8 (t); 33.6 (q); 33.3 (s); 32.9 (d); 22.1 (t); 21.9 (q); 21.1 (q); 18.8 (t); 15.9 (q).
MS (minor isomer): 236 (8, Mþ), 221 (21), 177 (9), 149 (12), 135 (13), 123 (100), 121 (22), 109 (46), 95
1
32
33
)
)
For the 60-MHz H-NMR analysis of a mixture of three isomers, see [32b].
A chromatographically enriched 75:25 mixture of stereoisomers exhibited [a]2D0 ¼ ꢀ0.67 (c ¼ 1.93,
CHCl3).

Helvetica Chimica Acta – Vol. 97 (2014)
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(51), 81 (44), 69 (50), 67 (29), 55 (30), 41 (28). MS (major isomer): 236 (3, Mþ), 221 (22), 177 (11), 149
(15), 136 (21), 123 (100), 121 (32), 109 (65), 95 (62), 81 (57), 69 (59), 67 (37), 55 (35), 41 (32).
(ꢀ)-2-[(1S,2R,4aS,8aR)-Decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]acetaldehyde ((ꢀ)-14a).
Epoxide (þ)-13 (80 mg, 0.315 mmol) in toluene (1 ml) was added to a mixture of Al(OiPr)3 (64.3 mg,
0.315 mmol) and AlCl3 (42 mg, 0.31 mmol) in refluxing toluene (5 ml). After 3 h, the cold soln. was
hydrolyzed with H2O. Extraction afforded after drying (Na2SO4), concentration, and CC (SiO2;
cyclohexane/AcOEt 99 :1 to 9 :1) pure (ꢀ)-14a (25% yield). [a]2D0 ¼ ꢀ4.03 (c ¼ 0.1, CHCl3). IR: 2922,
2868, 2849, 1726, 1459, 1377, 1203, 1084, 1029, 975, 747, 699. 1H-NMR: 9.77 (t, J ¼ 1, 1 H); 1.79 – 0.92 (m,
15 H); 0.87 (s, 3 H); 0.85 (d, J ¼ 7, 3 H); 0.82 (s, 3 H); 0.80 (s, 3 H). 13C-NMR: 203.4 (d); 54.9 (d); 51.3
(d); 44.0 (t); 41.9 (t); 39.4 (t); 37.6 (s); 36.5 (t); 33.6 (d); 33.4 (q); 33.3 (s); 21.8 (t); 21.7 (q); 21.2 (q); 18.7
(t); 14.5 (q). MS: 236 (12, Mþ), 221 (33), 203 (9), 192 (29), 177 (15), 137 (8), 123 (100), 109 (25), 107
(13), 95 (33), 93 (12), 81 (31), 69 (31), 67 (21), 55 (29), 41 (28). Vaguely woody, cedar.
(þ)-2-[(1S,2R,4aS,8aR)-Decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]ethanol ((þ)-15a). Isolated
in 18% yield during the purification of (ꢀ)-14a. Also obtained in 94% yield by reduction of (ꢀ)-14a with
LiAlH4 (1.0 mol-equiv.) in THF. [a]2D0 ¼ þ6.83 (c ¼ 0.31, CHCl3). IR: 3323, 2921, 2852, 1457, 1384, 1198,
1048, 1038, 1016, 814, 721, 704, 626. 1H-NMR: 3.65 – 3.60 (m, 1 H); 3.52 – 3.47 (m, 1 H); 2.32 (br. s, OH);
1.77 – 0.93 (m, 15 H); 0.86 (d, J ¼ 7, 3 H); 0.84 (s, 3 H); 0.81 (s, 3 H); 0.79 (s, 3 H). 13C-NMR: 64.6 (t); 55.2
(d); 53.9 (d); 42.2 (t); 39.0 (t); 38.0 (s); 36.8 (t); 34.2 (d); 33.4 (q); 33.3 (s); 32.4 (t); 21.8 (t); 21.8 (q); 21.1
(q); 18.7 (t); 14.2 (q). MS: 238 (19, Mþ), 223 (21), 138 (9), 123 (100), 109 (29), 95 (30), 81 (29), 69 (28),
67 (19), 55 (22), 41 (20).
(þ)-2-[(1S,2S,4aS,8aR)-Decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]ethanol ((þ)-15b). Ob-
tained in 95% yield from (ꢀ)-14b [13], according to the LiAlH4 procedure used for (þ)-15a. [a]D20
¼
þ28.6 (c ¼ 1.2, CHCl3). IR: 3235, 2991, 2926, 2901, 2867, 2843, 1454, 1439, 1383, 1366, 1193, 1052,
1
1023, 1000, 962, 934, 916, 861. H-NMR: 3.72 – 3.62 (m, 1 H); 3.59 – 3.51 (m, 1 H); 1.85 – 1.79 (m, 1 H);
1.72 – 1.32 (m, 13 H); 1.25 – 1.19 (m, 1 H); 1.14 (dt, J ¼ 4.4, 14.2, 1 H); 0.93 (d, J ¼ 7, 3 H); 0.85 (s, 6 H);
8.81 (s, 3 H). 13C-NMR: 62.3 (t); 56.7 (d); 49.8 (d); 42.1 (t); 39.5 (t); 38.1 (s); 34.7 (t); 33.5 (q); 33.3 (s);
30.3 (d); 29.3 (t); 21.6 (q); 18.4 (t); 17.4 (t); 16.5 (q); 15.6 (q). MS: 238 (22, Mþ), 223 (27), 138 (10), 123
(100), 109 (34), 95 (33), 81 (29), 69 (25), 67 (19), 55 (17), 41 (15).
(þ)-(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2,5,5,8a-tetramethylnaphthalene-1-carbaldehyde ((þ)-
16a). A soln. of SO2Cl2 (138 mg, 1.007 mmol) in CH2Cl2 (2.5 ml) was added dropwise to a soln. of
(þ)-6a (75 :25 (1S)/(1R) mixture; 260 mg, 0.959 mmol) in CH2Cl2 (2.5 ml) at 08. The mixture was then
heated at 408 for 2 h. Since only the minor stereoisomer reacted, the cold mixture was poured into H2O
(20 ml) and extracted with CH2Cl2. The org. phase was washed with sat. aq. NaHCO3 and then brine,
dried (Na2SO4), and concentrated. The residue34) (320 mg) was dissolved in DMF (5 ml) and heated at
1508 for 58 h in the presence of LiCl (53 mg, 1.25 mmol). The cold mixture was diluted with H2O (20 ml)
and then extracted with AcOEt. The org. phase was washed with brine, dried (Na2SO4), concentrated,
and purified by CC (SiO2; cyclohexane/AcOEt 99 :1) to afford pure (þ)-16a (6% yield). [a]2D0 ¼ þ52.0
(c ¼ 1.0, CHCl3). For data, see [13c][21][27][45][46c][47].
(þ)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]ethanone ((þ)-
16c). Obtained in 90% yield according to the procedure reported for the racemate [50]. Alternatively,
a soln. of (2R,4aS,8aS)-1-ethynyldecahydro-2,5,5,8a-tetramethylnaphthalen-1-ol [20][24] (56 :44 mix-
34
)
A purified (CC (SiO2)) sample of the intermediate single a-chloroaldehyde of undetermined
configuration exhibited the following anal. data. [a]2D0 ¼ ꢀ31.6 (c ¼ 0.9, CHCl3). IR: 2955, 2938,
1
2882, 1742, 1464, 1392, 1210, 1120, 1032, 986, 823, 750. H-NMR: 9.41 (s, 1 H); 2.49 (quint., J ¼ 6.5,
1 H); 2.17 (tt, J ¼ 5.7, 13, 1 H); 1.85 (dt, J ¼ 3.3, 12.1, 1 H); 1.75 (dt, J ¼ 3.3, 13, 1 H); 1.68 – 1.35 (m, 7
H); 1.30 – 1.22 (m, 2 H); 1.20 (s, 3 H); 1.19 (d, J ¼ 8, 3 H); 0.91 (s, 3 H); 0.85 (s, 3 H). 13C-NMR: 192.2
(d); 87.9 (s); 47.2 (d); 42.0 (s); 41.3 (t); 37.1 (d); 35.0 (t); 33.6 (q); 33.3 (s); 28.3 (t); 21.4 (q); 18.9 (2q);
18.0 (t); 17.2 (t). MS: 256 (5, Mþ), 241 (9), 220 (7), 205 (6), 191 (27), 177 (7), 151 (9), 149 (9), 138
(17), 135 (14), 123 (100), 121 (19), 109 (40), 107 (23), 105 (22), 95 (57), 93 (18), 91 (19), 81 (37), 69
(60), 67 (19), 55 (24), 41 (27); 20% yield, 66% yield based on recovered (þ)-6a.

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Helvetica Chimica Acta – Vol. 97 (2014)
ture, 1.5 g, 6.44 mmol)35) in 99% HCOOH (11.07 ml, 290 mmol) was heated at 1108 for 0.5 h. The cold
mixture was poured onto ice and then extracted with Et2O (3 ꢂ 80 ml). The org. phase was washed with
sat. aq. NaHCO3 and brine, dried (Na2SO4), concentrated, and then purified by CC (SiO2; cyclohexane/
AcOEt 99 :1) to afford (þ)-16c (79% yield), contaminated with 4% of the deconjugated isomer [51b].
[a]2D0 ¼ 74.6 (c ¼ 1.1, CHCl3). IR: 2924, 2866, 2847, 1687, 1457, 1442, 1428, 1388, 1376, 1366, 1348, 1251,
1195, 1167, 1060, 1050, 976, 946, 860, 692, 610. 1H-NMR: 2.26 (s, 3 H); 2.05 (dd, J ¼ 4.4, 8.8, 2 H); 1.73 –
1.57 (m, 2 H); 1.54 (s, 3 H); 1.53 – 1.41 (m, 5 H); 1.32 – 1.19 (m, 2 H); 1.18 (s, 3 H); 0.90 (s, 3 H); 0.85 (s,
3 H). 13C-NMR: 209.9 (s); 147.1 (s); 127.2 (s); 50.6 (d); 41.7 (t); 37.4 (t); 37.2 (s); 34.0 (q); 33.3 (q); 33.2
(s); 32.1 (t); 21.5 (q); 20.6 (q); 20.3 (q); 18.7 (t); 18.6 (t). MS: 234 (4, Mþ), 219 (15), 191 (100), 149 (22),
147 (10), 137 (10), 135 (16), 123 (15), 121 (50), 109 (29), 107 (15), 105 (10), 95 (47), 93 (10), 91 (15), 79
(10), 69 (15), 55 (10), 43 (31), 41 (12). Woody, dry, paper, weak.
(þ)-(4aS,8aS)-8-Ethynyl-1,2,3,4,4a,5,6,8a-octahydro-4,4,7,8a-tetramethylnaphthalene ((þ)-17).
SOCl2 (65 ml, 106 mg, 0.894 mmol) was added dropwise to a soln. of (1R,2R,4aS,8aS)-1-ethynyldecahy-
dro-2,5,5,8a-tetramethylnaphthalen-1-ol (56 :44 mixture of diastereoisomers [20][24]; 190 mg,
0.813 mmol) in pyridine (3 ml) at ꢀ 408. After 30 min, H2O and then Et2O were added. The temp.
was adjusted to 208, and the mixture was extracted. The org. phase was washed with H2O and brine, dried
(Na2SO4), then concentrated. Purification by CC (SiO2; cyclohexane/AcOEt 99 :1 to 98 :2) afforded
(þ)-17 (40% yield36)). [a]D20 ¼ þ107.8 (c ¼ 0.4, CHCl3). IR: 3310, 2923, 2865, 2851, 2086, 1457, 1441, 1426,
(2R,4aS,8aS)-1-Ethynyldecahydro-2,5,5,8a-tetramethylnaphthalen-1-ol: 1H-NMR: 2.53 (s, 1 H);
1.89 – 1.83 (m, 1 H); 1.74 (dt, J ¼ 3.6, 12.3, 2 H); 1.65 – 1.16 (m, 10 H); 1.02 (d, J ¼ 7, 3 H); 0.99 (s,
3 H); 0.87 (s, 3 H); 0.83 (s, 3 H). 13C-NMR: 84.5 (s); 80.8 (s); 76.2 (d); 48.8 (d); 42.8 (s); 41.7 (t); 36.1
(d); 33.5 (t); 33.3 (q); 33.1 (s); 31.9 (t); 21.7 (q); 21.1 (t); 18.6 (t); 16.4 (q); 13.5 (q). MS: 234 (0, Mþ),
219 (18), 201 (15), 191 (12), 177 (18), 163 (27), 159 (13), 151 (17), 149 (21), 145 (14), 137 (23), 135
(26), 123 (100), 121 (26), 119 (14), 109 (43), 107 (30), 105 (16), 97 (25), 95 (57), 93 (21), 91 (21), 82
(60), 79 28), 69 (40), 67 (33), 55 (42), 53 (27), 43 (22), 41 (41). (1S,2R,4aS,8aS)-1-Ethynyldecahydro-
2,5,5,8a-tetramethylnaphthalen-1-ol: 1H-NMR: 2.39 (s, 1 H); 1.94 – 1.86 (m, 1 H); 1.76 (s, OH);
1.63 – 1.46 (m, 7 H); 1.39 – 1.18 (m, 4 H); 1.11 (s, 3 H); 1.04 (d, J ¼ 7, 3 H); 0.87 (s, 3 H); 0.82 (s, 3 H).
13C-NMR: 86.2 (s); 78.1 (s); 73.3 (d); 44.1 (d); 42.0 (s); 41.9 (t); 35.6 (d); 33.3 (q); 33.2 (s); 32.7 (t);
29.7 (t); 21.8 (q); 21.1 (t); 18.6 (t); 17.3 (q); 16.9 (q). MS: 234 (2, Mþ), 219 (17), 201 (19), 191 (12), 177
(20), 163 (30), 159 (14), 151 (19), 149 (14), 137 (13), 135 (13), 123 (100), 121 (27), 119 (16), 110 (32),
109 (43), 107 (29), 105 (20), 97 (27), 95 (56), 93 (14), 91 (14), 82 (60), 79 (30), 77 (19), 69 (42), 67
(34), 55 (44), 53 (27), 41 (42).
35
)
36
)
The isolated main side product (43% yield) was an inseparable 75:25 mixture of (4aR,6R,8aS)-5-
[(E)-2-chloroethenyl]decahydro-1,1,4a,6-tetramethylnaphthalene. This compound became the
unique reaction product (78% yield), when this transformation was performed at 208. Anal. data
deduced from the mixture of diastereoisomers: IR: 2926, 2869, 2848, 1946, 1454, 1388, 1376, 1365,
1334, 1229, 1204, 1191, 1127, 1103, 1050, 1027, 994, 979, 947, 927, 847, 814, 785, 754, 727, 693, 669,
658, 634. 1H-NMR (major): 6.09 (d, J ¼ 2.5, 1 H); 2.44 – 2.38 (m, 1 H); 1.97 – 1.92 (m, 1 H); 1.70 – 1.60
(m, 2 H); 1.55 – 1.38 (m, 8 H); 1.15 (s, 3 H); 0.96 (d, J ¼ 6.3, 3 H); 0.85 (s, 6 H). 13C-NMR: 194.4 (s);
132.8 (s); 90.3 (d); 53.8 (d); 42.1 (t); 38.9 (s); 38.7 (t); 36.6 (t); 33.8 (s); 33.1 (q); 31.0 (d); 21.8 (t); 21.7
(q); 20.3 (q); 19.7 (q); 18.8 (t). MS: 254 (7, Mþ), 252 (20), 237 (11), 217 (31), 201 (20), 182 (16), 175
(16), 173 (10), 161 (21), 159 (13), 155 (14), 150 (38), 147 (38), 145 (24), 141 (22), 135 (100), 133 (23),
131 (30), 129 (13), 123 (53), 121 (33), 119 (44), 117 (23), 115 (22), 109 (28), 107 (38), 105 (62), 103
(11), 97 (20), 95 (33), 93 (31), 91 (62), 81 (32), 79 (33), 77 (39), 69 (59), 67 (25), 65 (21), 55 (37), 53
(15), 41 (43). 1H-NMR (minor): 6.04 (d, J ¼ 2.7, 1 H); 2.37 – 2.33 (m, 1 H); 2.16 – 2.12 (m, 1 H); 1.85 –
1.77 (m, 2 H); 1.55 – 1.38 (m, 8 H); 1.10 (s, 3 H); 0.97 (d, J ¼ 6.3, 3 H); 0.89 (s, 3 H); 0.87 (s, 3 H).
13C-NMR: 194.7 (s); 132.9 (s); 90.1 (d); 53.7 (d); 42.0 (t); 39.0 (s); 38.8 (t); 36.6 (t); 33.9 (s); 33.4 (q);
31.2 (d); 21.0 (t); 21.6 (q); 20.2 (q); 19.7 (q); 18.6 (t). MS: 254 (8, Mþ), 252 (22), 237 (11), 217 (33),
201 (17), 182 (16), 175 (16), 173 (10), 161 (20), 159 (13), 155 (14), 150 (39), 147 (39), 145 (23), 141
(21), 135 (100), 133 (23), 131 (29), 129 (16), 123 (56), 121 (32), 119 (39), 117 (20), 115 (22), 109 (26),
107 (38), 105 (59), 103 (11), 97 (20), 95 (32), 93 (31), 91 (57), 81 (31), 79 (32), 77 (40), 69 (57), 67
t
(23), 65 (20), 55 (33), 53 (15), 41 (40). Further treatment (tBuOK, BuOH, 828 [58]; 94% yield)
afforded (þ)-9a.

Helvetica Chimica Acta – Vol. 97 (2014)
211
1388, 1374, 1243, 1231, 1205, 1029, 1013, 975, 861, 836, 729, 630. 1H-NMR: 3.04 (br. s, 1 H); 2.12 (dt, J ¼
6.5, 13.1, 1 H); 2.02 (ddt, J ¼ 1.4, 3.1, 13.1, 1 H); 1.85 (s, 3 H); 1.69 (ddt, J ¼ 1.9, 6.7, 13.1, 1 H); 1.61 (tq, J ¼
3.4, 13.7, 1 H); 1.56 (s, 1 H); 1.50 (dquint., J ¼ 3.4, 14, 1 H); 1.43 (s, 1 H); 1.44 – 1.39 (m, 2 H); 1.16 (dt, J ¼
4.0, 13.3, 1 H); 1.09 (dd, J ¼ 2.0, 12.7, 1 H); 1.06 (s, 3 H); 0.89 (s, 3 H); 0.84 (s, 3 H). 13C-NMR: 141.6 (s);
126.8 (s); 82.1 (s); 80.4 (d); 50.9 (d); 41.8 (t); 38.2 (t); 37.0 (s); 33.3 (s); 33.1 (t); 33.1 (q); 22.1 (q); 21.5 (q);
20.5 (q); 19.1 (t); 18.4 (t). MS: 216 (58, Mþ), 201 (100), 173 (16), 159 (19), 145 (41), 131 (74), 129 (19),
128 (18), 119 (99), 117 (17), 115 (22), 109 (14), 107 (10), 105 (51), 103 (10), 91 (40), 81 (11), 79 (14), 77
(20), 69 (24), 55 (12), 41 (19).
(þ)-(1S,2R,4aS,8aS)-Octahydro-2,5,5,8a-tetramethyl-2H-spiro[naphthalene-1,2’-oxirane] ((þ)-18a).
Obtained in 70% yield from (ꢀ)-8a as a 85 :15 mixture (þ)-18a/18b according to the procedure used for
(þ)-13. Anal. pure material was obtained in 27% yield after purification by CC (SiO2; cyclohexane/
AcOEt 99 :1). [a]2D0 ¼ þ64.3 (c ¼ 1.1, CHCl3). IR: 3054, 2933, 2868, 1460, 1387, 1378, 1364, 1346, 1232,
1212, 1186, 1149, 1098, 1047, 1024, 976, 969, 940, 911, 899, 881, 835, 822, 768, 731, 681, 604. 1H-NMR: 2.67
(d, J ¼ 4.2, 1 H); 2.58 (d, J ¼ 4.2, 1 H); 2.21 – 2.16 (m, 1 H); 1.70 – 1.65 (m, 2 H); 1.57 (tq, J ¼ 3.5, 13.7,
1 H); 1.48 – 1.40 (m, 2 H); 1.33 – 1.24 (m, 4 H); 1.14 (dt, J ¼ 4, 13.7, 1 H); 1.08 (s, 3 H); 1.06 (dt, J ¼ 4, 12.4,
1 H); 0.86 (s, 3 H); 0.82 (s, 3 H); 0.67 (d, J ¼ 6.8, 3 H). 13C-NMR: 66.9 (s); 50.0 (d); 45.8 (t); 41.5 (t); 38.0
(s); 33.4 (s); 33.4 (t); 32.8 (q); 31.2 (t); 29.7 (d); 22.1 (t); 21.7 (q); 19.6 (q); 18.3 (t); 15.0 (q). MS: 222 (40,
Mþ), 207 (100), 191 (27), 177 (66), 175 (38), 165 (20), 153 (59), 151 (38), 149 (21), 147 (35), 138 (32),
135 (30), 133 (19), 123 (90), 121 (58), 119 (30), 109 (44), 107 (57), 105 (35), 98 (30), 95 (54), 93 (45), 91
(40), 84 (38), 81 (66), 79 (40), 77 (26), 69 (48), 67 (40), 55 (48), 53 (20), 43 (22), 41 (54).
(1R,2R,4aS,8aS)-Octahydro-2,5,5,8a-tetramethyl-2H-spiro[naphthalene-1,2’-oxirane]
(18b).
AcOOH (39% in AcOH; 143 mg, 0.125 ml, 0.74 mmol) was added dropwise to a soln. of (ꢀ)-8b
(101 mg, 0.49 mmol) and AcONa (19 mg, 0.233 mmol) in CH2Cl2 (5 ml) at 08. After 20 min at 08, and 1 h
at 208, the fully converted mixture was diluted with CH2Cl2 (10 ml), washed with sat. aq. NaHCO3, brine,
and H2O, dried (Na2SO4), and concentrated to afford a 55 :45 mixture (þ)-18a/18b (91% yield). IR:
2921, 2852, 1460, 1378, 1364, 1346, 1232, 1212, 1186, 1048, 1025, 975, 940, 899, 823, 732, 683. Deduced from
the mixture: 1H-NMR: 2.89 (d, J ¼ 3.8, 1 H); 2.59 (d, J ¼ 4.0, 1 H); 1.88 (dq, J ¼ 3.9, 13.0, 1 H); 1.70 – 1.65
(m, 2 H); 1.57 (tq, J ¼ 3.5, 13.7, 1 H); 1.48 – 1.40 (m, 2 H); 1.33 – 1.24 (m, 4 H); 1.14 (dt, J ¼ 4, 13.7, 1 H);
1.11 (s, 3 H); 1.06 (dt, J ¼ 4, 12.4, 1 H); 0.87 (s, 3 H); 0.85 (s, 3 H); 0.68 (d, J ¼ 6.1, 3 H). 13C-NMR: 68.5
(s); 53.1 (d); 46.0 (t); 42.3 (t); 38.5 (s); 34.5 (t); 33.6 (s); 33.2 (d); 32.6 (q); 31.2 (t); 22.1 (t); 22.0 (q); 18.4
(t); 17.5 (q); 15.0 (q). MS: 222 (31, Mþ), 207 (84), 204 (8), 190 (19), 177 (52), 175 (25), 165 (14), 161
(10), 153 (40), 151 (29), 149 (18), 147 (27), 138 (42), 135 (36), 133 (20), 123 (100), 122 (32), 121 (50), 119
(27), 109 (55), 107 (51), 105 (30), 98 (25), 95 (64), 93 (43), 91 (37), 84 (45), 81 (70), 79 (40), 77 (22), 69
(60), 67 (42), 55 (49), 43 (21), 41 (51), 39 (16). Woody, straw, dusty, earthy.
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Received July 19, 2013