A new preparation of 1,3,3-trimethylbicyclo[2.2.2]octan-2,6-dione, a never isolated intermediate in a total synthesis of (+)-norpatchoulenol. Formal total synthesis of (±)-iso-norpatchoulenol

Article abstract of DOI:10.1002/hlca.200490191

A new preparation and the isolation and spectroscopic characterization of 1,3,3-trimethylbicyclo[2.2.2]octan-2,6-dione (3), a so far elusive key intermediate in the Liu-Ralitsch total synthesis of (+)-norpatchoulenol ((+)-1a), is described. The preparation of 3 constitutes also a formal total synthesis of (±)-iso-norpatchoulenol ((±)-1b), since 3 is correlated to an intermediate in the Monti and co-workers synthesis of (±)-1b.

Full text of DOI:10.1002/hlca.200490191

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Helvetica Chimica Acta ± Vol. 87 (2004)
A New Preparation of 1,3,3-Trimethylbicyclo[2.2.2]octan-2,6-dione, a Never
Isolated Intermediate in a Total Synthesis of (‡)-Norpatchoulenol.
Formal Total Synthesis of (Æ)-Iso-Norpatchoulenol
by Angela La Bella, Francesca Leonelli, Ilse De Salve, Luisa M. Migneco, and Rinaldo Marini Bettolo*
Dipartimento di Chimica and Istituto di Chimica Biomolecolare del CNR, Sezione di Roma,
Universit a¡ degli Studi di Roma −La Sapienza×, Piazzale Aldo Moro 5, P.O. Box 34 Roma 62, I-00185 Rome
(
phone: ‡390649913615; fax. ‡390649913750; e-mail: rinaldo.marinibettolo@uniroma1.it)
A new preparation and the isolation and spectroscopic characterization of 1,3,3-trimethylbicyclo[2.2.2]oc-
tan-2,6-dione (3), a so far elusive key intermediate in the LiuÀRalitsch total synthesis of (‡)-norpatchoulenol
(
(
(‡)-1a), is described. The preparation of 3 constitutes also a formal total synthesis of (Æ)-iso-norpatchoulenol
(Æ)-1b), since 3 is correlated to an intermediate in the Monti and co-workers synthesis of (Æ)-1b.
Introduction. ± (‡)-Norpatchoulenol (ˆ1R,4aS,6R,8aS)-4a,5,6,7,8,8a-hexahydro-
8
a,9,9-trimethyl-1,6-methanonaphthalen-1(2H)-ol; (‡)-1a) is a minor component of
patchouli oil, obtained by steam distillation of Pogostemon patchouli leaves, and is one
of the major determinants of the patchouli scent [1]. Several authors have reported
syntheses of 1a [2]. Liu and Ralitsch described the total synthesis of (‡)-1a from (‡)-
camphor-10-sulphonic acid (Scheme 1) (2) [2h]. Trapping of the 1,3-diketone inter-
mediate 3 with a Wittig reagent to give 4 was a key feature of their approach. Thereby,
the authors successfully managed to overcome the problem of the preparation of 4,
since −under no conditions applied could the desired product (3) be obtained× by direct
cyclization of 5a, while, starting from 5b or 5c, the diketone 3 was obtained in very low
yield. Compound 4 was then converted to (‡)-1a via 6. The latter compound is also an
intermediate in the synthesis of (Æ)-iso-norpatchoulenol 1b, described in 1996 by Monti
and co-workers (see Scheme 2) [3]. Thus, intermediate 3 is related to both 1a and 1b via
compound 6. However, compound 3 had originally been obtained much earlier, though
not isolated, by Curtin and Fraser during their studies on the reactivity of 2,6,6-
trimethylcyclohexa-2,4-dien-1-one towards a series of dienophiles [4].
In the frame of a project directed to the synthesis of patchouli-alcohol-like
fragrances, whose bicyclo[2.2.2]octane system we intend to construct by the intra-
molecular aldol condensation of 3-oxocyclohexaneacetaldehydes [5], a methodology
not yet extended to the synthesis of this class of compounds, we prepared the
−
apparently unstable× 1,3-diketone 3. Owing to the importance of 3 as a synthetic
intermediate (or reaction product), we wish to describe hereafter its preparation,
isolation, and spectroscopic characterization.
Results and Discussion. ± The starting material for this study was the known 6-
hydroxybicyclo[2.2.2]octan-2-one 7 [6a], available in three steps from the cyclo-
hexanone 8 [7] according to Scheme 2. Compound 7 was obtained as an endo/exo 85 :15
¹
2004 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta ± Vol. 87 (2004)
2121
Scheme 1. LiuÀRalitsch Synthesis of (‡)-Norpatchoulenol (1a) via 1,3,3-Trimethyl-bicyclo[2.2.2]octan-2,6-
dione (3)
mixture, endo-7 being the major component. In principle, both epimers, endo- and exo-
1
7
), were potential intermediates for further work. However, for practical reasons, the
synthesis was carried on with only endo-7. The latter was protected as tetrahydropyr-
anyl (THP) ether by standard methods to give 9, which was then converted to the gem-
dimethylated compound 10 by reaction with t-BuOK and MeI. THP Deprotection of 10
2
in mildly acidic medium gave the endo-hydroxy ketone 11 ) as the only product.
The endo-configuration of the HOÀC(6) group of 11 was attributed by comparing
the HÀC(6) and C(6) NMR chemical shifts of 11 with those of endo- and exo-7. The
corresponding values for endo-7, exo-7, and 11 were, for HÀC(6), d 3.85, 3.75, and 3.85,
respectively, and those for C(6), 73.8, 69.8, and 74.6. Thus, epimerization at C(6) was
excluded during the formation of 9 and 11.
3
Pyridinium dichromate (PDC) oxidation ) of 11 in CH Cl finally gave 3. The
2
2
direct conversion of 10 to 3 could be also achieved with the Jones reagent. Interestingly,
the so-far elusive 3 turned out to be a stable compound, and could be fully
characterized. Its structure was further confirmed by Wittig reaction to 4 with
(
methoxymethyl)triphenylphosphonium chloride, the same reagent used by Liu and
Ralitsch for their one-pot transformation of 5a into 4 [2h]. The isomeric product due to
the attack of the Wittig reagent at the more-hindered CˆO group was not observed.
Conclusions. ± In view of the syntheses of Liu and Ralitsch [2h], and Monti and co-
workers [3], the preparation of 3 (and 4) constitutes formal total syntheses of both
norpatchoulenol ((Æ)-1a) and iso-norpatchchoulenol ((Æ)-1b). Moreover, by correlat-
ing endo-7 [6a] with 1a [2h] and 1b [3], the 3-oxo-cyclohexaneacetaldehyde intra-
1)
2)
3)
For a preparation of (À)-endo-7 and (À)-exo-7, see [6a] and [6b], resp.
As for 3, Curtin and Fraser [4] also reported of 11. However, they did not isolate it.
For oxidations of a 6-hydroxybicyclo[2.2.2]octan-2-one to a bicyclo[2.2.2]octan-2,6-dione, see [6a][8].

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Helvetica Chimica Acta ± Vol. 87 (2004)
Scheme 2. Preparation of the Elusive Intermediate 3, and Formal Total Syntheses of Norpatchoulenol (1a) and
Iso-Norpatchoulenol (1b)
a) C
:1, reflux; 86%. d) 3,4-dihydro-2H-pyran, CH
n HCl 4 :1, r.t.; 73%. g) Jones reagent, acetone; 80%. h) pyridinium dichromate (PDC), CH
Ph
PˆC(H)OMe, THF, 08; 86%.
6
H
6
, TsOH, ethylene glycol, reflux; 86%. b) OsO
Cl , TsOH, r.t.; 96%. e) t-BuOK, THF, MeI, r.t.; 70%. f) THF/
Cl ; 89%. i)
4 4 2
, THF, pyridine, NaIO , H O, r.t.; 65%. c) THF/2n HCl
2
1
2
2
2
2
3
molecular aldol condensation is extended to the synthesis of patchouli-alcohol-like
fragrances, showing the complementarity of this methodology to others adopted to date
to this end.
Financial support by the Universit a¡ degli Studi di Roma −La Sapienza× (Ateneo 60%) and the Ministero
dell×Istruzione, Universit a¡ e Ricerca (COFIN 2000: −Sintesi di Sostanze di Comunicazione Chirali×, and COFIN
2
002: −Aromi e Fragranze×) is gratefully acknowledged.
Experimental Part
General. All solns. were evaporated to dryness under vacuum. All solvents were of anal. or HPLC grade.
Compound 8 was prepared from commercial 2-methylanisole (Aldrich) according to [7]. The purity of all
compounds was evaluated by HPLC analysis: Shimadzu LC-10AD with RID detector; 250/4 Nucleosil 100-5
column (Macherey-Nagel), at a flow of 0.8 ml/min; t
R
in min. TLC: Merck silica gel 60F254. M.p.: Mettler FP-61
À1
1
apparatus, uncorrected. IR Spectra: Shimadzu 470 and Perkin-Elmer 298 spectrophotometers; in cm . H- and
1
3
C-NMR: Bruker AC-300P (300.13 and 75.48 MHz, resp.), and Varian Gemini-200 (200 and 50 MHz, resp.); d
in ppm rel. to internal Me
4
Si (ˆ0 ppm), J in Hz. GC/MS: HP5890 GC (OV1 capillary column, 12 m  0.2 mm),
HP5970 MSD; in m/z (rel. %).
Data of endo-7 (ˆ1S,4R,6R)-6-Hydroxy-1-methylbicyclo[2.2.2]octan-2-one) [6a]. HPLC (hexane/AcOEt
1
7
3
2
0 :30): t
R
14.30 (100%). M.p. 124.4 ± 126.48 (hexane/Et
2
O 70 :30). IR (CCl
4
): 1727. H-NMR (CDCl
3
): 3.86 ±
1
3
3
.83 (m, 1 H); 2.54 ± 2.01 (5 H); 1.72 ± 1.31 (5 H); 1.00 (s, 3 H). C-NMR (CDCl ): 215.9; 73.8; 48.7; 44.0; 36.7;
8.1; 27.7; 25.1; 16.7.
Data of exo-7 [6a]. HPLC (hexane/AcOEt 70 :30): t
R
11.77 (100%). M.p. 104.6 ± 106.68 (hexane). IR
): 216.5;
1
): 3.85 ± 3.64 (m, 1 H); 2.53 ± 1.15 (10 H); 0.98 (s, 3 H). 13C-NMR (CDCl
(
CCl
4
): 1724. H-NMR (CDCl
3
3
6
9.8; 49.3; 43.6; 37.3; 27.2; 25.0; 23.2; 16.0.

Helvetica Chimica Acta ± Vol. 87 (2004)
2123
1
-Methyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]bicyclo[2.2.2]octan-2-one (9). To a stirred soln. of endo-7
710 mg, 4.6 mmol) in CH Cl (11 ml), cooled to 08 under Ar, were added portionwise 3,4-dihydro-2H-pyran
1 ml, 11 mmol) and a cat. amount of TsOH. The mixture was allowed to warm to r.t. When TLC (hexanes/Et
0 :70) showed the disappearance of the starting material, a sat. NaHCO soln. (2 ml) was added under stirring.
The two phases were separated, and the org. layer was washed with H O and brine, dried (Na SO ), and
evaporated. The residue was purified by CC (SiO ; hexanes/Et O 75 :25) to afford 9 (1 g; 96%) as a
(
(
2
2
2
O
3
3
2
2
4
2
2
diastereoisomeric mixture. Colouless oil. HPLC (hexane/AcOEt 90 :10): t
R
11.60 min (100%). IR (CCl
4
): 1725.
1
H-NMR (CDCl
3
): 4.74 ± 4.45 (m, 1 H), 3.90 ± 3.62 (m, 2 H), 3.50 ± 3.33 (m, 1 H), 2.35 ± 0.90 (18 H). EI-MS: 238
‡
(0.4, M ), 154 (62), 93 (43), 85 (100), 67 (20).
1
,3,3-Trimethyl-6-[(tetrahydro-2H-pyran-2-yl)oxy]bicyclo[2.2.2]octan-2-one (10). To a stirred soln. of 9
475 mg, 2 mmol) in THF (7 ml) was added under Ar a suspension of t-BuOK (449 mg, 4 mmol) in THF (5 ml).
O 70 :30) showed the disappearance
of the starting material, the mixture was neutralized with 0.5n HCl, washed with H O and brine, dried (Na SO ),
and evaporated. The residue was purified by CC (SiO ; hexanes/Et O 90 :10) to afford 10 (372 mg; 70%) as a
(
MeI (0.6 ml, 10 mmol) was then added dropwise. When TLC (hexanes/Et
2
2
2
4
2
2
diastereoisomeric mixture. Colorless oil. HPLC (hexane/AcOEt 90 :10): t
R
6.92 min (98%). IR (CCl
4
): 1720.
1
H-NMR (CDCl
9 H). EI-MS: 266 (0.1, M ), 182 (45), 137 (14), 95 (11), 85 (100), 67 (12).
-Hydroxy-1,3,3-trimethylbicyclo[2.2.2]octan-2-one (11). Compound 10 (230 mg, 0.9 mmol) was dissolved
in THF/1n HCl 4 :1 (10 ml). This soln. was stirred at r.t., until TLC analysis (hexanes/Et O 60 :40) showed the
disappearance of the starting material (after ca. 72 h). The mixture was then neutralized with a sat. NaHCO
soln. and diluted with Et O. After separation of the layers, the aq. phase was thoroughly extracted with Et O, the
combined org. extracts were washed with H O and brine, dried (Na SO ), and evaporated. The resulting residue
O 85 :15) to afford 11 (120 mg; 73%). M.p. 84.5 ± 86.58 (hexane/Et
): 3.92 ± 3.79 (m, 1 H); 2.20 ± 1.37 (9 H); 1.13 (s, 3 H); 1.09 (s, 3 H);
3
): 4.80 ± 4.49 (m, 1 H); 3.91 ± 3.61 (m, 2 H); 3.52 ± 3.39 (m, 1 H); 2.13 ± 1.35 (13 H); 1.17 ± 0.87
‡
(
6
2
3
2
2
2
2
4
was purified by CC (SiO
2
1
; hexanes/Et
2
2
O
7
0
0 :30). IR (CCl
.98 (s, 3 H). C-NMR (CDCl
4
): 1720. H-NMR (CDCl
3
1
3
3
): 220.2; 74.6; 48.7; 45.5; 38.7; 34.4; 28.0; 24.3; 23.2; 22.3; 16.9. HPLC (hexane/
‡
AcOEt 70 :30): t
R
7.40 min (100%). EI-MS: 182 (2, M ), 95 (100), 94 (35), 88 (64), 79 (15), 69 (12), 67 (12).
1
,3,3-Trimethylbicyclo[2.2.2]octane-2,6-dione (3). Method 1: To a stirred soln. of 11 (80 mg, 0.44 mmol) in
Cl (10 ml), pyridinium dichromate (PDC; 330 mg, 0.88 mmol) was added. The mixture was stirred for 24 h
at r.t. After filtration through Florisil and phase separation, the org. soln. was washed with a sat. aq. CuSO . soln.
and brine, dried (Na SO ), and evaporated. The residue was purified by CC (SiO ; hexanes/Et O 75 :25) to
afford 3 (71 mg; 89%).
Method 2: To a stirred soln. of 10 (320 mg, 1.2 mmol) in anh. acetone (5 ml), cooled to 08, was added
dropwise 0.8 ml of Jones reagent (prepared by addition of CrO (10 g, 0.1 mmol) at 08 to 96% H SO (8.6 ml)
and H O (14 ml), followed by dilution with additional H O (12 ml)). The mixture was then allowed to warm to
r.t.. When TLC analysis (hexanes/Et O 70 :30) showed the disappearance of the starting material, the mixture
was treated with a 10% aq. Na soln., and filtered (Celite). The org. soln. was evaporated, the residue was
diluted with Et O, washed with sat. NaHCO soln., H O, and brine, dried (Na SO ), and evaporated. The
resulting residue was purified by CC (SiO ; hexanes/Et O 85 :15) to afford 3 (173 mg; 80%).
Data of 3. Colorless oil. HPLC (hexane/AcOEt 9 :10): t 11.68 min (100%). IR (CCl ): 1709. H-NMR
CDCl
): 2.66 (A of ABMX; JAB ˆ 19.50; JAX ˆ JAM ˆ 3.02; 1 H); 2.36 (B of ABMX; JAB ˆ 19.50; JBX ˆ 2.93;
BM ˆ 0; 1 H); 2.24 ± 2.06 (m, 2 H); 1.90 ± 1.69 (m, 3 H); 1.26 (s, 3 H); 1.06 (s, 3 H); 1.05 (s, 3 H). C-NMR
CH
2
2
4
2
4
2
2
3
2
4
2
2
2
2 2 5
S O
2
3
2
2
4
2
2
1
R
4
(
J
3
1
3
‡
(
CDCl
3
): 213.2; 208.6; 62.4; 46.0; 42.0; 38.4; 29.8; 24.4; 23.9; 22.2; 12.6. EI-MS: 180 (24, M ), 165 (37), 110 (10),
09 (25), 108 (24), 95 (22), 81 (100), 69 (75).
-(Methoxymethylidene)-1,3,3-trimethylbicyclo[2.2.2]octan-2-one (4). To a stirred soln. of (methoxy-
methyl)triphenylphosphonium chloride (1.3 g, 3.8 mmol) in THF (7.5 ml) was added t-BuOK (284 mg,
.5 mmol) at 08C under Ar atmosphere. A reddish color indicated ylide formation. After 1 h, a soln. of 3
100 mg, 0.54 mmol) in THF (2 ml) was added dropwise to the Wittig reagent. The mixture was stirred until TLC
hexanes/Et O 80 :20) showed the disappearance of the starting material (after ca. 2 h). The mixture was
O, and thoroughly extracted with Et O. The combined org. extracts were
O and brine, dried (Na SO ), and evaporated. The residue was purified by CC (SiO ; hexanes/
1
6
2
(
(
2
warmed to r.t., quenched with H
washed with H
2
2
2
2
4
2
Et
2
O 90 :10) to afford 4 (97 mg; 86%). Colorless oil. HPLC (hexane/AcOEt 90 :10): t
R
ˆ 4.77 and 5.17 (100%);
1
(
E)/(Z) 96 :4. IR (CCl
4
): 1718. H-NMR (CDCl
3
): 5.84 ± 5.76 (m, 1 H); 3.57 (s, 3 H); 2.67 ± 2.58 (m, 1 H); 2.27 ±
.15 (m, 1 H); 2.00 ± 1.51 (m, 5 H); 1.12 (s, 3 H); 1.01 (s, 3 H); 1.00 (s, 3 H). 1 C-NMR (CDCl
3
): 218.7; 141.8;
2
1
1
3
‡
15.5; 59.6; 46.0; 45.5; 38.1; 31.9; 27.5; 24.2; 24.1; 22.9; 16.4. EI-MS: 208 (27, M ), 180 (43), 165 (17), 137 (100),
23 (22), 105 (37), 77 (19).

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Helvetica Chimica Acta ± Vol. 87 (2004)
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Received May 10, 2004