Ti(III)-promoted cyclizations. Application to the synthesis of (E)-endo-bergamoten-12-oic acids. Moth oviposition stimulants isolated from Lycopersicon hirsutum

Article abstract of DOI:10.1016/j.tet.2006.07.020

The Ti(III)-promoted radical cyclization of epoxyenone 8 is described as the key step to access the diol 10 as a convenient starting material of the target molecules. The synthesis of β-(E)-endo-bergamoten-12-oic acid 2a from (+)-8,9-epoxycarvone 8 was su

Full text of DOI:10.1016/j.tet.2006.07.020

Tetrahedron 62 (2006) 8933–8942
Ti(III)-promoted cyclizations. Application to the synthesis
of (E)-endo-bergamoten-12-oic acids. Moth oviposition
stimulants isolated from Lycopersicon hirsutum
*
Francisco A. Bermejo, Alfonso Fernandez Mateos, Andres Marcos Escribano,
*
ꢀ
Rodrigo Martın Lago, Lydia Mateos Buron, Marıa Rodrıguez Lopez
ꢀ
´
´
´
ꢀ
and Rosa Rubio Gonzalez
ꢀ
ꢀ
´
ꢀ
´
Departamento de Quımica Organica, Facultad de Quımicas, Universidad de Salamanca,
Pza de la Merced s.n., 37008 Salamanca, Spain
Received 23 June 2006; revised 5 July 2006; accepted 6 July 2006
Available online 28 July 2006
Abstract—The Ti(III)-promoted radical cyclization of epoxyenone 8 is described as the key step to access the diol 10 as a convenient starting
material of the target molecules. The synthesis of b-(E)-endo-bergamoten-12-oic acid 2a from (+)-8,9-epoxycarvone 8 was successfully
achieved by Suzuki–Miyaura coupling of the terminal alkene 20 with b-iodomethacrylate 21c, followed by deprotection and dehydration
processes. Moreover, synthesis of the a-(E)-endo-1-hydroxy-bergamoten-12-oic acid derivative 34 was achieved by iterative elongation
processes of the diol 10 lateral chain.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
The use of titanocene(III) chloride in cyclization processes
on functionalized epoxides has offered a plausible alterna-
tive for accessing polycyclic structures since the time that
Nugent and RajanBabu first reported the Ti(III)-promoted
epoxide opening reactions and subsequent reactivity of the
radical intermediates.6 Based on the experience gained in
the reactivity of Ti(III) against epoxy ketones we considered
the possibility of preparing the tricyclic core present in the
bergamotene series by using this cyclization method, start-
ing from (+)-8,9-epoxycarvone 8. If our assumption is
correct then this may help to open new strategies for the
synthesis of biologically active natural products such as
those represented in Figure 1 (1–6).7
The isolation of the a and b forms of (E)-endo-bergamoten-
12-oic acids 1a and 2a (Fig. 1) from the leaves of Lycoper-
sicon hirsutum by Coates et al. in 19881 opened the door to
synthetic work, which was successfully achieved by Mori
and Matsushima in 1994.2 These two sesquiterpenoids
seem to influence the oviposition behavior of Heliothis zea
(Boddie) whose larvae are major agricultural pests of
tomatoes, corn and cotton.3 The synthesis of these H. zea
oviposition stimulants may have potential application in ag-
riculture since these sesquiterpenoids might prove effective
when combined with pesticide baits for current pest control.
The starting material chosen by Mori et al. to construct the
pinane-type carbon skeleton of bergamotenoic acids was
the tricyclic lactone 6.4 Starting from 6, construction of
the side chain of both sesquiterpenes required the applica-
tion of a preparatively demanding 13-step sequence that
included the chromatographic separation of an almost
equimolecular mixture of alkenes. Additionally, the stereo-
controlled synthesis of 6 from R-(ꢀ)-carvone 7 was reported
by our group in 1998 in a parallel synthetic study aimed at
the synthesis of (+)-ampullicin 4 and (+)-isoampullicin 5.5
Keywords: Sesquiterpenoids; b-Halomethacrylates; (E)-b-endo-Bergamo-
ten-12-oic acids; (S)-(+)-Carvone.
* Corresponding authors. Tel.: +34 923 294481; fax: +34 923 294574
(F.A.B.); e-mail: fcobmjo@usal.es
Figure 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.020

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F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
2. Results and discussion
recently reported by Baba et al.13 Deoxygenation methods
based on dissolving-metal reductions (Li, HMPA or ethylene
diamine) of other functionalities (acetate, mesylate, tosy-
late) failed repeatedly due to competitive Grob fragmenta-
tion processes, activated when the tertiary alcohol was
made to react under strong basic conditions.14 The ether
14 exhibits the tricyclic core of massarinolin B (3), a bio-
active sesquiterpenic acid isolated from Massarina tunicata
by Shearer et al. (A-25-1; Lophiostomataceae).15
We now wish to describe the synthesis of 6 through a novel
route based on the titanium-promoted intramolecular cycli-
zation of (+)-8,9-epoxycarvone 8, which is easily obtained
by epoxidation of (S)-(+)-carvone as a mixture of diastereo-
mers.8
Addition of the reagent Cp2TiCl to the epoxide 8 solution
(Method A) afforded a mixture of two diastereomeric pri-
mary alcohols 9:10 in a 3:2 ratio (68% yield) together with
a small amount of the b-hydrogen elimination product:
(S)-(+)-5-[1-(hydroxymethyl)vinyl]-2-methyl-cyclohex-2-
enone 119 (10%). No change in the diastereoselectivity was
observed by reverse addition (Method B), although a small
increase in the elimination product 11 was observed
(15%).10 The reaction, which affords the diols 9 and 10, is
a chemo- and regioselective radical 4-exo cyclization pro-
cess onto a carbonyl based on a seminal work of our group
with epoxyenones and Ti(III).11
The tricyclic ether 14 was oxidized under treatment with
chromium trioxide in acetic anhydride to afford the tricyclic
lactone 6 following procedures reported by Magnus and
Erman.4 Transformation of 6 into the terminal olefin 20
was based on a modification of a procedure reported by
Mori and Matsushima,16 which included selective deprotec-
tion of the pyvaloate 17 to the primary alcohol 18 by treat-
ment with diisobutylaluminium hydride in a mixture of
toluene and dichloromethane at ꢀ78 ꢁC (89% yield), fol-
lowed by Dess–Martin periodinane oxidation17 to aldehyde
19 and Wittig olefination with methylenetriphenylphosphor-
ane (40% yield for the last two steps) (Scheme 1).
We assume that the outcome of 9 as the major diastereomer
in the reaction mixture must be ascribed to the greater stabil-
ity of one of the two complexes obtained by chelation of
titanium within the two diastereomers (see Fig. 2). The equa-
torial orientation of the hydroxymethyl group in complex A
led to the major isomer 9 through a more stable titanium
complex than the one developed through the axially oriented
hydroxymethyl group in complex B, which afforded the
minor diastereomer 10.12
Elongation of olefin 20 was achieved by means of an effi-
cient Pd-catalyzed Suzuki–Miyaura coupling18 between 20
and the (E)-b-halomethacrylates 21a–d.19 Optimized reac-
tion conditions for the coupling process between the olefinic
product and (E)-b-halomethacrylates 21a–d were found
using (ꢀ)-b-pinene 22 as starting material under different
reaction conditions (Table 1).
Treatment of 10 with PPTS in dichloromethane at room tem-
perature led to the tricyclic tertiary alcohol 12 in a 72%
yield. Structural assignment of 12 was based on complete
spectroscopic analysis, including bidimensional 1H–1H and
1H–13C correlations. The use of p-toluenesulfonic acid
under the same reaction conditions led to the decomposition
of the product.
The best yields of the coupling product 23 were obtained by
reaction of (ꢀ)-b-pinene with 9-BBN and further treatment
with b-bromomethacrylate 21a, using palladium tetrakistri-
phenylphosphine as the catalyst, potassium carbonate as the
base, and a mixture of dimethylformamide and water (20:1)
as the solvent at 50 ꢁC for 48 h (Table 1, entry 9).
By applying the optimized conditions to the coupling of the
olefin 20 with (E)-b-iodomethacrylate 21c we were able to
isolate the coupling product 24a with 87% isolated yield
(Table 1, entry 11).
Deoxygenation of the tertiary hydroxy function of 12 to 14
was achieved in two different ways: first by conversion
into thiocarbonylimidazole 13, followed by treatment with
tri-n-butyltin hydride in refluxing toluene (60% overall yield
for the two-step sequence), and second by direct reduction of
alcohol 12, by using chlorodiphenylsilane as a hydride
source in the presence of a catalytic amount of indium
trichloride (80% isolated yield) following the procedure
Deprotection of the silyl groups by treatment of 24a with
tetra-n-butylammonium fluoride and further treatment with
an ethereal solution of diazomethane led to the isolation of
the methyl ester 24c in quantitative yields.
Figure 2.

F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
8935
Scheme 1. (a) PPTS, THF, reflux, 4 h (72%); (b) thiocarbonyldiimidazole, CH2Cl2, rt, 24 h (75%); (c) (from 13) nBu3SnH, AIBN, toluene, reflux, 5 h (80%);
(from 12) InCl3, Ph2SiHCl, ClCH2CH2Cl, 80 ꢁC, 3 h (80%); (d) see Ref. 4; (e–g): see Ref. 2; (h) DIBAL-H, CH2Cl2–toluene (1:1), 0 ꢁC, 20 min (90%); (i)
Dess–Martin, CH2Cl2, 0 ꢁC (73%); (j) (Ph3P)3P]CH2, DME, rt, 15 h (56%); (k) 20, 9-BBN, THF, rt, 15 h, 21, DMF–H2O (20:1), Pd(PPh3)4, 50 ꢁC, 48 h
(see Table 1); (l) (i) nBu4NF, THF, rt; (ii) CH2N2, ether (70% two steps); (m) nBu4NF, THF, rt, 48 h (75%); (n) Tf2O, DMAP, CH2Cl2, rt, four days (83%);
(o) 2 N KOH, MeOH, rt, 24 h (75%).
Table 1. Pd-catalyzed Suzuki–Miyaura couplingsa
R2BH Base
R
R
X
+
COOR
COOR
[Pd] Solvent
Entry
Alkene
R2BH
Catalyst
HMAc
Base
Solvent
Product yield (%)d
1
2
3
4
5
6
7
8
22
22
22
22
22
22
22
22
22
20
20
20
20
(RO)2BHb
9-BBN
PdCl2(dppf)
PdCl2(dppf)
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21c
21b
21d
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K2CO3
K2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
23 (10)
23 (15)
23 (15)
23 (17)
23 (20)
23 (27)
23 (60)
23 (65)
23 (72)
24a (85)
24a (87)
24b (70)
24b (78)
(RO)2BHb
9-BBN
9-BBN
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
DMF
9-BBN
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
(RO)2BHb
9-BBN
9-BBN
9
10
11
12
13
9-BBN
9-BBN
9-BBN
9-BBN
Pd(Ph3P)4
Pd(Ph3P)4
a
All reactions were run at 50 ꢁC.
(RO)2BH–catecholborane.
HMA–halomethacrylate.
Isolated yields.
b
c
d
e
DMF–H2O (20:1).
Dehydration of 24c by treatment with trifluoromethylsul-
fonic anhydride in the presence of excess of DMAP led to
a reaction mixture with the b-form 2b as the major dehydra-
tion product (83% isolated yield). Unfortunately, we were
not able to isolate the a-form 1b by chromatography on
silica gel impregnated with silver nitrate, although we
were able to detect its presence by 1H NMR in the reaction
mixture (8% yield). Saponification of the methyl ester 2b led
to the isolation of (+)-2a quantitatively.
selective acetylation of the primary alcohol, silylation of
the tertiary hydroxy function, and saponification of the ace-
tate with ethanolic potassium hydroxide, to yield the primary
alcohol 27 with 92% yield. Previous attempts to elongate the
side chain without protection of the tertiary hydroxyl group
resulted in a Grob fragmentation to afford the starting car-
vone. Something similar happened when we attempted
a Horner–Wittig reaction with the hydroxyaldehyde ob-
tained by selective oxidation of the diol 10. Elongation of
the lateral chain was first achieved with malonate displace-
ment on the mesylate 28, followed by decarboxylation to
yield the methyl ester 30 with 68% yield (Scheme 2).
Additionally, conversion of diol 10 into 27 required a three-
step sequence of the protection–deprotection protocol:

8936
F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
(0.040–0.063 mm). Rf values refer to TLC carried out on
0.25 mm Merck 60 F254 silica gel plates, with the same elu-
ant as that indicated for the column chromatography unless
otherwise indicated. Yields reported are for chromatograph-
ically pure isolated products unless otherwise mentioned.
4.2. Reductive opening of (D)-8,9-epoxycarvone 8:
preparation of 9 and 10
Solution a: titanocene dichloride Cp2TiCl2 (3.3 g,
13.5 mmol) and powdered Zn (2.6 g, 40.5 mmol) were
placed in a two-necked 50 mL round-bottomed flask under
an argon atmosphere. Anhydrous freshly distilled and
deoxygenated THF (25 mL) was added, and stirring was
maintained for 1 h at room temperature (a deep green color
appeared after 15 min).
Scheme 2. (a) Ac2O, pyr (100%); (b) TBDMSCl, imidazole, DMF (95%);
(c) KOH, EtOH (97%); (d) MsCl, pyr (96%); (e) NaCH(CO2CH3)2, toluene
(85%); (f) NaCl, H2O, DMSO (80%); (g) LAH, ether (88%); (h) (ClCO)2,
(DMSO), Et3N, CH2Cl2 (98%); (i) NaH, (EtO)2POCH(CH3)COOEt,
toluene (86%); (j) nBu4NF, THF (90%).
Solution b: (+)-8,9-epoxycarvone 86 (1 g, 6.1 mmol) was
placed in a two-necked round-bottomed flask and anhydrous
freshly distilled and deoxygenated THF (60 mL) was added
under an argon atmosphere.
Transformation of the methyl ester 30 into a-(E)-endo-1-
hydroxy-bergamoten-12-oic ethyl ester 34 was achieved
by LAH reduction to the primary alcohol 31, followed by
Swern oxidation and Wittig olefination of the aldehyde 32
to afford the ethyl ester 33 with 75% overall yield. Finally,
deprotection of the silyl ether led us to isolate the ethyl ester
34 analog with 90% yield.
Method A: solution a was added dropwise via cannula to
solution b under an argon atmosphere. The reaction mixture
was stirred for 3–5 h at room temperature.
3. Conclusion
Method B: solution b was added dropwise via cannula to
solution a under an argon atmosphere. The reaction mixture
was stirred for 3–5 h at room temperature.
The Ti(III)-promoted cyclization of (+)-8,9-epoxycarvone 8
led to an equimolecular mixture of diastereomers, from
which the diol 10 was isolated and further used as starting
material for the synthesis of b-(E)-endo-bergamoten-12-
oic acid 2a. The key step in the synthesis proved to be a
Suzuki–Miyaura coupling between the terminal alkene 20
and the b-iodomethacrylate 21c. The synthesis of the
a-(E)-endo-1-hydroxy-bergamoten-12-oic acid derivative
34 starting from 10 was achieved by iterative elongation
sequences of the lateral chain.
Work up: when the reaction mixture turned from deep green
to red, saturated solutions of NaH2PO4 (75 mL) and NaCl
(75 mL) were added. Stirring was maintained overnight
and the reaction mixture was filtered. The filtrate was ex-
tracted with ether (3ꢂ25 mL), and the combined organic
layers were washed with a saturated NaCl solution and dried
over Na2SO4. Evaporation of the solvent at reduced pressure
led to the isolation of the crude reaction product. Fraction-
ation was successfully achieved by flash chromatography
on silica gel. Elution with hexane–ethyl acetate (1:1) af-
forded diols 9 (413 mg, 41%) and 10 (275 mg, 27%) and
(S)-(+)-5-[1-(hydroxymethyl)vinyl]-2-methyl-cyclohex-2-
enone 117 (150 mg, 15%).
4. Experimental
4.1. General methods
Melting points are uncorrected. 1H NMR spectra were
measured at either 200 or 400 MHz and 13C NMR were mea-
sured at 50 or 100 MHz in CDCl3 and referenced to TMS
(1H) or solvent (13C), except where indicated otherwise. IR
spectra were recorded for neat samples on NaCl plates,
unless otherwise noted. Standard mass spectrometry data
were acquired by using GC–MS system in EI mode with
a maximum m/z range of 600. Optical rotations were deter-
mined on a digital Perkin–Elmer 241 polarimeter in a 1 dm
cell. When required, all solvents and reagents were purified
by standard techniques: tetrahydrofuran (THF) was purified
by distillation from sodium and benzophenone ketyl and de-
gassed before use. Dimethylformamide (DMF) was dried
over CaH2, distilled under reduced pressure, and degassed
before use. All reactions were conducted under a positive
pressure of argon, utilizing standard bench-top techniques
for the handling of air-sensitive materials. Chromatographic
separations were carried out under pressure on silica gel
using flash column techniques20 on Merck silica gel 60
4.2.1. (1R,5S,6S)-2,6-Dimethyl-6-hydroxymethylbi-
cyclo[3.1.1]hept-2-en-1-ol 9. [a]2D0 +38 (c 1.8, CHCl3); Rf
0.15 (hexane–ethyl acetate 4:6); IR n 3385, 2930, 1653,
1
1456, 1375, 1339, 1240, 1152, 1107, 995, 781 cmꢀ1; H
NMR (CDCl3) d 1.04 (s, 3H), 1.6–2.4 (m, 5H), 1.73 (s,
3H), 3.67 (d, J¼11 Hz, 1H), 4.26 (d, J¼11 Hz, 1H), 5.2 (s,
1H) ppm; 13C NMR (CDCl3) d 14.2 (CH3), 17.0 (CH3),
30.5 (CH2), 31.2 (CH), 39.8 (CH2), 46.7 (C), 69.5 (CH2),
79.0 (C), 117.3 (CH), 146.1 (C) ppm; EIMS m/z (%) 168
(M+, 6), 150 (13), 135 (11), 108 (52), 93 (24), 82 (100), 67
(17). HRMS (EI): calcd for C10H17O2 (M++H+) 169.1228,
found 169.1233.
4.2.2. (1R,5S,6R)-2,6-Dimethyl-6-hydroxymethylbi-
cyclo[3.1.1]hept-2-en-1-ol 10. [a]2D0 ꢀ18.4 (c 1.2, CHCl3);
Rf 0.23 (hexane–ethyl acetate 4:6); IR n 3338, 2925, 1654,
1597, 1421, 1263, 1164, 1022 cmꢀ1 1H NMR (CDCl3)
;
d 1.34 (s, 3H), 1.8 (s, 3H), 1.6–2.3 (m, 5H), 3.4 (d,
J¼10.3 Hz, 1H), 3.75 (d, J¼10.3 Hz, 1H), 5.27 (s, 1H)

F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
8937
ppm; 13C NMR (CDCl3) d 16.7 (CH3), 17.0 (CH3), 30.9
(CH2), 34.2 (CH), 39.4 (CH2), 46.3 (C), 65.6 (CH2), 77.6
(C), 117.5 (CH), 145.2 (C) ppm; EIMS m/z (%) 168 (M+,
2.5), 150 (12), 135 (8), 108 (38), 93 (19), 82 (100), 67
(11). HRMS (EI): calcd for C10H17O2 (M++H+) 169.1228,
found 169.1235.
and the mixture was stirred overnight at room temperature.
The reaction product was extracted with ether (25 mL).
The organic layers were dried over Na2SO4, and the solvent
was evaporated off to afford 144 (0.059 g, 80%); [a]2D0
+26.52 (c 1.64, CHCl3); Rf 0.5 (hexane–ethyl acetate 8:2);
IR n 2965, 2924, 2866, 1452, 1375, 1229, 1173, 1134,
1032, 905 cmꢀ1; 1H NMR (CDCl3) d 1.26 (s, 6H), 1.43 (d,
J¼9.2 Hz, 1H), 1.58–2.03 (m, 7H), 3.36 (d, J¼8.7 Hz,
1H), 3.81 (d, J¼8.7 Hz, 1H) ppm; 13C NMR (CDCl3)
d 19.7 (CH3), 22.7 (CH2), 22.9 (CH2), 25.3 (CH3), 32.5
(CH2), 41.4 (CH), 51.9 (C), 52.3 (CH), 72.6 (CH2), 86.9
(C) ppm; EIMS m/z (%): 152 (M+, 3.2), 137 (8), 123 (10),
109 (19), 97 (100), 79 (46), 69 (51), 55 (30).
4.3. Cyclization of diol 10 catalyzed by PPTS:
(1R,4S,6S,1R)-1,7-dimethyl-6-hydroxy-9-oxa-
tricyclo[4.3.0.0.4,7]nonane 12
PPTS (0.38 g, 1.5 mmol) was added to a solution of 9
(0.25 g, 1.5 mmol) in freshly distilled THF (45 mL). The
reaction mixture was refluxed for 48 h. The solvent was
evaporated at reduced pressure, water (25 mL) was added,
and the reaction mixture was extracted with ethyl acetate.
The combined organic layers were washed with saturated
NaHCO3 (3ꢂ25 mL), dried (Na2SO4), filtered, and concen-
trated to give a residue (0.18 g), which was fractionated by
flash chromatography over silica gel. Elution with hexane–
ethyl acetate (7:3) afforded 12 (0.18 g, 72%); [a]2D0 +6 (c
0.2, CHCl3); Rf 0.25 (hexane–ethyl acetate 7:3); IR n 3447,
4.5.2. Compound 14 (from 12). To a mixture of InCl3
(11 mg, 0.05 mmol) and 12 (170 mg, 1 mmol) in dry 1,2-di-
chloroethane (1 mL), chlorodiphenylsilane (0.43 g, 2 mmol)
was added under an argon atmosphere. The reaction mixture
was stirred at 80 ꢁC for 3 h. The resulting mixture was
poured into Et2O (25 mL) and water (20 mL). The reaction
mixture was extracted with Et2O, and the organic layer
was dried over MgSO4. The evaporation of the ether solution
gave the crude product, which was fractionated by flash
chromatography on silica gel. Elution with hexane–ethyl
acetate (1:1) afforded 14 (0.12 g, 80%), which exhibited
the spectroscopic properties described above for 14.
1
2926, 1724, 1674, 1462, 1365, 1171, 1035, 917 cmꢀ1; H
NMR (CDCl3) d 1.14 (s, 3H), 1.24 (s, 3H), 1.5–2.6 (m,
7H), 3.46 (d, J¼9 Hz, 1H), 3.81 (d, J¼9 Hz, 1H) ppm; 13C
NMR (CDCl3) d 15.0 (CH3), 20.0 (CH3), 22.6 (CH2), 30.4
(CH2), 34.8 (CH2), 35.8 (CH), 54.1 (C), 71.6 (CH2), 81.4
(C), 89.2 (C) ppm; EIMS m/z (%), 168 (M+, 10), 153 (12),
125 (100), 95 (46), 69 (62). HRMS (EI): calcd for
C10H17O2 (M++H+) 169.1228, found 169.1223.
4.6. (10R,20R,50S,60S)-(2,6-Dimethyl-2-trimethylsilyloxy-
bicyclo[3.1.1]-hept-6-yl)-methanol 18
To a solution of 172 (0.74 g, 2.26 mmol) in dichloromethane
(8 mL) and toluene (8 mL) at ꢀ78 ꢁC, was added dropwise
a solution of DIBAL-H (1.5 M in toluene, 23 mL, 33.
6 mmol) under inert atmosphere. The reaction mixture was
stirred for 30 min and then allowed to settle at ꢀ5 ꢁC for
5 h. Ethyl acetate (70 mL) and an aqueous solution of potas-
sium tartrate (5.0 M) were added and the reaction mixture
was stirred overnight at room temperature. The organic layer
was separated and the aqueous phase was extracted with
ethyl acetate. The combined extracts were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The
residue was chromatographed on silica gel. Elution with
hexane–ethyl acetate (95:5) afforded 18 (0.49 g, 89.5%);
[a]2D0 ꢀ31.8 (c 16.7, CHCl3); Rf 0.4 (hexane–ethyl acetate
98:2); IR n 3157, 2961, 2922, 2874, 1373, 1252, 1040,
4.4. (1R,4S,6S,1R)-1,7-Dimethyl-6-[10-(imidazolyl)thio-
carbonyloxy]-9-oxa-tricyclo[4.3.0.0.4,7]nonane 13
To a solution of 12 (0.112 g, 0.66 mmol) in freshly distilled
dichloromethane (5 mL) thiocarbonyldiimidazole (0.142 g,
0.80 mmol) was added. The reaction mixture was stirred
under an argon atmosphere at room temperature for 24 h.
Evaporation of the solvent gave a crude product (0.26 g),
which was fractionated by flash chromatography on silica
gel. Elution with hexane–ethyl acetate (1:1) afforded 13
(0.139 g, 75%); Rf 0.4 (ethyl acetate); [a]2D0 +71.19 (c 0.55,
CHCl3); IR n 3133, 2924, 2853, 1678, 1525, 1474, 1462,
1367, 1286, 1235, 1092, 1035, 1021, 895, 886, 823, 761,
667, 645 cmꢀ1
;
1H NMR (CDCl3) d 0.68 (t, J¼5.2 Hz,
1H), 1.08 (dd, J1¼6 Hz, J2¼3 Hz, 1H), 1.34 (s, 3H), 1.49
(s, 3H), 1.61 (m, 2H), 2.10 (m, 3H), 4.22 (d, J¼10.6 Hz,
1H), 4.66 (d, J¼10.6 Hz, 1H), 7.07 (s, 1H), 7.42 (s, 1H),
8.15 (s, 1H) ppm; 13C NMR (CDCl3) d 12.6 (CH2), 21.3
(CH3), 23.5 (CH3), 24.8 (CH), 26.0 (CH2), 38.8 (CH2),
46.9 (C), 58.4 (C), 79.4 (CH2), 91.8 (C), 115.8 (CH), 130.8
(CH), 135.3 (CH), 166.0 (C) ppm; HRMS (EI): calcd for
C14H19O2N2S (M++H+) 279.1162, found 279.1173.
839 cmꢀ1 1H NMR (CDCl3) d 0.17 (s, 9H), 0.98 (d,
;
J¼10.9 Hz, 1H), 1.31 (s, 3H), 1.34 (s, 3H), 1.62–2.02 (m,
7H), 2.70 (dd, J1¼3.0 Hz, J2¼10.7 Hz, 1H), 3.15 (dd,
J1¼10.7 Hz, J2¼10.7 Hz, 1H), 3.95 (dd, J1¼3.0 Hz,
J2¼10.7 Hz, 1H) ppm; 13C NMR (CDCl3) d 2.5 (CH3),
22.8 (CH3), 24.2 (CH2), 27.7 (CH2), 30.6 (CH3), 32.7
(CH2), 39.3 (CH), 42.0 (C), 53.5 (CH), 66.7 (CH2), 79.8
(C) ppm; HRMS (EI): calcd for C13H25O2NaSi (M++Na+)
265.1594, found 265.1587.
4.5. Preparation of (1R,4S,6R,7S)-1,7-dimethyl-9-oxa-
tricyclo[4.3.0.04,7]nonane 14
4.7. (10R,20R,50S,60S)-(2,6-Dimethyl-2-trimethylsilyloxy-
bicyclo[3.1.1]-hept-6-yl)-carboxaldehyde 19
4.5.1. Compound 14 (from 13). A solution of 13 (0.134 g,
0.53 mmol) and AIBN (20 mg) in toluene (2.5 mL) was
heated to reflux and tri-n-butyltin hydride (0.12 mL,
1.2 mmol) was added dropwise. The reaction was stirred at
the same temperature for 5 h. Then, the solvent was evapo-
rated off and a saturated NaF solution (10 mL) was added
To a solution of Dess–Martin periodinane14 (4.0 g,
9.5 mmol) in dichloromethane (40 mL), at 0 ꢁC under an
argon atmosphere, a solution of 18 (1.4 g, 6 mmol) in
dichloromethane (20 mL) was added dropwise. The reaction
mixture was stirred for 20 min. Then, the reaction mixture

8938
F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
was diluted with ether (50 mL) and aqueous 1.5 M NaOH
solution (75 mL) was added. The reaction mixture was
stirred for 15 min. The organic layer was washed with
1.5 M NaOH, water, and brine, dried over Na2SO4, and the
solvent was evaporated in vacuo. The residue was chromato-
graphed on silica gel. Elution with hexane–ethyl acetate
(99.5:5) afforded 19 (0.93 g, 72.5%); [a]2D0 ꢀ5.13 (c 15.8,
CHCl3); Rf 0.5 (hexane–ethyl acetate 99:1); IR n 2957,
was allowed to reach room temperature, water (50 mL) was
added, and the reaction mixture was extracted with ether.
The combined ether extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The crude product
was chromatographed on silica gel. Elution with hexane–
ethyl acetate (95:5) afforded 23 (see yields Table 1). [a]D20
ꢀ5.11 (c 1.27, CHCl3); Rf 0.5 (hexane–ethyl acetate 9:1);
IR n 2921, 1711, 1648, 1383, 1250, 1153, 1116, 1066,
1
2930, 1716, 1251, 1132, 1046, 1007, 859, 840 cmꢀ1; H
938, 838, 748, 696 cmꢀ1 1H NMR (CDCl3) d 0.03 (s,
;
NMR (CDCl3) d 0.10 (s, 9H), 1.13 (d, J¼10 Hz, 1H), 1.27
(s, 6H), 1.6–2.6 (m, 7H), 9.66 (s, 1H) ppm; 13C NMR
(CDCl3) d 2.3 (CH3), 16.5 (CH3), 23.0 (CH2), 26.1 (CH2),
29.2 (CH3), 33.1 (CH2), 39.9 (CH), 50.2 (C), 57.9 (CH), 76.6
(C), 203.9 (C) ppm; HRMS (EI): calcd for C13H24O2NaSi
(M++Na+) 263.1438, found 263.1426.
9H), 0.84 (d, J¼10 Hz, 1H), 1.04 (s, 3H), 0.9–2.4 (m,
12H), 1.16 (s, 3H), 1.80 (s, 3H), 4.21 (t, J¼10 Hz, 2H),
6.72 (t, J¼6Hz, 1H) ppm; 13C NMR (CDCl3) d ꢀ1.5
(3CH3), 12.5 (CH3), 17.4 (CH2), 22.3 (CH2), 23.2 (CH3),
27.0 (CH2), 28.2 (CH3), 33.8 (CH2), 36.3 (CH2), 38.7 (C),
41.1 (CH), 41.4 (CH), 45.8 (CH), 62.4 (CH2), 127.5 (C),
141.6 (CH), 168.4 (C) ppm; HRMS (EI): calcd for
C19H34O2NaSi (M++Na+) 345.2220, found 345.2210.
4.8. (10R,20R,50S,60S)-(2,6-Dimethyl-6-vinylbicyclo-
[3.1.1]hept-2-yloxy)-trimethylsilane 20
4.10. (D)-(10R,20R,50R,60S)-(E)-5-[2,6-Dimethyl-2-(tri-
methyl-silanyloxy)bicyclo[3.1.1]hept-6-yl]-2-methyl-
pent-2-enoic acid trimethyl-silanylmethyl ester 24a
To a solution of aldehyde 192 (0.88 g, 14.16 mmol) in dry
DME (5 mL), a solution of methylenetriphenylphosphorane
(4.7 g, 17 mmol) in DME (25 mL) was added dropwise. A
white precipitate was formed immediately. The reaction
mixture was stirred at room temperature overnight. Then,
a saturated NaHCO3 solution (25 mL) was added and the
volatiles were removed in vacuo. The reaction product was
then extracted with dichloromethane. The combined layers
were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was chromatographed on silica
gel. Elution with hexane afforded 20 (0.49 g, 56%); [a]D20
+31.20 (c 1.5, CHCl3); Rf 0.5 (hexane); IR n 3075, 2961,
2919, 2868, 1629, 1451, 1411, 1370, 1343, 1249, 1167,
1128, 1047, 1020, 1001, 903, 858, 838, 753, 679 cmꢀ1; 1H
NMR (CDCl3) d 0.08 (s, 9H), 0.99 (d, J¼10.1 Hz, 1H),
1.29 (s, 3H), 1.31 (s, 3H), 1.5–2.4 (m, 7H), 4.80 (dd,
J1¼1.2 Hz, J2¼2.2 Hz, 1H), 4.87 (dd, J1¼2.0 Hz,
J2¼10.4 Hz, 1H), 6.48 (dd, J1¼11.2 Hz, J2¼17.6 Hz, 1H)
ppm; 13C NMR (CDCl3) d 2.7 (3CH3), 24.8 (CH3), 25.8
(CH2), 29.4 (CH2), 30.6 (CH3), 34.1 (CH2), 41.6 (CH),
43.5 (C), 55.7 (CH), 78.6 (C), 109.6 (CH2), 145.9 (CH)
ppm; HRMS (EI): calcd for C14H26ONaSi (M++Na+)
261.1645, found 261.1671.
Solution a: (2,6-dimethyl-6-vinylbicyclo[3.1.1]hept-2-yl-
oxy)-trimethylsilane 20 (0.15 g, 0.63 mmol) was placed in
a two-necked round-bottomed flask and anhydrous freshly
distilled and deoxygenated THF (1 mL) was added under
an argon atmosphere. 9-BBN (0.5 M in THF, 1.9 mL,
0.95 mmol) was added dropwise and the reaction mixture
was stirred overnight at room temperature.
Solution b: to a solution of halomethacrylate 21c (0.26 g,
0.82 mmol) in a exhaustively degasified mixture of DMF–
H2O (7.5 mL, 20:1), Pd(Ph3P)4 (40 mg, 0.04 mmol) and
powdered K2CO3 (0.46 g, 3.34 mmol) were added.
Solution a was added via syringe to solution b and the reac-
tion mixture was stirred at 50 ꢁC for 48 h. Then, the mixture
was allowed to reach room temperature, water (25 mL) was
added, and the reaction mixture was extracted with ether.
The combined ether extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The crude product
was chromatographed on silica gel. Elution with hexane–
ethyl acetate (95:5) afforded 24a (0.39 g, 87%); [a]D20
+6.28 (c 1.36, CHCl3); Rf 0.5 (hexane–ethyl acetate 9:1);
IR n 2955, 2916, 1711, 1651, 1463, 1365, 1250, 1139,
4.9. (L)-(1S,2R,5S)-5-(6,6-Dimethylbicyclo[3.1.1]hept-2-
yl)-2-methyl-pent-2-enoic acid 2-(trimethyl-silanyl)-
ethyl ester 23
1
1054, 1002, 840 cmꢀ1; H NMR (CDCl3) d 0.04 (s, 9H),
0.08 (s, 9H), 1.02 (t, J¼8.0 Hz, 2H), 1.21 (s, 3H), 1.26 (s,
3H), 1.82 (s, 3H), 1.4–2.4 (m, 12H), 4.22 (t, J¼8.0 Hz,
2H), 6.78 (t, J¼7.2 Hz, 1H) ppm; 13C NMR (CDCl3)
d ꢀ1.5 (3CH3), 2.7 (3CH3), 12.3 (CH3), 17.3 (CH2), 23.9
(CH3), 24.1 (CH2), 27.9 (CH2), 29.6 (CH2), 31.3 (CH3),
33.2 (CH2), 35.0 (CH2), 39.8 (CH), 40.7 (C), 54.9 (CH),
62.4 (CH2), 78.7 (C), 127.0 (C), 143.7 (CH), 168.5 (C)
ppm; HRMS (EI): calcd for C23H44O3NaSi2 (M++Na+)
447.2721, found 447.2719.
4.9.1. Suzuki–Miyaura couplings. General procedure.
Solution a: (ꢀ)-b-pinene 22 (0.26 g, 1.9 mmol) was placed
in a two-necked round-bottomed flask and anhydrous freshly
distilled and deoxygenated THF (1 mL) was added under an
argon atmosphere. Hydroborane (catecholborane, 9-BBN)
(2.3 mmol) in THF (5 mL) was added dropwise and the re-
action mixture was stirred overnight at room temperature.
Solution b: to a solution of b-bromomethacrylate 21a
(0.65 g, 2.25 mmol) in a exhaustively degasified mixture
of DMF–H2O (20 mL, 20:1) the catalyst [Pd(Ph3P)4,
PdCl2(dppf), PdCl2(CH3CN)2] (0.08 mmol) and the base
(K3PO4 or K2CO3) (9 mmol) were added.
4.11. (D)-(10R,20R,50R,60S)-(E)-5-[2,6-Dimethyl-2-(tri-
methyl-silanyloxy)bicyclo[3.1.1]hept-6-yl]-2-methyl-
pent-2-enoic acid methyl ester 24b
Solution a: (2,6-dimethyl-6-vinylbicyclo[3.1.1]hept-2-yl-
oxy)-trimethylsilane 20 (0.12 g, 0.52 mmol) was placed in
a two-necked round-bottomed flask and anhydrous freshly
Solution a was added via syringe to solution b and the reac-
tion mixture was stirred at 50 ꢁC for 48 h. Then, the mixture

F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
8939
distilled and deoxygenated THF (1 mL) was added under
an argon atmosphere. 9-BBN (0.5 M in THF, 1.6 mL,
0.78 mmol) was added dropwise and the reaction mixture
was stirred overnight at room temperature.
dried over Na2SO4, and concentrated in vacuo. The crude
product was chromatographed on silica gel. Elution with
hexane–ethyl acetate (1:1) afforded 24c (0.16 g, 74.4%).
4.13. (D)-(60S,10S,50S)-2-Methyl-5-(6-methyl-2-methylene-
bicyclo[3.1.1]hept-6-yl)-pent-2-enoic acid methyl ester:
b-(E)-endo-bergamoten-12-oic acid methyl ester 2b
Solution b: to a solution of halomethacrylate 21d (0.13 g,
0.57 mmol) in a exhaustively degasified mixture of DMF–
H2O (7.5 mL, 20:1), Pd(Ph3P)4 (40 mg, 0.04 mmol) and
powdered K2CO3 (0.38 g, 2.76 mmol) were added.
Trifluoromethanesulfonic anhydride (0.91 g, 3.24 mmol)
was added to a solution of 24c (0.17 g, 0.65 mmol) and di-
methylaminopyridine (0.95 g, 7.76 mmol) in dry dichloro-
methane (30 mL). The reaction mixture was stirred for
four days at room temperature. Then, the reaction mixture
was poured over a 5% aqueous NaHCO3 solution (50 mL)
and extracted with ether. The combined ether extracts were
washed with brine, dried over Na2SO4, and concentrated un-
der reduced pressure. The residue was chromatographed on
silica gel. Elution with hexane–ethyl acetate (9:1) afforded
2b (0.132 g, 83%); Rf 0.25 (hexane–ethyl acetate 9:1);
[a]2D0 +20.0 (c 2.1, CHCl3); IR n 2949, 1717, 1443, 1272,
Solution a was added via syringe to solution b and the reac-
tion mixture was stirred at 50 ꢁC for 48 h. Then, the mixture
was allowed to reach room temperature, water (25 mL) was
added, and the reaction mixture was extracted with ether.
The combined ether extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The crude product
was chromatographed on silica gel. Elution with hexane–
ethyl acetate (95:5) afforded 24b (0.14 g, 79.9%); [a]D20
+10.62 (c 1.97, CHCl3); Rf 0.5 (hexane–ethyl acetate 9:1);
IR n 2955, 2917, 1717, 1645, 1437, 1249, 1128, 1045,
1
1
1005, 839 cmꢀ1; H NMR (CDCl3) d 0.06 (s, 9H), 0.98 (d,
878, 744 cmꢀ1; H NMR (CDCl3) d 0.98 (s, 3H), 1.88 (s,
J¼10.0 Hz, 1H), 1.20 (s, 3H), 1.25 (s, 3H), 1.75 (s, 3H),
1.4–2.4 (m, 11H), 3.70 (s, 3H), 6.78 (t, J¼7.2 Hz, 1H) ppm;
13C NMR (CDCl3) d 2.7 (3CH3), 12.2 (CH3), 23.9 (CH3),
24.1 (2CH2), 27.9 (CH2), 31.3 (CH3), 33.2 (CH2), 35.0
(CH2), 39.8 (CH), 40.7 (C), 51.5 (CH3), 54.9 (CH), 78.7
(C), 126.6 (C), 144.1 (CH), 168.8 (C) ppm; HRMS (EI): calcd
for C19H34O3NaSi (M++Na+) 361.2169, found 361.2153.
3H), 0.8–2.8 (m, 12H), 3.73 (s, 3H), 4.62 (m, 1H), 4.82
(m, 1H), 6.77 (t, J¼8 Hz, 1H) ppm; 13C NMR (CDCl3)
d 12.1 (CH3), 18.0 (CH3), 24.8 (CH2), 28.3 (CH2), 28.5
(CH2), 32.5 (CH2), 37.0 (CH2), 42.7 (C), 43.1 (CH), 51.5
(CH3), 52.3 (C), 103.3 (CH2), 127.1 (C), 142.8 (CH),
155.6 (C), 168.5 (C) ppm; EIMS m/z (%): 248 (M+, 6),
217 (6), 189 (3), 173 (3), 158 (16), 135 (10), 122 (54), 119
(100), 93 (82), 79 (64), 77 (41), 55 (43). HRMS (EI): calcd
for C16H25O2 (M++H+) 249.1856, found 249.1862.
4.12. Preparation of (D)-(10R,20R,50R,60S)-(E)-5-[2-hy-
droxy-2,6-dimethylbicyclo[3.1.1]hept-6-yl]-2-methyl-
pent-2-enoic acid methyl ester 24c
4.14. (D)-(60S,10S,50S)-2-Methyl-5-(6-methyl-2-methylene-
bicyclo[3.1.1]hept-6-yl)-pent-2-enoic acid methyl ester:
b-(E)-endo-bergamoten-12-oic acid 2a
4.12.1. Compound 24c (from 24a). Tetrabutylammonium
fluoride (0.2 g, 0.63 mmol) was added to a solution of 24a
(0.16 g, 0.39 mmol) in dry THF (1 mL) at 0 ꢁC under an
argon atmosphere. The mixture was stirred at room tem-
perature for 24 h. The solvent was evaporated in vacuo and
a solution of 5% NaHCO3 was added. The aqueous solution
was extracted with ether at basic pH and then acidified with
6 N HCl to pH 4–5. The reaction mixture was then extracted
with ether, washed with brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was treated with an ethereal
diazomethane solution to afford a crude methyl ester
(0.110 g). The crude product was chromatographed on silica
gel. Elution with hexane–ethyl acetate (1:1) gave 24c
(0.072 g, 70%); [a]2D0 +8.0 (c 1.5, CHCl3); Rf 0.3 (hexane–
ethyl acetate 1:1); IR n 3507, 2953, 2919, 1712, 1651,
1444, 1282, 1126, 924, 743 cmꢀ1; 1H NMR (CDCl3) d 1.02
(d, J¼10.0 Hz, 1H), 1.23 (s, 3H), 1.25 (s, 3H), 1.82 (s, 3H),
1.4–2.4 (m, 12H), 3.71 (s, 3H), 6.78 (t, J¼7.2 Hz, 1H)
ppm; 13C NMR (CDCl3) d 12.2 (CH3), 23.8 (CH3), 23.9
(CH2), 24.2 (CH2), 28.3 (CH2), 32.1 (CH2), 35.1 (CH2),
40.2 (CH), 40.9 (C), 51.5 (CH3), 54.0 (CH), 75.9 (C), 126.7
(C), 143.7 (CH), 168.8 (C) ppm; HRMS (EI): calcd for
C16H26O3NaSi (M++Na+) 289.1774, found 289.1766.
To a stirred solution of 2b (0.094 g, 0.38 mmol) in MeOH
(2 mL), 2 N KOH (2 mL, 4 mmol) was added at room tem-
perature. The mixture was stirred for 24 h at that tempera-
ture. MeOH was removed in vacuo and the residual
aqueous solution was acidified to pH 3 with 2 N HCl. The
aqueous phase was extracted with ether (3ꢂ15 mL), the
combined ether extracts were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. The
residue was chromatographed on silica gel. Elution with
hexane–ethyl acetate (8:2) afforded 2a (0.067 g, 75%); Rf
0.40 (hexane–ethyl acetate 8:2); [a]2D0 +30 (c 2.1, CHCl3);
IR n 3072, 2962, 2955, 1687, 1640, 1421, 1384, 1287,
1
930, 878 cmꢀ1; H NMR (CDCl3) d 0.98 (s, 3H), 1.10–
1.36 (m, 2H), 1.45 (d, J¼10 Hz, 1H), 1.65–1.90 (m, 2H),
1.84 (s, 3H), 1.95–2.17 (m, 3H), 2.20–2.35 (m, 1H), 2.30
(dt, J1¼5.6 Hz, J2¼10 Hz, 1H), 2.57 (t, J¼5.6 Hz, 2H),
4.62 (s, 1H), 4.82 (s, 1H), 6.93 (t, J¼8 Hz, 1H) ppm; 13C
NMR (CDCl3) d 11.8 (CH3), 18.1 (CH3), 25.1 (2CH2),
28.3 (CH2), 28.6 (CH2), 32.4 (CH2), 37.1 (CH2), 43.2
(CH), 49.2 (C), 52.4 (CH), 103.4 (CH2), 126.7 (C), 145.6
(CH), 155.7 (C), 173.6 (C) ppm; HRMS (EI): calcd for
C15H22O2Na (M++Na+) 257.1512, found 257.1508.
4.12.2. Compound 24c from 24b. Tetrabutylammonium
fluoride (0.29 g, 0.92 mmol) was added to a solution of
24b (0.28 g, 0.84 mmol) in THF (2 mL) at 0 ꢁC under an ar-
gon atmosphere. The reaction mixture was stirred for 48 h at
room temperature. Then, the solvent was evaporated off, the
residue was dissolved in ethyl acetate, washed with brine,
4.15. (1RS,5SR,6RS)-(1-Hydroxy-2,6-dimethylbicyclo-
[3.1.1]hept-2-en-6-yl)-methyl acetate 25
To a solution of diol 10 (594 mg, 3.54 mmol) in pyri-
dine (0.30 mL, 3.89 mmol), acetic anhydride (0.33 mL,

8940
F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
3.54 mmol) was added. The reaction mixture was stirred at
0 ꢁC under an argon atmosphere for 9 h and then diluted
with Et2O, and poured into ice water. The organic layer
was separated and the aqueous phase was extracted with
Et2O. The combined organic extracts were washed with
NaHCO3 (5%), brine, and dried with Na2SO4. Removal of
the solvent afforded acetate 25 (742 mg, 100%), as a color-
less oil; Rf 0.60 hexane–ethyl acetate (1:1); IR n 3480, 2940,
4.18. (1RS,5SR,6RS)-[1-(tert-Butyldimethylsilyloxy)-2,6-
dimethylbicyclo[3.1.1]hept-2-en-6-yl]methyl methane-
sulfonate 28
To a stirred solution of the alcohol 27 (300 mg, 1.06 mmol)
in dichloromethane (7 mL) and pyridine (0.17 mL,
2.12 mmol), at 0 ꢁC methanesulfonyl chloride (0.12 mL,
1.6 mmol) was added. After 25 h at 25 ꢁC, the mixture was
poured into ice water and stirred for additional 2 h at room
temperature. The two-phase system was extracted with
ether. The combined ethereal extracts were washed with
water and brine, dried (Na2SO4) and, concentrated under
reduced pressure to give the mesylate 28 (0.37 g, 96%); Rf
0.50 (hexane–diethyl ether 1:1); IR n 2474, 1464, 1358,
1726, 1452, 1383, 1171, 1032 cmꢀ1 1H NMR (CDCl3)
;
d 1.15 (s, 3H), 1.51 (d, J¼8.1 Hz, 1H), 1.67 (s, 3H), 1.94
(s, 3H), 2.0–2.2 (m, 3H), 2.21 (t, J¼7.0 Hz, 1H), 3.80 (d,
J¼11.0 Hz, 1H), 4.02 (d, J¼11.0 Hz, 1H), 5.16 (br s, 1H)
ppm; 13C NMR (CDCl3) d 16.3 (CH3), 16.6 (CH3), 20.6
(CH3), 30.6 (CH2), 34.3 (CH), 38.9 (CH2), 44.3 (C), 67.3
(CH2), 76.9 (C), 117.3 (CH), 145.4 (C) 171.4 (C) ppm;
HRMS (EI): calcd for C12H18O3Na (M++Na+) 233.1148,
found 233.1136.
1
1250, 1175 cmꢀ1; H NMR (CDCl3) d 0.04 (s, 3H), 0.14
(s, 3H), 0.87 (s, 9H), 1.26 (s, 3H), 1.64 (d, J¼8.1 Hz, 1H),
1.70 (q, J¼1.5 Hz, 3H), 2.1–2.25 (m, 3H), 2.48 (t,
J¼6.1 Hz, 1H), 2.94 (s, 3H), 4.06 (d, J¼9.2 Hz, 1H), 4.20
(d, J¼9.2 Hz, 1H), 5.29 (br s, 1H) ppm.
4.16. (1RS,5SR,6RS)-[1-(tert-Butyldimethylsilyloxy)-2,6-
dimethylbicyclo[3.1.1]hept-2-en-6-yl]methyl acetate 26
4.19. (1SR,5SR,6SR)-Dimethyl-2-[1-(tert-butyldimethyl-
silyloxy)-2,6-dimethylbicyclo[3.1.1]hept-2-en-6-yl]-
methyl malonate 29
A mixture of the hydroxy ester 25 (581 mg, 2.77 mmol),
tert-butyldimethylsilyl chloride (1.04 g, 6.91 mmol) and
imidazole (573 mg, 8.42 mmol) in dry DMF (14 mL) was
stirred for five days under an argon atmosphere at 40 ꢁC,
poured into ice water, and extracted with hexane. The extract
was washed with water and brine, dried (Na2SO4), and con-
centrated in vacuo. The residue was filtered through a small
pad of silica gel, and concentrated to yield the silyl ether 26
as a colorless oil (0.82 g, 95%); Rf 0.80 (hexane–ethyl ace-
tate 1:1); IR n 2955, 2859, 1744, 1470, 1252, 1175, 1063,
To a solution of sodium dimethylmalonate, prepared from
sodium (25.5 mg, 1.11 mmol) and dimethylmalonate
(201.3 mg, 1.52 mmol) in toluene (1 mL), a solution of the
mesyl compound 28 (366 mg, 1.01 mmol) in toluene
(3.5 mL) was added. After three days at reflux the mixture
was cooled, and then poured into ice water, and extracted
with diethyl ether. The combined organic extracts were
washed with brine and dried with Na2SO4. The solvent
was evaporated at reduced pressure to afford a crude product,
which was chromatographed on silica gel. Elution with hex-
ane–ether (80:20) gave the diester 29 (0.34 g, 85%); Rf 0.40
(hexane–diethyl ether 1:1); IR n 2953, 2859, 1740, 1435,
1
837 cmꢀ1; H NMR (CDCl3) d 0.10 (s, 3H), 0.15 (s, 3H),
0.90 (s, 9H), 1.22 (s, 3H), 1.64 (d, J¼8.1 Hz, 1H), 1.70 (s,
3H), 2.0–2.2 (m, 3H), 2.01 (s, 3H), 2.48 (t, J¼7.2 Hz, 1H),
3.96 (d, J¼10.8 Hz, 1H), 4.02 (d, J¼10.8 Hz, 1H), 5.24
(br s, 1H) ppm; 13C NMR (CDCl3) d ꢀ2.9 (CH3), ꢀ1.9
(CH3), 17.7 (CH3), 18.3 (C), 18.8 (CH3), 20.8 (CH3), 25.9
(3CH3), 30.8 (CH2), 34.6 (CH), 39.1 (CH2), 45.2 (C), 67.1
(CH2), 78.5 (C), 117.3 (CH), 147.2 (C), 171.4 (C) ppm.
HRMS (EI): calcd for C18H33O3Si (M++H+) 325.2193,
found 325.2196.
1
1236, 1165, 1015 cmꢀ1; H NMR (CDCl3) d 0.04 (s, 3H),
0.12 (s, 3H), 0.90 (s, 9H), 1.08 (s, 3H), 1.06 (d, J¼8.2 Hz,
1H), 1.8–2.2 (m, 5H), 1.70 (q, J¼1.5 Hz, 3H), 2.42 (t,
J¼6.0 Hz, 1H), 3.39 (dd, J1¼3.0 Hz, J2¼5.9 Hz, 1H), 3.68
(s, 3H), 3.70 (s, 3H), 5.25 (br s, 1H) ppm; 13C NMR
(CDCl3) d ꢀ3.0 (CH3), ꢀ2.0 (CH3), 18.2 (C), 18.8 (2CH3),
25.8 (3CH3), 30.6 (CH2), 31.8 (CH2), 36.0 (CH), 39.0
(CH2), 45.3 (C), 48.3 (CH), 52.1 (2CH3), 79.8 (C), 117.6
(CH), 147.0 (C), 170.4 (C), 170.7 (C) ppm; HRMS (EI):
calcd for C21 H37O5Si (M++H+) 397.2404, found 397.2397.
4.17. (1RS,5SR,6RS)-[1-(tert-Butyldimethylsilyloxy)-2,6-
dimethylbicyclo[3.1.1]hept-2-en-6-yl]methanol 27
To a stirred solution of 26 (545 mg, 1.68 mmol) in EtOH
(5.3 mL), 5 M KOH (0.8 mL) was added. The reaction
mixture was stirred at room temperature under an argon
atmosphere for 80 min and then concentrated to afford a
residue, which was dissolved in H2O and extracted with
Et2O. The combined organic extracts were washed with
brine and dried with Na2SO4. Removal of the solvent af-
forded 27 (0.46 g, 97%) as a colorless oil; Rf 0.40 (hex-
ane–ethyl acetate 1:1); IR n 3403, 2955, 2859, 1462, 1238,
4.20. Methyl (1SR,5SR,6SR)-3-[1-(tert-butyldimethyl-
silyloxy)-2,6-dimethylbicyclo[3.1.1]hept-2-en-6-yl]-
propanoate 30
To a solution of the diester 29 (206 mg, 0.52 mmol) in
DMSO (0.6 mL), water (18 mg, 1 mmol) and sodium chlo-
ride (61 mg, 1.04 mmol) were added. The suspension was
refluxed for 7 h under an argon atmosphere, after which it
was diluted with ethyl acetate. The solution was washed
with water, and brine, dried (Na2SO4), and evaporated to af-
ford the ester 30 (0.14 g, 80%) as a colorless oil; Rf 0.50
(hexane–diethyl ether 7:3); IR n 2930, 2857, 1742, 1462,
1
1169, 1015 cmꢀ1; H NMR (CDCl3) d 0.04 (s, 3H), 0.15
(s, 3H), 0.87 (s, 9H), 1.25 (s, 3H), 1.60 (d, J¼8.2 Hz, 1H),
1.72 (br s, 3H), 2.0–2.2 (m, 3H), 2.48 (t, J¼5.2 Hz, 1H),
3.37 (d, J¼10.3 Hz, 1H), 3.58 (d, J¼10.3 Hz, 1H), 5.25
(br s, 1H) ppm; 13C NMR (CDCl3) d ꢀ3.0 (3CH3), ꢀ2.0
(CH3), 17.6 (CH3), 18.2 (C), 18.8 (CH3), 25.9 (3CH3),
30.6 (CH2), 34.7 (CH), 39.1 (CH2), 47.0 (C), 65.7 (CH2),
79.1 (C), 117.6 (CH), 146.7 (C) ppm; HRMS (EI): calcd
for C16H31O2Si (M++H+) 283.2088, found 283.2080.
1
1236, 1167, 1015 cmꢀ1; H NMR (CDCl3) d 0.03 (s, 3H),
0.13 (s, 3H), 0.90 (s, 9H), 1.14 (s, 3H), 1.60 (d, J¼8.0 Hz,
1H), 1.72 (br s, 3H), 1.8–2.3 (m, 7H), 2.24 (t, J¼6.1 Hz,
1H), 3.62 (s, 3H), 5.23 (br s, 1H) ppm; 13C NMR (CDCl3)

F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
8941
d ꢀ3.0 (CH3), ꢀ2.0 (CH3), 18.2 (C), 19.0 (CH3), 19.1 (CH3),
25.9 (3CH3), 28.5 (CH2), 29.5 (CH2), 30.6 (CH2), 35.8 (CH),
39.1 (CH2), 45.3 (C), 51.1 (CH3), 79.5 (C), 117.5 (CH),
147.0 (C), 174.7 (C) ppm; HRMS (EI): calcd for
C19H35O3Si (M++H+) 339.2350, found 339.2338.
(10.2 mg, 0.27 mmol) and dry toluene (0.6 mL). To this
stirred mixture at 0 ꢁC triethyl 2-phosphonopropionate
(76 mg, 0.32 mmol) was added dropwise, and the mixture
was stirred for 30 min at room temperature to ensure a com-
plete reaction. To this nearly clear solution the aldehyde 32
(90 mg, 0.29 mmol) in toluene (0.6 mL) was added drop-
wise. The mixturewas stirred for an additional 3 hand diluted
with ether, and water was then added dropwise. The organic
layer was separated and the aqueous phasewas extracted with
ether. The combined extracts were washed with brine and
dried (Na2SO4). Evaporation of the solvent afforded the un-
saturated ester 33 as a colorless oil (98 mg, 86%); Rf 0.50
(hexane–diethyl ether 7:3); IR n 2930, 2857, 1718, 1620,
4.21. (1SR,5SR,6SR)-3-[1-(tert-Butyldimethylsilyloxy)-
2,6-dimethylbicyclo[3.1.1]hept-2-en-6-yl]propan-1-ol 31
LiAlH4 (29.64 mg, 0.78 mmol) was added to a solution of
the ester 30 (133 mg, 0.39 mmol) in diethyl ether
(0.7 mL). The reaction mixture was stirred vigorously at
room temperature under an argon atmosphere for 2 h, after
which it was quenched with Na2SO4$10H2O. The resulting
mixture was filtered, and the filtrate was then evaporated
off under reduced pressure to afford unsaturated alcohol
31 (0.10 g, 88%); Rf 0.40 (hexane–diethyl ether 1:1); IR n
3356, 2951, 2857, 1462, 1236, 1167, 1063, 1015 cmꢀ1; 1H
NMR (CDCl3) d 0.04 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H),
1.18 (s, 3H), 1.1–2.1 (m, 7H), 1.58 (d, J¼8.1 Hz, 1H),
1.72 (br s, 3H), 2.43 (t, J¼6.2 Hz, 1H), 3.53 (t, J¼6.0 Hz,
2H), 5.19 (br s, 1H) ppm; 13C NMR (CDCl3) d ꢀ2.9
(CH3), ꢀ2.0 (CH3), 18.2 (C), 19.0 (CH3), 19.4 (CH3), 25.9
(3CH3), 28.1 (CH2), 29.3 (CH2), 30.6 (CH2), 35.9 (CH),
39.0 (CH2), 45.6 (C), 63.8 (CH3), 79.9 (C), 117.3 (CH),
147.3 (C) ppm; HRMS (EI): calcd for C18H35O2Si
(M++H+) 311.2400, found 311.2401.
1452, 1252, 1167, 1098, 1015 cmꢀ1 1H NMR (CDCl3)
;
d 0.04 (s, 3H), 0.15 (s, 3H), 0.89 (s, 9H), 1.19 (s, 3H), 0.8–
2.15 (m, 7H), 1.27 (t, J¼7 Hz, 3H), 1.60 (d, J¼8.1 Hz, 1H),
1.74 (s, 3H), 1.79 (s, 3H), 2.42 (t, J¼6.0 Hz, 1H), 4.15 (q, J¼
7.0 Hz, 2H), 5.20 (br s, 1H), 6.69 (t, J¼7.8 Hz, 1H) ppm; 13C
NMR (CDCl3) d ꢀ2.9 (CH3), ꢀ1.9 (CH3), 11.9 (CH3), 14.1
(CH3), 18.2 (C), 19.0 (CH3), 19.4 (CH3), 24.2 (CH2), 25.9
(3CH3), 30.6 (CH2), 32.1 (CH2), 36.0 (CH), 39.1 (CH2),
45.7 (C), 60.1 (CH2), 79.7 (C), 117.4 (CH), 127.0 (C),
143.0 (CH), 147.2 (C), 168.1 (C) ppm; HRMS (EI): calcd
for C23H41O3Si (M++H+) 393.2819, found. 393.2804.
4.24. Ethyl (1SR,5SR,6SR)-(Z)-5-[1-hydroxy-2,6-di-
methylbicyclo[3.1.1]hept-2en-6-yl]-2-methylpent-2-
enoate 34
4.22. (1SR,5SR,6SR)-3-[1-(tert-Butyldimethylsilyloxy)-
2,6-dimethylbicyclo[3.1.1]hept-2-en-6-yl]propanal 32
A solution of the ester 33 (66 mg, 0.16 mmol) and nBu4NF
(159 mg, 0.5 mmol) in THF (1.1 mL) was stirred at room
temperature for 19 h. A saturated aqueous NH4Cl solution
was added, and the resulting mixture was extracted with
ethyl acetate. The combined extracts were washed with
brine, dried (Na2SO4), and filtered. The solvent was removed
to give the alcohol 34 (40 mg, 90%); Rf 0.20 (hexane–diethyl
ether 7:3); IR n 3489, 2932, 1693, 1647, 1449, 1370, 1279,
A solution of DMSO (0.04 mL) in dichloromethane
(0.18 mL) was added dropwise to a stirred solution of oxalyl
chloride (0.03 mL, 0.35 mmol) in dichloromethane (1.5 mL)
under an argon atmosphere at ꢀ60 ꢁC. After 5 min, a solution
of the alcohol 31 (100 mg, 0.32 mmol) in CH2Cl2–DMSO
(3:1, 2 mL) was added dropwise. The reaction mixture was
stirred for 20 min, triethylamine (0.22 mL, 1.6 mmol) was
added at ꢀ60 ꢁC, and stirring was continued for 10 min.
Then, the mixture was allowed to warm to room temperature
and stirred for 4 h, after which water was added. The organic
layer was separated and the aqueous phase was extracted
with dichloromethane. The combined extracts were washed
with water, dried (Na2SO4), and filtered. The solvent was re-
moved to afford the aldehyde 32 (71 mg, 100%) as a colorless
oil; Rf 0.60 (hexane–diethyl ether 1:1); IR n 2961, 2857,
1
1235, 1161, 1091 cmꢀ1; H NMR (CDCl3) d 0.8–2.15 (m,
7H), 1.26 (s, 3H), 1.31 (t, J¼7.2 Hz, 3H), 1.62 (d,
J¼8.4 Hz, 1H), 1.81 (s, 3H), 1.83 (s, 3H), 2.25 (t,
J¼6.8 Hz, 1H), 4.20 (t, J¼7.2 Hz, 2H), 5.25 (br s, 1H),
6.71 (t, J¼6.8 Hz, 1H) ppm; 13C NMR (CDCl3) d 12.1
(CH3), 14.2 (CH3), 17.3 (CH3), 18.0 (CH3), 24.3 (CH2),
30.8 (CH2), 31.5 (CH2), 34.9 (CH), 39.9 (CH2), 45.3 (C),
60.4 (CH2), 78.3 (C), 117.9 (CH), 127.3 (C), 142.7 (CH),
144.7 (C), 168.3 (C) ppm; HRMS (EI): calcd for
C17H27O3 (M++H+) 279.1954, found 279.1947.
1726, 1462, 1258, 1236, 1165, 1015 cmꢀ1 1H NMR
;
(CDCl3) d 0.05 (s, 3H), 0.14 (s, 3H), 0.90 (s, 9H), 1.17 (s,
3H), 1.1–2.3 (m, 7H), 1.59 (d, J¼8.0 Hz, 1H), 1.72 (s, 3H),
2.44 (t, J¼7.4 Hz, 1H), 5.22 (br s, 1H), 9.71 (s, 1H) ppm;
13C NMR (CDCl3) d ꢀ2.9 (CH3), ꢀ1.9 (CH3), 18.3 (C),
19.1 (CH3), 19.4 (CH3), 25.4 (CH2), 25.9 (3CH3), 30.6
(CH2), 35.9 (CH), 39.1 (CH2), 39.8 (CH2), 45.1 (C), 79.5
(C), 117.7 (CH), 147.0 (C), 203.1 (C) ppm; HRMS (EI):
calcd for C18H33O2Si (M++H+) 309.2245, found 309.2240.
Acknowledgements
ꢀ
We thank the Spanish Direccion General de Investigacion
Cientıfica y Tecnica (MEC PPQ2002-00290 and MEC
ꢀ
CTQ2005-05026/BQU) and the Junta de Castilla y Leon
(SA027/03) for providing financial support for this work.
ꢀ
´
ꢀ
ꢀ
M.R.L. and L.M.B. thank the Junta de Castilla y Leon for
research fellowships. The authors want to thank Acedesa-
Takasago, El Palmar, Murcia (Spain) for a generous gift of
(ꢀ)-b-pinene.
4.23. Ethyl (1SR,5SR,6SR)-(Z)-5-[1-(tert-butyldimethyl-
silyloxy)-2,6-dimethylbicyclo[3.1.1]hept-2-en-6-yl]-2-
methylpent-2-enoate 33
Supplementary data
A dry three-necked flask equipped with stirrer, condenser,
and a dropping funnel was purged with argon and charged
with a 65% dispersion oil of sodium hydride in mineral oil
Spectroscopic data for compounds described in Schemes 1
and 2 and Table 1 can be found in the online version.

8942
F. A. Bermejo et al. / Tetrahedron 62 (2006) 8933–8942
Rosales, A. J. Org. Chem. 2002, 67, 2566–2571; (g)
€
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.07.020.
Gansauer, A.; Lauterbach, T.; Natayan, S. Angew. Chem., Int.
Ed. 2003, 42, 5556–5573; (h) Justicia, J.; Oltra, J. E.; Cuerva,
J. M. J. Org. Chem. 2004, 69, 5803–5806; (i) Rosales, A.;
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