Convergent approaches to saudin intermediates

Article abstract of DOI:10.1002/hlca.200390223

Different convergent approaches to the highly oxygenated sesquiterpene natural product saudin (1), has been investigated. Our strategy has included a Michael addition and aldol condensation reaction as key steps. During the synthetic development, we have found serious steric hindrance when an α-Me-substituted alkyl vinyl ketone was used. Such steric hindrance has been overcome by synthesizing the vinyl ketone 16 through an anionic fragmentation, which was carefully studied. Finally, the intermediate 18 has been synthesized in a one-pot reaction from the vinyl ketone 16 and has been cyclized to obtain the promising tricyclic intermediate 20.

Full text of DOI:10.1002/hlca.200390223

Helvetica Chimica Acta Vol. 86 (2003)
2741
Convergent Approaches to Saudin Intermediates
by Raquel M. Cravero, Manuel Gonza¬lez-Sierra, and Guillermo R. Labadie*1)
¬
¬
IQUIOS (Instituto de QuÌmica Organica de SÌntesis), Departamento de QuÌmica Organica,
¬
Facultad de Ciencias BioquÌmicas y Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531,
S2002LRK, Rosario, Argentina
Different convergent approaches to the highly oxygenated sesquiterpene natural product saudin (1), has
been investigated. Our strategy has included a Michael addition and aldol condensation reaction as key steps.
During the synthetic development, we have found serious steric hindrance when an a-Me-substituted alkyl vinyl
ketone was used. Such steric hindrance has been overcome by synthesizing the vinyl ketone 16 through an
anionic fragmentation, which was carefully studied. Finally, the intermediate 18 has been synthesized in a one-
pot reaction from the vinyl ketone 16 and has been cyclized to obtain the promising tricyclic intermediate 20.
Introduction.
Saudin (1) is a natural product, which belongs to a group of
terpenoids isolated from the leaves of the toxic plant Cluytia richardiana [1][2]. This
compound shows a unique rearranged labdane skeleton, which contains seven
stereogenic centers, six of which are consecutive. Saudin (1) shows potent hypoglycemic
activity. The structural complexity of 1 has stimulated interest in its total synthesis [3
6]. Few years ago, Winkler and Doherty [7] carried out the first total synthesis of 1 in 15
steps, the key step being an intramolecular dioxenone photocycloaddition.
Recently, Boeckman et al. [8] have reported the first enantioselective total synthesis
of (‡)- and (À)-saudin and the corresponding absolute configurations. The core of their
synthetic approach was the use of a Lewis acid mediated stereoselective Claisen
rearrangement to introduce the correct configuration at the two quaternary C-atoms
(C(13) and C(16)).
1
)
Present address: Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT-
84112, USA (Tel.: ‡1801-5813014, e-mail: guille@chem.utah.edu).

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Helvetica Chimica Acta Vol. 86 (2003)
Following our efforts to develop strategies toward the synthesis of polyoxygenated
natural products [9 12], we were interested in the synthesis of 1 due to its structural
complexity and biological properties [13][14]. Here, we describe our efforts on the
stereoselective synthesis of an advanced tricyclic key intermediate 3 that can lead to 1.
The retrosynthetic analysis for our synthetic approach is shown in Scheme 1. This
analysis was based upon the hypothesis proposed by Mossa et al. [1], where 1 is assumed
to be in equilibrium with its open form. Therefore, we envisioned the synthesis of this
natural product through the open form by a spontaneous or acid-catalyzed cyclization.
The key intermediate 2 could be prepared by the oxidative cleavage of 3a or 3b.
Compounds 3a or 3b, in turn, can be generated from 4a or 4b, respectively, by
sequential Michael addition and aldol condensation. The compounds 4a or 4b can be
derived by Michael addition of methyl vinyl ketones 5a or 5b, respectively, to 2,3,4,5-
tetrahydro-3-methylfuran-2,4-dione (6), respectively (Scheme 1). The tricyclic com-
pound 3 could be prepared through an enantioselective Robinson annelation, by using a
modified Hajos and Parrish reaction between 6 and a conveniently substituted vinyl
ketone 5, previously introduced in our laboratory [15].
Scheme 1
To obtain compound 5b, we selected the cyclic monoterpenes (S)-(‡)-carvone (10)
and (À)-(R)-limonene (9a) as suitable starting materials, since these compounds have
been widely used in enantioselective synthesis of various natural products [16 20].

Helvetica Chimica Acta Vol. 86 (2003)
2743
Based on a literature report [21], the synthesis of the desired vinyl ketones could be
accomplished according to the retrosynthetic analysis presented in the Scheme 2.
Scheme 2
Results and Discussion. To proceed with our synthetic plan, first the reduction of
the CˆO group of carvone (10) was carried out with LiAlH4 in THF to furnish
exclusively the b-alcohol. The origin of this stereoselective reaction may be attributed
to the fact that the hydride attack occurs from the face opposite the isoprenyl chain.
The resulting alcohol was protected [22] with a Bn group to yield compound 9b in good
yield (Scheme 3).
Scheme 3
a) 1. LiAlH4, Et2O, À 788, 94%; 2. NaH, THF, Bu4NBr, BnBr, r.t.; 87%. b) 1. 9-Borabicyclo[3.3.1]nonane (9-
BBN), THF, 08; 2. 1m NaOH, 30% H2O2; 72%.
The next step, which involved selective hydroboration/oxidation with either 9-
borabicyclo[3.3.1]nonane (9-BBN) or disiamylborane, was carried out with both
limonene 9a and the protected alcohol 9b to furnish primary alcohols 11a and 11b,

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Helvetica Chimica Acta Vol. 86 (2003)
respectively. It was observed that both reagents selectively affect the exocyclic CˆC
bond to afford the alcohols in almost identical yields. To oxidize the alcohols 11a and
11b to the aldehydes, different oxidizing reagents and conditions were tested. After
optimization, the best yields of aldehydes 8a and 8b were obtained by using pyridinium
dichromate (PDC) in CH2Cl2, AcOH (catalytic), and 4-ä molecular sieves [23].
The introduction of the vinyl group with vinylmagnesium bromide in refluxing THF
resulted in low yields of desired vinyl alcohols, along with alcohol 11a as the main by-
product2). A possible explanation of the formation of 11a among the products implies
reduction of the aldehyde. Such a reduction would be possible if a b-H of the vinyl
group is concertedly transferred to the aldehyde CˆO group, resulting also in
formation of acetylene and the corresponding alkoxymagnesium bromide, quenched
afterwards during the workup3). The yield of the vinyl alcohol was considerably
improved when anhydrous CeCl3 was added to activate the CˆO group and, at the
same time, to prevent the reduction reaction [25 27]. The resulting allylic alcohols
were immediately oxidized to the corresponding vinyl ketones 7a and 7b under the
same conditions as mentioned above; however, due to poor stability of these vinyl
ketones, the yields could not be improved beyond 67% (Scheme 4).
Scheme 4
a) Pyridinium dichromate (PDC), molecular sieves (4 ä), AcOH, CH2Cl2; 70 85%. b) 1. Anh. CeCl3, THF,
r.t.; 2. 1m vinylmagnesium bromide, THF; 60 70%; 3. PDC, molecular sieves (4 ä), AcOH, CH2Cl2; 67%.
The next step involved the Michael addition between the synthesized vinyl ketones
7a 7b and furan-dione 6 which, in turn, was prepared according to known procedures
[28][29]. The reaction was performed under previously described conditions [30 32],
(H2O, AcOH (cat.), 708). Both vinyl ketones 7a and 7b were submitted to Michael
2
)
)
Similar behavior was recently reported for addition of vinyl Grignard reagents over aromatic aldehydes
[24].
The proposed mechanism of aldehyde reduction by allylmagnesium bromide:
3

Helvetica Chimica Acta Vol. 86 (2003)
2745
addition but, surprisingly, only 7a reacted generating the expected adduct 12
(Scheme 5), whereas 7b decomposed during the reaction. It has been reported [33]
that the HOMO of the nucleophile and the LUMO of the enone is the most-favorable
molecular-orbital combination that minimizes the anti-bonding interactions for
addition of a nucleophile to an enone. However, a study of the vinyl ketones 7a and
7b at ab initio level of calculation (B3LYP/6-31G*) revealed that their reactivities were
identical, as the conformational and the LUMO energies are similar. On the other
hand, calculations have also shown that compound 7b is considerably more polar than
7a, and this could be a possible explanation for its different behavior. In fact, an
increase in polarity would increase its susceptibility to polymerization due to the acidity
of the water phase in the reaction mixture.
Scheme 5
a) AcOH (cat.), H2O, 708; 72%.
Since vinyl ketone 7b could not be coupled with 6, we continued our synthesis with
the adduct 12. The cyclization was attempted under different conditions such as: l-
proline, DMF [30 32]; LDA, THF, N,N'-dimethylpropyleneurea (DMPU), À 788
[34]; cyclohexyl(isopropyl)amine, BrMgCH3, THF, À 788 [35]; (i-Pr)2NH, BrMgMe,
THF, À 788 [36]; K2CO3, MeOH, À 208 [37]; TsOH, benzene, reflux; and (i-Pr)2NH,
BrMgMe, THF, Me3SiCl, À 788 [5]. Unfortunately, all our efforts to perform the
intramolecular cyclization were unsuccessful.
At this point, we presumed that compound 12 did not undergo cyclization due to the
presence of the Me group in a-position to the CˆO group. Careful examination of the
transition states postulated for aldol cyclizations showed that, in our case, the two
possible chair-like conformations presented severe steric hindrance between the
CH2(5) and MeÀC(4') groups, in one conformation, and the same CH2(5) group and
the cyclohexene moiety in the other. Thus, it was clear that, in order to achieve the
desired ring closure, we needed to remove the Me group at C(4'). This prompted us to
explore a slightly different approach involving a cyclopentenyl methyl vinyl ketone.
Our retrosynthetic analysis to prepare the corresponding vinyl ketone or its precursor is
presented in Scheme 6.
We started with the Grignard addition to norbornenone 14 to obtain exclusively the
alcohol 15 in 99% yield, followed by an anionic fragmentation reaction of the
corresponding K-alkoxide of 15 (Scheme 7). In this reaction, the KH-generated

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 6
alkoxide was heated at 308 during 2 d to provide the methyl ketone 16 in 46% yield
[38 40]. Several attempts were made to improve the yield of the last step and the
results are summarized in Table 1.
Scheme 7
a) MeMgI, Et2O, 08; 99%; b) see Table 1.
Table 1. Attempts to Improve the Yield of the Ketone 16
Entry
Reagents
Temp. [8]
Time [h]
Yield [%]
1
2
3
4
5
KH, HMPA
KH, HMPA
KH, HMPA
KH, HMPA
80
60
40
r.t.
2.5
5.5
8
12
1.5
Decomposition
18
30
52
67
KH, 18-crown-6, THF
Reflux
It is known that, when these reactions are conducted in low-polarity solvents, the
insoluble ion pairs formed reduce the electron-donor quality of the oxido substituent
that induces the rearrangement [41]. To solve this problem, Paquette and Maleczka [42]
introduced the use of 18-crown-6 as a solvation agent of the anionic species, with THF
as the solvent, in oxy-Cope anionic rearrangements. Since our anionic fragmentation
reaction has the same electronic requirements, we applied this modification and
increased the final yield to 67% (Entry 5 in Table 1).
Finally, to generate the required vinyl ketone, we considered that the best option
would be one that would allow us to generate the vinyl ketone in situ. After some
preliminary work trying different reagents and conditions (HCHO and (i-Pr)2NH [43];
N-ethylanilinium trifluoroacetate with HCHO or 1,3,5-trioxane [44], methylmagne-
sium carbonate and 1,3,5-trioxane [45]), we finally adopted the modified Mannich
reaction by using the Eschenmoser reagent [46]. A soln. of ketone 16 in THF at À 788
was treated with LDA, and, after 30 min, the Eschenmoser salt dissolved in THF was
added at the same temperature, and the mixture was allowed to warm to room

Helvetica Chimica Acta Vol. 86 (2003)
2747
temperature. MeI was then added, and the quaternary ammonium salt was precipitated
from the crude reaction mixture by dilution with Et2O at À 208 (Scheme 8).
Scheme 8
‡
a) 1. LDA, THF; 2. CH2ˆN Me2IÀ
Our attempts to use the crude quaternary ammonium salt directly in a tandem
Michael reaction with 6 under standard conditions (K2CO3 in anhydrous MeOH),
failed. However, in a more-successful attempt, the quaternary ammonium salt was
heated at 708 with furan-dione 6 in H2O, with AcOH as catalyst. After purification, the
1H-NMR spectra showed characteristic signals of the expected product together with
two unexpected singlets, each for one H-atom, in the olefinic region at d 6.18 and
5.96 ppm. At the same time, 13C-NMR spectra showed the presence of two additional
sp2-C-atoms, one of them a quaternary C-atom (142.20 ppm) and other a terminal
methylene C-atom (129.21 ppm), and an aliphatic CH2 group was missing. All these
findings are in agreement with the presence of an additional terminal CˆC bond at a C-
atom in the a-position to the CˆO group, indicating that, during the alkylation step,
2 equiv. of Eschenmoser salt were incorporated, one in each of the a-positions to the
CˆO group, to give a diamino ketone. Afterwards, the double quaternary salt of the
diamino ketone was formed, and, during the Michael addition, a double vinyl ketone
was generated, which then reacted with 6 through the less-substituted CˆC bond to
give the product 19 (Scheme 9). To overcome this problem, we searched to find
reaction conditions that would allow us to generate exclusively the kinetic enolate
leading to the monoamino ketone. The best result was achieved when 1.2 equiv. of LDA
was used, and the temperature was lowered to À 1008. Compound 18 was obtained in
38% overall yield from 16. The results are summarized in Table 2. Although we were
able to obtain exclusively b-dimethylamino ketone 17, we could not improve the yield
over 40%.
Table 2. Preparation of 18 and 19 from 16
Ratio LDA/Substrate
Temp. [8]
Global yield [%]
Ratio 18/19
1.5 : 1
1 : 1
1.2 : 1
À 78
À 78
33
37
38
0 : 1
1.8 : 1
1 : 0
À 100
With furan-dione 18 in hand, we attempted the intramolecular cyclization reaction
under standard conditions (TsOH in toluene at reflux) to obtain the bicyclic compound
1
20 in quantitative yield. The structure of 20 was fully characterized through H- and
13C-NMR spectroscopy, and by comparison with similar compounds obtained
1
previously in our laboratory [15]. The H-NMR spectra of 20 showed a signal for

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 9
‡
a) 1. LDA, THF; 2. CH2ˆN Me2IÀ; 3. MeI, Et2O, 08; 4. AcOH, H2O, 6, 708.
two H-atoms at d 5.74 ppm assigned to those of the cyclopentene ring, this time as a
multiplet, in contrast to the singlet observed for the same H-atoms in the precursor. In
the 13C-NMR spectra, two signals, one at 130.10 and 129.22 ppm, were observed and
assigned to C(3') and C(4') of cyclopentene ring, whereas only one signal appeared, for
1
the same C-atoms of the precursor. An additional signal in the H-NMR spectra
(doublet at d 5.00 ppm (J ˆ 1.4 Hz)) assigned to HÀC(3) was shifted to low-field,
compared to that found in the starting material due to the C(3a)ˆC(4) bond proximity.
The signal of the MeÀC(7a) has also been observed at low field as a singlet at d
1.51 ppm. Most interesting is the signal that appears as a quintuplet at d 3.37 ppm, which
is assigned to HÀC(1'). When modeling the molecule by ab initio calculations, we have
found two different conformations as global minima with an energy difference of
0.50 kcal/mol, which show dihedral angles of 10.9 and À 178.68 for
C(5)ÀC(4)ÀC(1')ÀH. In the more-stable one, HÀC(1') is placed almost parallel to
1
the CˆO group, having peri-effect with it and, in this way, deshielding its H-NMR
signal. But with this energy difference, both conformers must be in equilibrium, and,
therefore, NMR spectra should show an average signal. To explain that, we finally
calculated the energy barrier for the rotation of this angle, and we found 29.98 kcal/mol,
high enough to justify that change of conformers is not possible.
Scheme 10
a) TsOH, toluene, reflux.

Helvetica Chimica Acta Vol. 86 (2003)
2749
Conclusions.
Starting from natural monoterpenes, two vinyl ketones were
prepared in six and four steps, respectively. On the other hand, starting from
norbornenone, a vinyl-ketone precursor, the dimethylamino ketone 17, was obtained by
an anionic fragmentation reaction that was carefully studied, followed by a selective
modified Mannich addition. All were reacted with furan-dione 6, but the vinyl ketone
7b did not provide the desired Michael product. Therefore, the two adducts 12 and 18
were submitted to an aldol reaction, but only the latter provided the expected product,
even after many reagents and conditions tested on 12. Undesirable interactions
between the Me group in a-position to the CˆO group and the CH2 group of the furan-
dione moiety would hinder the compound 12 to adopt the necessary conformation to
form the new CÀC bond. The aldol product 20 was fully characterized and will be used
to continue our synthesis. In conclusion, we have achieved the formation of an
interesting and properly functionalized intermediate toward the synthesis of the natural
product saudin (1) in an efficient way.
Experimental Part
General. All solvents were dried and distilled before use. All reactions were carried out under a dry, O2-free,
N2 atmosphere. TLC: aluminum-foil plates coated with 0.1-mm Merck silica gel 60 GF254. Column
chromatography (CC): Merck silica gel 60 H, under a low pressure of N2, with increasing AcOEt/hexane
gradients. M.p.: Ernst Leitz hot-stage microscope; uncorrected. IR Spectra: Bruker FT I-25 spectrophotometer.
1H- and 13C-NMR spectra: at 200.1 and 50.3 MHz on a Bruker AC-200-E NMR spectrometer in CDCl3 soln., 2D-
NMR experiments were run with standard Bruker software. High-resolution (HR) MS: at UCR Mass
Spectrometry Facility, Department of Chemistry, University of California, Riverside, USA. Elemental analyses:
at Atlantic Microlab, Inc., Georgia, USA. Ab initio calculations were performed with Gaussian 98 packages of
programs [47].
6-(Benzyloxy)-1-methyl-4-(1-methylethenyl)cyclohex-1-ene (9b). To a soln. of (S)-carvone (10; 1.40 g,
9.33 mmol) in 25 ml of anh. Et2O cooled to À 788, LiAlH4 (380 mg, 10 mmol) was added in small portions. The
mixture was stirred during 30 min at the same temp. Excess reducing reagent was carefully eliminated with wet
Et2O. The org. phase was washed with 5% NaOH and H2O, dried (Na2SO4), and evaporated to yield 1.04 g
(94%) of 2-methyl-5-(1-methylethenyl)cyclohex-2-en-1-ol as colorless oil. IR (film): 3380, 3350, 3280, 3070,
2910, 2840, 1740, 1430, 1370, 1320, 1280, 1080, 1035, 1000, 970, 955, 915, 890, 855, 805, 745. 1H-NMR: 1.74
(s, MeÀC(2)); 1.74 (s, CH2ˆCHMe); 1.9 2.4 (CH2); 4.17 (br. s, HÀC(1)); 4.73 (s, CH2ˆCHMe); 5.5 (br.
s, HÀC(3)). 13C-NMR: 70.60 (C(1)); 136.08 (C(2)); 20.39 (MeÀC(2)); 123.58 (C(3)); 30.83 (C(4)); 40.32
‡
(C(5)); 37.76 (C(6)); 18.80 (CH2ˆCHMe); 148.77 (CH2ˆCHMe); 108.89 (CH2ˆCHMe); MS: 152 (24, M ),
136 (12), 107 (20), 91 (100), 79 (46), 65 (24), 41 (32).
NaH (1.53 g, 60%, oil suspension) was washed three times with hexane in two-necked round-bottom flask
under dry N2. Later, a soln. of the alcohol (3.865 g, 25.43 mmol) in 10 ml of anh. THF was added. After 15 min,
hydride was consumed, and then Bu4NBr (200 mg) was added, followed by BnBr (3.00 ml, 25.43 mmol). The
mixture was stirred under N2 at r.t. for 1 h and then flowed on 100 ml of brine. The phases were separated, the aq.
phase was extracted with Et2O (5 Â 30 ml), and the org. extracts were combined, washed with brine (2 Â 25 ml),
dried (Na2SO4), and evaporated at reduced pressure. The crude oil was purified through reduced-pressure
distillation to yield 5.36 g (87%) of 9b. Colorless oil. IR (film): 3060, 3020, 2900, 2850, 1635, 1490, 1445, 1365,
1325, 1300, 1265, 1150, 1090, 1020, 915, 885, 800, 730, 690. 1H-NMR: 1.73 (s, MeÀC(1)); 1.73 (s, CH2ˆCHMe);
4.06 (br. s, HÀC(6)); 4.51 (d, J ˆ 11.8, 1 H, PhCH2); 4.67 (d, J ˆ 11.8, 1 H, PhCH2); 4.73 (s, CH2ˆCHMe); 5.52
(br. s, HÀC(2)); 7.24 7.37 (m, 5 arom. H). 13C-NMR: 78.27 (C(6)); 135.91 (C(1)); 20.90 (MeÀC(1)); 125.09
(C(2)); 31.53 (C(3)); 40.32 (C(4)); 34.59 (C(5)); 19.95 (CH2ˆCH-Me); 149.57 (CH2ˆCHMe); 109.59
‡
(CH2ˆCHMe); 70.80 (PhCH2); 139.25 (arom. quat. C); 127.80 (Co); 128.76 (Cm); 128.06 (Cp). MS: 242 (2, M ),
‡
‡
231 (12), 201 (11), 169 (15), 133 (5), 107 (20), 91 (100), 78 (30), 65 (14). HR-MS: 242.1664 (C17H22O , M ; calc.
242.1671).
2-(4-Methylcyclohex-3-enyl)propan-1-ol (11a). To the ice-cooled soln. of 9-borabicyclo[3.3.1]nonane (9-
BBN; 40 ml, 0.84m, 33.6 mmol), 4.15 ml of (R)-limonene (9a; 25.7 mmol) in 10 ml of THF was dropped during

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Helvetica Chimica Acta Vol. 86 (2003)
1 h. The mixture was allowed to stir at r.t. over 2 h. Subsequently, 8.3 ml of 3m NaOH and 8.3 ml of 30% P/V
H2O2 were added dropwise alternatingly, maintaining the temp. under 108. The resulting heterogeneous mixture
was warmed to 408 and vigorously stirred for 2 h. Layers were separated, and the aqueous phase was extracted
with Et2O (3 Â 30 ml), and the org. extracts were combined, dried (Na2SO4), and evaporated. The product was
purified by distillation to yielding 3.76 g (80%) 11a. Colorless oil. IR (film): 3410, 3350, 3290, 2920, 2905, 1455,
1385, 1160, 1050, 1035, 1020, 990, 915, 803. 1H-NMR: 0.90, 0.94 (d, J ˆ 5.0, 3 HÀC(3)); 1.64 (s, MeÀC(4')); 3.49,
3.63 (m, 2 HÀC(1)); 5.37 (br. s, HÀC(3')). 13C-NMR: 66.12, 66.14 (C(1)); 39.97, 39.77 (C(2)); 13.06, 13.47
(C(3)); 35.05, 34.95 (C(1')); 30.54, 30.41 (C(2')*); 120.45, 120.51 (C(3')); 133.82 (C(4')); 23.27 (MeÀC(4'));
‡
29.62, 27.49 (C(5')*); 27.03, 25.27 (C(6')*). MS: 152 (43, M ), 136 (14), 121 (44), 107 (42), 94 (100), 79 (77), 67
(72), 55 (37), 41 (40).
2-[(5-(Benzyloxy)-4-methylcyclohex-3-enyl]propan-1-ol (11b). The same procedure for 11a with 9b
(1.500 g, 6.20 mmol), 13 ml of anh. THF, 16.2 ml of 9-BBN (0.5m, 8.1 mmol), 2.07 ml of 3n NaOH, and 2.07 ml
of 30% H2O2 led to 11b. CC provided 1.17 g (72%) of 11b. Colorless oil. IR (film): 3420, 2940, 1710, 1460, 1380,
1280, 1180, 1120, 1080, 1050, 730. 1H-NMR: 0.94, 0.91 (d, J ˆ 6.7, 3 HÀC(3)); 1.75 (s, MeÀC(4')); 3.51 (br.
s, 2 HÀC(1)); 4.51 (br. s, 2 HÀC(5')); 4.50 (d, J ˆ 11.7, 1 H, PhCH2); 4.66 (d, J ˆ 11.7, 1 H, PhCH2); 4.93
(s, 2 HÀC(6')); 5.52 (br. s, HÀC(3')); 7.26 7.36 (m, 5 arom. H). 13C-NMR: 66.30 (C(1)); 35.27 (C(2)); 13.34,
13.90 (C(3)); 40.46 (C(1')); 30.37 (C(2')); 125.20 (C(3')); 135.98 (C(4')); 19.98 (MeÀC(4')); 78.50 (C(5')); 35.13
(C(6')); 70.82 (PhCH2); 139.52 (arom. quat. C); 127.84 (Co); 128.72 (Cm); 128.03 (Cp). HR-MS: 260.1784
‡
‡
(C17H24O2 , M ; calc. 260.1776).
2-(4-Methylcyclohex-3-enyl)propanal (8a). In a 100-ml flask protected from light, to 11a (2.0 g, 13 mmol) in
50 ml of anh. CH2Cl2, pyridinium dichromate (PDC)/Al2O3 (4.77 g, 38.16 mmol) was added with stirring under
N2. After 20 min, the mixture was filtered under reduced pressure over a silica-gel pad and copiously washed
with CH2Cl2. The filtrate was dried (Na2SO4) and evaporated. The crude product was purified by distillation at
reduced pressure to give 1.68 g (85%) of 8a. Colorless oil. IR (film): 2930, 2885, 2950, 2685, 1710, 1450, 1430,
810. 1H-NMR: 1.08 (d, J ˆ 5, 3 HÀC(3)); 1.60 (s, MeÀC(4')); 5.36 (br. s, HÀC(3')); 9.66 (s, HÀC(1)).
13C-NMR: 205.37 (C(1)); 50.61, 50.60 (C(2)); 10.16, 10.07 (C(3)); 34.15 (C(1')); 25.26, 27.13 (C(2')*); 119.77,
‡
119.71 (C(3')); 133.92 (C(4')); 23.24 (MeÀC(4')); 29.61, 27.67 (C(5')*), 29.97, 29.49 (C(6')*). MS: 152 (2, M ), 94
(100), 79 (69), 67 (22), 55 (15), 41 (18).
2-[5-(Benzyloxy)-4-methylcyclohex-3-enyl]propanal (8b). According to the same procedure for 8a, 11b
(200 mg, 0.77 mmol) was dissolved in 11.3 ml of anh. CH2Cl2, and PCC/Al2O3 (3.85 g, 3.08 mmol) was added.
CC provided 138 mg (70%) of 8b. Yellowish oil. IR (film): 2960, 2945, 2655, 1730, 1460, 1345, 1280, 1105, 1085,
1040, 810. 1H-NMR: 1.07, 1.10 (2d, J ˆ 4.4, 4.4, 3 HÀC(3)); 1.72 (s, MeÀC(4')); 4.01 (m, HÀC(5')); 4.45 (d, J ˆ
25, 1 H, PhCH2); 4.65 (d, J ˆ 25, 1 H, PhCH2); 5.49 (br. s, HÀC(3')); 7.26 7.36 (m, 5 arom. H); 9.67
(d, 2 HÀC(1)). 13C-NMR: 206.2 (C(1)); 50.81, 50.53 (C(2)); 11.26, 11.47 (C(3)); 31.25 (C(1')); 26.36, 27.43
(C(2')*); 120.17, 120.11 (C(3')); 134.02 (C(4')); 22.64 (MeÀC(4')); 24.61, 23.67 (C(5')*), 28.67, 25.49 (C(6')*),
‡
72.82 (PhCH2); 138.92 (arom. quat. C); 125.94 (Co); 124.65 (Cm); 127.63 (Cp). HR-MS: 272.1771 (C18H24O2 ,
‡
M ; calc. 272.1776).
4-(4-Methylcyclohex-3-enyl)pent-1-en-3-one (7a). Method A (without anh. CeCl3). In two-necked round-
bottom flask with a reflux condenser, a soln. of 8a (95 mg, 0.37 mmol) in 10 ml of anh. THF was cooled to 08.
Then, 1m vinylmagnesium bromide in THF (0.5 ml, 0.5 mmol) was added. The mixture was heated at reflux over
2 h. After cooling to r.t., 10 ml of 3m NaOH was added, and the phases were separated. The aq. phase was
extracted with Et2O (4 Â 25 ml), and the org. extracts were combined and washed with H2O, dried (Na2SO4),
and evaporated. After purification by CC 68.6 mg (60%) of vinyl alcohol as yellowish oil and 19.8 mg (15%) of
11a were obtained.
Method B (with CeCl3). To a soln. of 8a (300 mg, 2.03 mmol) in 10 ml of anh. THF was added anh. CeCl3
(500.4 mg), and the mixture was stirred for 20 min. Thereafter, vinylmagnesium bromide (2.24 ml of 1m THF
soln; 2.24 mmol) was added at r.t. and the mixture was allowed to react over 1 h. Then, 10 ml of 10% AcOH was
added, and the soln. was extracted with Et2O (3 Â 15 ml). Org. extracts were washed with brine and sat.
NaHCO3, dried (MgSO4), and evaporated: 248 mg of colorless oil were obtained (70% yield). The crude
product was oxidized to the vinyl ketone immediately without purification. A fraction purified by CC showed
the following 1H-NMR signals: 0.90 (d, J ˆ 5, 3 HÀC(5)); 1.64 (s, MeÀC(4')); 4.2 (m, 2 HÀC(3)); 5.15 (br.
s, 2 HÀC(1)); 5.4 (br. s, HÀ(3')); 5.8 (m, HÀC(2)).
To a soln. of the alcohol (270 mg, 1.6 mmol) in 10 ml of CH2Cl2, protected against light, PDC (715 mg,
1.92 mmol), 1.2 g of molecular sieves (4 ä), and finally 25 ml of AcOH were added simultaneously. The mixture
was allowed to stir over 30 min, and then filtered through Celite and silica gel pad with CH2Cl2. Solvent was
evaporated, and the product was purified by distillation at reduced pressure to give 178 mg (67%) of 7a. IR

Helvetica Chimica Acta Vol. 86 (2003)
2751
(film): 2980, 2905, 2705, 1680, 1600, 1380, 1250, 1100, 1020, 970. 1H-NMR: 1.04 (d, J ˆ 5.0, 3 HˆC(5)); 1.62
(s, MeÀC(4')); 2.70 (m, HÀC(1')); 2.70 (m, HÀC(4)); 5.40 (br. s, 1 HÀC(5')); 5.35 (br. s, 1 HÀC(5')); 5.76
(dd, J ˆ 2.1, 10.2, HÀC(2)); 6.46 (ddd, J ˆ 17.6, 10.2, 2.89, HÀC(1)). 13C-NMR: 135.45 (C(1)); 127.83 (C(2));
204.24 (C(3)); 48.47, 47.64 (C(4)); 13.24 (C(5)); 35.72 (C(1')); 30.10 (C(2')*), 119.87 (C(3')); 133.86 (C(4'));
23.26 (MeÀC(4')); 28.21 (C(5')*), 27.79 (C(6')*).
4-[5-(Benzyloxy)-4-methylcyclohex-3-enyl]pent-1-en-3-one (7b). Method B was applied. Aldehyde 8b
(260 mg, 1.0 mmol) was dissolved in 10 ml of anh. THF, and 250 mg of anh. CeCl3 and vinylmagnesium bromide
(1m in THF, 1.12 ml, 1.12 mmol) were added. 195 mg (68%) of a colorless oil was obtained. A fraction purified by
CC showed the following 1H-NMR signals: 0.94 (d, J ˆ 5, 3 HÀC(5)); 1.75 (s, MeÀC(4')); 3.80 (m, 2 HÀC(3));
4.72, 4.5 (d, PhCH2); 5.15 (br. s, 2 HÀC(1)); 5.5 (br. s, HÀC(3')); 5.8 (m, HÀC(2)); 7.37 7.34 (m, 5 arom. H).
The same preparation technique for 7a was applied. Vinyl alcohol (440 mg, 1.6 mmol) was dissolved in
10 ml of CH2Cl2 and PDC (715 mg, 1.92 mmol), 1.2 mg of molecular sieves (4 ä), and 25 ml of AcOH were used:
284 mg (69%) of 7b were obtained. IR (film): 3120, 2960, 2925, 2735, 1660, 1580, 1380, 1260, 1050, 1020, 970,
880. 1H-NMR: 1.06 (d, J ˆ 4.8, 3 HÀC(5)); 1.64 (s, MeÀC(4')); 2.70 (m, HÀC(1')); 2.70 (m, HÀC(4)); 4.51
(d, J ˆ 11.8, 1 H, PhCH2); 4.67 (d, J ˆ 11.8, 1 H, PhCH2); 5.34 (br. s, HÀC(3')); 5.86 (dd, J ˆ 2.6, 10.7, HÀ(2));
6.56 (ddd, J ˆ 15.6, 11.2, 3.09, 2 HÀC(1)); 7.24 7.37 (m, 5 arom. H). 13C-NMR: 134.75 (C(1)); 126.83 (C(2));
203.74 (C(3)); 47.47, 46.63 (C(4)); 13.27 (C(5)); 36.42 (C(1')); 31.20 (C(2')*), 117.24 (C(3')); 134.86 (C(4'));
22.26 (MeÀC(4')); 29.01 (C(5')*); 28.89 (C(6')*); 72.80 (PhCH2); 136.25 (arom. quat. C); 126.70 (Co); 129.06
(Cm); 127.96 (Cp).
3-Methyl-3-[4-(4-methylcyclohex-3-enyl)-3-oxopentyl]furan-2,4-dione (12). A mixture of 7a (160 mg,
0.95 mmol) and 2,3,4,5-tetrahydro-3-methylfuran-2,4-dione (6; 75 mg, 0.64 mmol) was dissolved in 10 ml of
dist. H2O, and 10 ml of AcOH was added. Under protection against light, the mixture was heated at 708 during
3 h. Thereafter, the mixture was saturated with NaCl and extracted with CH2Cl2 (3 Â 20 ml). The combined org.
phases were dried (Na2SO4), and solvent was evaporated to provide 150 mg of a yellow oil. Purification by CC
yielded 130 mg (72%) of 12. Yellowish oil. IR (film): 2960, 2940, 1800, 1760, 1440, 1370, 1340, 1310, 1270, 1130,
1075, 1050, 950, 920, 850, 805, 760, 740, 705. 1H-NMR: 0.99, 1.02 (2d, J ˆ 4.7, 5.2, 3 HÀC(5')); 1.33 (s, MeÀC(3));
1.63 (s, MeÀC(4'')); 1.90 (m, 2 HÀC(5'')); 1.90 (m, 2 HÀC(2'')); 2.36 (m, HÀC(4')); 2.55 (m, 2 HÀC(2')); 4.71
(d, J ˆ 17, 1 HÀC(5)); 4.86 (d, J ˆ 17, 1 HÀC(5)); 5.35 (br. s, HÀC(3'')). 13C-NMR: 72.14 (C(1)); 208.76 (C(2));
46.46 (C(3)); 20.50, 20.60 (MeÀC(3)); 176.75 (C(4)); 35.50 (C(1')*); 35.55 (C(2')); 213.87 (C(3')); 35.6 (C(4'));
13.01, 13.09 (C(5')); 31.52, 30.66 (C(1'')); 28.18, 20.12 (C(2'')); 119.69 (C(3'')); 133.83 (C(4'')); 23.23
‡
‡
(MeÀC(4'')); 30.04, 29.88 (C(5'')); 27.73, 28.01 (C(6'')). HR-MS: 292.1678 (C17H24O4 , M ; calc. 292.1675).
2-Methylbicyclo[2.2.1]hept-5-en-2-ol (15). In a two-necked round-bottom flask, with a reflux refrigerant
and a pressurized aggregate ampoule, to 83.4 mmol of MeMgBr dissolved in 30 ml of anh. Et2O a soln. of 14
(3.83 g, 35.42 mmol) in 20 ml of anh. Et2O was introduced in the ampoule. The flask was cooled to 08, and 14 was
dropped to the Grignard reagent, and the mixture was refluxed over 30 min. After cooling, the mixture was
added in 50 ml of sat. NH4Cl. The phases were separated, and the aq. phase was extracted with Et2O (5 Â 20 ml),
and the org. extracts were pooled, dried (Na2SO4), and evaporated to yield 4.35 g (99%) of 15 as a yellowish
1
liquid. H- and 13C-NMR, IR, and mass spectra are identical with those reported in [37].
1-(Cyclopent-3-enyl)propan-2-one (16). Method 1. In a two-necked round-bottom flask KH (40% oil
suspension; 3.88 g, 38.82 mmol) was carefully washed with hexane. A reflux condenser was incorporated, and
KH was suspended in 70 ml of anh. hexamethylphosphoramide (HMPA). Simultaneously, 15 (4.4 g, 35.3 mmol)
dissolved in 17 ml of anh. HMPAwas added dropwise during 5 min to the cooled suspension of KH. The reaction
was allowed to proceed for 15 min at this temp., and then the mixture was heated at 458 overnight. After cooling,
the mixture was carefully poured into 80 ml of sat. NH4Cl, and then extracted with Et2O (3 Â 40 ml). Org.
extracts were pooled and washed with brine, dried (Na2SO4), and evaporated by distillation at normal pressure
to yield the crude product. This crude material was purified by CC (silica gel; CH2Cl2). The solvent was
evaporated at normal pressure, and the residue was distilled to give 1.98 g of 16 as a colorless liquid.
Method 2. In a two-necked round-bottom flask, 20% oil suspension KH (965 mg, 4.82 mmol) was washed
with hexane. Reflux condenser was incorporated, and KH was suspended in 20 ml of anh. THF. Then, anh.
HMPA (0.84 ml, 4.84 mmol) was added, and the soln. was cooled to 08. A soln. of 15 (300 mg, 2.42 mmol) in 4 ml
of anh. THF was added dropwise to the KH suspension under stirring. The reaction was continued for 15 min at
r.t., and then 18-crown-6 (1.27 g, 4.84 mmol) in 4 ml of THF was added to the mixture. The resulting mixture was
heated under reflux for 1 h. After cooling to À 788, 15 ml of sat. NH4Cl was carefully added. The mixture was
warmed up to r.t. and the same workup as in Method 1 led to 205 mg of 16. IR (CHCl3): 3025, 2965, 1720, 1445,
1320, 1380, 1355, 1275, 1250, 1190, 1180, 1105, 970, 845, 755. 1H-NMR: 1.93 (dd, J ˆ 12.4, 4.0, 2 HÀC(2)); 2.14
(s, 3 HÀC(3)); 2.53 (m, HÀC(1')); 2.62 (m, 2 HÀC(2), 2 HÀC(5')); 5.86 (s, HÀC(3'), HÀC(4')). 13C-NMR:

2752
Helvetica Chimica Acta Vol. 86 (2003)
29.92 (C(1)); 208.60 (C(2)); 50.57 (C(3)); 32.44 (C(1')); 38.67 (C(2'), C(5')); 129.41 (C(3'), C(4')). MS: 124 (22,
‡
M ), 82 (46), 44 (100).
3-[4-(Cyclopent-3-enyl)-3-oxobutyl]-3-methylfuran-2,4-dione (18). To a soln. of (i-Pr)2NH (1.02 ml,
7.9 mmol) in 8 ml of anh. THF, LiBu (5.7 ml, 1m in hexane; 6.8 mmol) was carefully added at r.t. This soln.
was stirred at this temp. over 10 min and then cooled to À 1008. Ketone 16 (700 mg, 5.64 mmol) in 10 ml anh.
THF was added dropwise under stirring over 30 min, and the temperature was kept at À 1008. In a separate
flask, a suspension of Eschenmoser salt (2.1 g, 11.28 mmol) in 10 ml of anh. THF was prepared and cooled to À
1008. With a canula, the enolate was transferred to Eschenmoser suspension, and the mixture was left to react for
35 min. Thereafter, the mixture was warmed to r.t., and the reaction was quenched with brine. The mixture was
extracted with Et2O (3 Â 30), then the Et2O phases were pooled and extracted with 6n HCl (3 Â 15 ml). Acidic
extracts were neutralized with 1m NaOH and extracted again with Et2O (4 Â 10 ml), dried (Na2SO4), and
evaporated to provide 870 mg of crude product. Amino ketone was dissolved in 2 ml of MeI, and the mixture
was cooled to À 208. Et2O was added dropwise to facilitate the precipitation of ammonium salt, and then the
mixture was left to react at À 208 for an additional h. The precipitate was separated and washed with cold Et2O
twice and dried under vacuum. The solid was dissolved in 10 ml of H2O; 6 (428 mg, 3.76 mmol) and AcOH
(50 ml) were added. The soln. was kept at 708 over 3 h. The aq. soln. was saturated with NaCl and extracted with
CH2Cl2 (3 Â 15 ml). Org. extracts were combined, dried (Na2SO4), and evaporated. Purification by CC
provided 536 mg (38% from 16) of 18. Yellow oil. IR (film): 2935, 1820, 1755, 1460, 1325, 110, 1270, 1100, 1065,
1
985, 855, 755, 730. H-NMR: 1.31 (s, MeÀC(8)); 2.47 (m, 2 HÀC(2'), 2 HÀC(4')); 4.59 (d, J ˆ 12, 1 HÀC(5));
4.75 (d, J ˆ 12, 1 HÀC(5)); 5.62 (s, HÀC(3''), HÀC(4'')). 13C-NMR: 176.65 (C(2)); 46.40 (C(3)); 20.22
(MeÀC(3)); 209.36 (C(4)); 72.09 (C(5)); 28.15 (C(1')); 36.52 (C(2')); 208.86 (C(3')); 49.27 (C(4')); 32.22
‡
(C(1'')); 38.61 (C(2''), C(5'')); 129.36 (C(3''), C(4'')). MS: 250 (10, M ), 184 (13), 169 (10), 115 (52), 79 (13), 71
(47), 66 (100), 55 (35), 41 (26).
With LDA/16 1:1, 3-[4-(cyclopent-3-enyl)-3-oxopent-4-enyl]-3-methylfuran-2,4-dione 19 was isolated. IR
(film): 2945, 1820, 1755, 1710, 1520, 1495, 1425, 1310, 1255, 1105, 1075, 950, 885, 785, 715. 1H-NMR 1.32
(s, MeÀC(3)); 2.47 (m, 2 HÀC(1'), 2 HÀC(2')); 4.56 (d, J ˆ 16.5, 1 HÀC(5)); 4.78 (d, J ˆ 16.5, 1 HÀC(5)); 5.65
(s, HÀC(3''), HÀC(4'')); 5.96 (s, 1 H, ˆCH2); 6.15 (s, 1 H, ˆCH2). 13C-NMR: 175.45 (C(2)); 47.04 (C(3)); 20.34
(MeÀC(3)); 208.09 (C(4)); 72.34 (C(5)); 37.01, 28.15 (C(1')); 38.70 (C(2')); 201.84 (C(3')); 129.21 (C(5')); 142.2
(C(4')); 32.56 (C(1'')); 38.71 (C(2''), C(5'')); 129.47 (C(3''), C(4'')).
4-(Cyclopent-3-enyl)-7,7a-dihydro-7a-methyl-3H,6H-[2]benzofuran-1,5-dione (20). A soln. of 230 mg of 18
in toluene (5 ml) and 5 mg of TsOH was heated at reflux for 2 h. The soln. was diluted with AcOEt, washed with
brine and H2O, dried (MgSO4), and evaporated. Purification by CC provided 213 mg (100%) of 20. White
crystalline solid. M.p. 121 122.58 (Et2O) IR (film): 2940, 2870, 1785, 1740, 1680, 1460, 1365, 1275, 1190, 1120,
1010, 960, 745, 710. 1H-NMR: 1.51 (s, MeÀC(7a)); 3.37 (m, HÀC(1')); 5.00 (d, J ˆ 1.4, 2 HÀC(3)); 5.74 (t, J ˆ
2.5, HÀC(3'), HÀC(4')). 13C-NMR: 178.13 (C(1)); 66.94 (C(3)); 154.52 (C(3a)); 137.41 (C(4)); 195.85 (C(5));
32.95 (C(6)); 29.02 (C(7)); 41.36 (C(7a)); 21.36 (MeÀC(7a); 33.20 (C(1')); 38.98 (C(2')); 129.12 (C(3')); 130.10
‡
(C(4')) 39.68 (C(5')). MS: 232 (33, M ), 217 (27), 204 (100), 175 (40), 147 (27), 131 (30), 115 (37), 91 (73), 77
‡
‡
(80), 65 (40), 41 (50). HR-MS: 233.1170 (C14H17O3 , [M ‡ H] ; calc. 233.1178).
We are grateful to Universidad Nacional de Rosario, Consejo Nacional de Investigaciones CientÌficas y
¬
¬
¬
Tecnologicas (CONICET) and Agencia Nacional de Promocion CientÌfica y Tecnologica (ANPCYT) for
generous financial support.
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Received March 12, 2003