An entry to curcuphenol/elvirol core structures via a retro-aldol reaction

Article abstract of DOI:10.1002/cbdv.201000160

Analogs of curcuphenol/elvirol, naturally occurring bisabolane sesquiterpenes, were prepared in six steps from alkyl-α-tetralones employing an aromatization reaction of cyclic dienone precursors and olefination of the key aldehyde intermediates. The in vi

Full text of DOI:10.1002/cbdv.201000160

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CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
An Entry to Curcuphenol/Elvirol Core Structures via a retro-Aldol Reaction
by Marꢀa F. Planoa), Guillermo R. Labadiea), Melissa R. Jacobb), Babu L. Tekwanib), and
Raquel M. Cravero*a)
a) Instituto de Quꢀmica Rosario (IQUIR-CONICET), Facultad de Ciencias Bioquꢀmicas y
´
Farmaceuticas, Universidad Nacional de Rosario. Suipacha 531, S2002LRK-Rosario, Argentina
(e-mail: cravero@iquir-conicet.gov.ar)
b) National Center for Natural Products Research, School of Pharmacy, University of Mississippi,
University, MS 38677, USA
Analogs of curcuphenol/elvirol, naturally occurring bisabolane sesquiterpenes, were prepared in six
steps from alkyl-a-tetralones employing an aromatization reaction of cyclic dienone precursors and
olefination of the key aldehyde intermediates. The in vitro antifungal activities of 6a, 6b, 6d, and 6g are
also reported.
Introduction. – Substituted phenols play a crucial role in biosynthetic trans-
formations [1], and they represent important building blocks for organic synthesis [2–
5]. Hence, there is a continuing interest for syntheses of phenolic substrates which are
not available by conventional aromatic substitutions.
The marine sesquiterpenes 1 and 2 (Scheme 1), isolated from the sponges Didiscus
flavus and Epipolasis spp., were found to possess strong antibacterial, antifungal,
antitumor, and antimalarial activities [6]. Elvirol (3), which was isolated from the plant
Elvira biflora (Compositae), is a structural isomer of curcuphenol whose structure does
not obey the isoprene rule [7][8]. Several synthetic pathways for these compounds
have been reported in the literature [9–11]. On the biogenetic origin of bisabolene
natural products, a hypothesis suggests that the phenolic sesquiterpenes could be
formed by aromatization of their cyclic ketone precursors [12]. These molecular
structures and their interesting bioactivities prompted us to undertake the preparation
of meta- and para-alkylated phenolic compounds, as a synthetic approach to the natural
products 1–3.
Results and Discussion. – 1. Synthetic Strategy. In a preliminary communication
[13], we reported that an oxygenated functionality, vicinal to a quaternary C-atom of
the cyclohexadienones 4, causes ring-cleavage in K2CO3/MeOH media at room
temperature to afford the 4-phenylbutanals 5a–5g (Scheme 2). A similar cleavage and
a retro-Fries migration of an acyl group under different reaction conditions have been
already observed by Waring and Zaidi in the synthesis of 4-acylcyclohexa-2,5-dienone
[14]. Hagiwara et al. have also obtained bisabolane terpenoids via another synthetic
route through 1,4-addition of aldehydes to vinyl ketones, followed by an intramolecular
condensation [15].
ꢁ 2011 Verlag Helvetica Chimica Acta AG, Zꢂrich

CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
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Scheme 1. Retrosynthetic Plan towards Bisabolane Sesquiterpenes
Scheme 2. Preparation of 4-Phenylbutanals 5
We used previously the 1,4-diene chemistry of a-tetralones in the synthetic study of
saudin [16–18] and ouabain [19]. In this work, we report the syntheses of curcuphenol/
elvirol analogs 6 as biomimetic approach to bisabolane family, employing the strategy

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of re-aromatization of the 1,4-dienones 4 (Scheme 1). These compounds are positional
isomers of 1 and 3 with diverse substituents, R, R1, and R2 groups, which make them of
particular interest to study the structural requirements for biological activity.
2. Syntheses of Analogs 6. As depicted in Scheme 3, each synthesis began with the
introduction of the substituents R1 by means of the known Birch alkylation reaction
(BAR) in 7a–7c and 7g. The corresponding dienes with different degrees of oxidation
were obtained in yields of 70–98%.
Scheme 3. Synthesis of Analogs 6
a) i. NH3, K, Et2O, t-BuOH, ꢀ788; ii. LiBr; iii. RX, from ꢀ788 to r.t. b) NaBH4, MeOH,
ꢀ788, 30 min. c) PhCOCl, Pyridine, 4-(dimethylamino)pyridine (DMAP), 08, 2 h. d) Pyridinium
dichromate (PDC), t-BuOOH, Celiteꢃ, CH2Cl2. e) K2CO3, MeOH, r.t., 36 h. f) (Isopropyl)(triphenyl)-
phosphonium iodide (1.5–2 mmol), THF at ꢀ788, 1.6m BuLi (1.5–2 mmol) 0.5 h, r.t. 0.5 h., aldehyde
(1 mmol), ꢀ788 (0.5 h), then 0.5 h. at r.t.

CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
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As an exception, 7-methoxy-a-tetralone (¼ 3,4-dihydro-2H-naphthalen-1-one)
gave on alkylation with methoxymethyl chloride (MOMCl) an aromatic product in
low yield, probably derived from a retro-FriedelꢀCrafts reaction. The CO group was
selectively reduced with NaBH4 in MeOH at ꢀ788 to produce the b-configured
alcohols 9 by axial attack of the hydride at the CO group (60–95%). Protection of the
OH group in 9 with PhCOCl furnished the corresponding syn-benzoates 10a–10g (80–
98%). The a-configured alcohols were generated, using l-Selectrideꢃ in THF at ꢀ788,
from dienes 8, and acetates (as substitutes for the benzoates 10) were also suitable
compounds for the next steps.
Our initial efforts were directed towards the formation of the cross-conjugated
system by the 3,5-dimethylpyrazol/CrO3 method (cf. [20]). However, the yield of
products 4 was moderate. On the other hand, the bis-allylic oxidation using PDC/t-
BuOOH/Celiteꢃ in benzene or CH2Cl2 afforded pure dienones 4a–4g in satisfactory
yields (60–85%). Both protocols required careful control of reaction time, temper-
ature, and product purification.
3. Conditions and Mechanism of Dienone Rearrangement. Preparation of 5.
Experiments on the rearrangement of 4 to 5, performed in acid media (such as H2SO4,
polyphosphoric acid, supported-polyphosphoric acid on SiO2, and CF3COOH) were
not successful, in contrast to retro-aldol conditions (treatment of 4 in MeOH with
K2CO3), which led to the 4-arylbutanals 5a–5g in satisfactory yields (Scheme 4).
Scheme 4. Reaction Mechanism for the Preparation of 5
As outlined in Scheme 4, fragmentation of 4 is facile due to the stable phenolate
system, which develops in the course of product 5 formation. Finally, we focused on
Wittig olefination of 5 for the construction of hexenyl side chain of 6 with 3-
phenylpropanal (12) as model compound and (isopropyl)(triphenyl)phosphonium
iodide (1:1; on a mmol scale; Scheme 3). Alkene 13 was obtained by reaction of 12 in
THF with the ylide of (isopropyl)(triphenyl)phosphonium iodide, formed with NaH or
t-BuOK (55–608; 20% yield). Decreasing the reaction temperature to 30–258 and
using BuLi, we were able to isolate the b-hydroxy aldehyde and its dehydrated
compound. Both products arose from an aldol self-condensation [21].
Better yields of 13 were obtained with the ylide of BuLi and the phosphonium salt,
and exact adjustment of the temperature in each addition reaction (from ꢀ788 to room
temperature, 82%). When this procedure was employed in case of the compounds
without substitution in ortho-positions 5a, 5e, and 5h (protected phenol), and the a-
tetralols 11a (60% yield), 11e (69%), and 11h1) were obtained (Scheme 5). With these
results in hand, we investigated the role of BuLi/ylide in this reaction.
1
)
We speculate that the bicycle 11h derived from the reaction control on 5h was formed by the
participation of the unoccupied ortho-position of the phenol.

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CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
Scheme 5. Preparation of a-Tetralols 11
a) (Isopropyl)(triphenyl)phosphonium iodide (1 mmol), THF, ꢀ788, 1.6m BuLi (1 mmol) 1.5 h, r.t.,
1.5 h, aldehyde (1 mmol) dissolved in THF (0.94 ml/mmol) at ꢀ788, 0.5 h; then r.t. for 1–3 h.
Thus, submission of 5a, 5b, 5d, and 5g to an excess of the Wittig reagent (aldehyde/
ylide 1:2) at ꢀ788, then room temperature, for 30 min, provided 6a, 6b, 6d, and 6g in
good yields [22]. Under these reaction conditions and based on pKa value, phenols 5
can be deprotonated by the ylide, at least in part. Thus, phosphoranes formed between
the phenoxides of 5 and triphenylphosphonium ions have quaternary a-C-atoms, and,
therefore, a Wittig reaction on 5 is not feasible [23]. Accordingly, we postulated that
resonance anionic species of 5a and 5e derived from the deprotonation of phenols and,
located on unoccupied ortho-positions, react more slowly to form a-tetralols 11a and
11e, respectively, than undergo the olefination reaction (Scheme 5)2). a-Tetralol 11h is
the product of an ortho-lithiation of 5h (protected Ar-OH) in the presence of the strong
base BuLi and subsequent ring formation [25]. The presence of an excess of the Wittig
reagent led to an intermolecular approach to be successful in producing the olefins 6a,
6b, 6d, and 6g which are not precursors of 11.
Compounds 6 can be considered as basal structures of elvirol and curcuphenol 1–3.
In particular, the analog 6g has the most structural resemblance, whereas 6a has no
substitution on the side chain. Compound 6b is the most substituted analog, and 6d
contains an oxygenated function on the aromatic ring.
4. Antimicrobial Activity. The synthetic compounds 6 were evaluated for in vitro
antimalarial, antifungal (Table 1), and antibacterial (Table 2) activities.
All compounds 6 proved to be inactive against Plasmodium falciparum at the
highest concentration 4.8 mg/ml, in agreement with the behavior observed for curcudiol.
As well, both compounds 6b and 6g were inactive against the Gram-negative bacteria
E. coli and Pseudomonas aeruginosa, in addition to Mycobacterium intracellulare, at
20 mg/ml. Compound 6a showed antifungal activity in vitro against C. glabrata
2
)
This reaction resembles the combination of a phenol molecule which is capable of adding itself to
the formaldehyde under base catalysis (LedererꢀManasse reaction) [24].

CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
1103
Table 1. Inhibitory Activities of Compounds 6a, 6b, 6d, and 6g against C. albicans, C. glabrata, C. krusei,
C. neoformans, and A. fumigatus
Compound
IC50/MIC/MFC [mg/ml]a)
C. albicans C. glabrata
NAb)/NA/NA 13.53/20.0/20.0 NA/NA/NA
C. krusei
C. neoformans
A. fumigatus
6a
6b
6d
6g
5.45/20.0/20.0
7.4/20.0/20.0
8.55/NT/NT
19.53/NA/NA
NA/NA/NA
NA/NT/NT
10.2/NA/NA
0.8/1.25/5.0
NA/NA/NA
NA/NTc)/NT
11.0/20.0/20.0
7.4/20.0/20.0
NA/NT/NT
3.0/10.0/10.0
0.7/1.25/1.25
NA/NA/NA
NA/NT/NT
13.6/NA/NA 5.0/10.0/10.0
0.8/1.25/2.5 0.8/2.5/2.5
Amphotericin B 0.5/1.25/2.5
a) IC50: Concentration that affords 50% inhibition growth; minimum inhibitory concentration (MIC):
lowest concentration that allows no detectable growth; minimum fungicidal concentration (MFC):
lowest concentration that kills the organism. b) NA: Not active at 20 mg/ml. c) NT: Not tested.
Table 2. IC50, MIC, and MBC Values of Compounds 6a, 6b, 6d, and 6g toward S. aureus and MRSa
Compound
IC50/MIC/MBC [mg/ml]a)
S. aureus
MRSa
6a
6b
6d
6g
11.18/20.0/NAb)
5.8/10.0/20.0
NA/NTc)/NT
5.6/10.0/10.0
0.1/0.25/1.0
16.2/20.0/NA
6.0/10.0/NA
NA/NT/NT
5.9/10.0/NA
0.1/0.25/1.0
Ciprofloxacin
a) IC50: Concentration that affords 50% inhibition growth; minimum inhibitory concentration (MIC):
lowest concentration that allows no detectable growth; minimum bactericidal concentration (MBC):
lowest concentration that kills the organism. b) NA: Not active at 20 mg/ml. c) NT: Not tested.
(13.53 mg/ml), C. neoformans (5.45 mg/ml), and A. fumigates (19.53 mg/ml). Also 6a was
active against Staphylococcus aureus (IC50 ¼11.18 mg/ml) and methicillin-resistant S.
aureus (MRSa; IC50 ¼16.2 mg/ml).
Compound 6b showed inhibitory activity against the fungi Candida glabrata and
Cryptococcus neoformans (IC50 ¼7.4 mg/ml for both), and the Gram-positive bacteria S.
aureus and methicillin-resistant S. aureus (MRSa) (IC50 5.8 and 6.0 mg/ml, resp.).
Compound 6g exhibited antiproliferative activity against Cryptococcus glabrata (IC50 ¼
3.0 mg/ml) and C. neoformans (IC50 ¼5.0 mg/ml), and it was also active against S. aureus
(IC50 ¼5.6 mg/ml) and MRSa (IC50 ¼5.9 mg/ml). The antifungal and antimicrobial
bioactivity tests on compound 6d showed only inhibitory activity against the fungi C.
neoformans (IC50 8.55 mg/ml). Therefore, analogs 6b and 6g are promising with regard
to curcuphenol, and they are 1.3 times more active against Gram-positive S. aureus and
MRSa. Based on the observation, these analogs may have improved in vitro
antimicrobial activity relative to curcuphenol; the location of OH and Me groups on
the aromatic ring of 6g may be possibly responsible for this change in the selectivity of
inhibition.
In summary, we have developed a six-step synthetic route to the curcuphenol as well
as elvirol series, applying a Wittig reaction to install the side chain of seven aldehydes,

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CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
which allow chemoselectivity with respect to the formation of products 6 or a-tetralols
11. The formation of 11 could be useful as a method for preparing bicyclic precursors
like 8-methoxytetralones, otherwise difficult to obtain by any other means. Our findings
may also be considered as a contribution to the aforementioned biogenic hypothesis, or
as a biomimetic approach to bisabolane/curcumane-type substances by means of an
aromatization step of dienones 4 and (hydroxyphenyl)-butanals as precursors.
Compounds 6b and 6g are functional analogs of curcuphenol, of which we have
evidence for an improved antimicrobial activity as compared with the natural product.
Moreover, our group is investigating synthetic proceedings in the quest for new and
improved antimicrobial compounds.
The authors wish to express their gratitude to UNR (Universidad Nacional de Rosario) and
´
Fundacion J. Prats. This work was supported by CONICET (Consejo Nacional de Investigaciones
´
´
´
Cientꢀficas y Tecnicas) and ANPCYT (Agencia Nacional de Promocion Cientꢀfica y Tecnica). M. F. P.
thanks CONICETand UNL (Universidad Nacional del Litoral-Santa Fe) for a fellowship. We also thank
Ms. Marsha Wright and Mr. John Trott at the National Center for Natural Products Research (University
of Mississippi) for biological testing, which was supported by the NIH, NIAID, Division of AIDS, Grant
No. AI 27094 and the USDA Agricultural Research Service Specific Cooperative Agreement No. 58-6408-
2-0009. This investigation received financial support from the UNICEF/UNDP/WORLD BANK/WHO
Special Programme for Research and Training in Tropical Diseases (TDR) to G. R. L.
Experimental Part
General. All solvents were dried and distilled before use. All reactions were carried out under anh.
conditions under N2. All the org. extracts were dried over anh. Na2SO4. Reactions were monitored by
TLC on Al-foil plates coated with 0.1-mm Analtech silica gel 60 GF254; spot visualization under UV
light. Column chromatography (CC): Analtech silica gel for flash chromatography (SiO2), under a low
pressure of N2; elution with hexane/AcOEt mixtures. M.p.: Ernst Leitz hot-stage microscope;
1
uncorrected. IR Spectra: Bruker FT I-25 spectrophotometer; in cmꢀ1. H- and 13C-NMR spectra (300
and 75 MHz, resp.): Bruker AC-300-E spectrometer; the samples were dissolved in CDCl3 as solvent with
Me4Si as internal standard; d in ppm, J in Hz. HR-ESI-MS: at the UCR Mass Spectrometry Facility,
Department of Chemistry, University of California, Riverside, U.S.A.
Typical Procedures. Synthesis of Dienones 4. To a soln. of 10 (1 mmol) in benzene (16.6 ml),
protected against light, was added pyridinium dichromate (PDC; 1.6 mmol), Celiteꢃ (0.4 g), and t-
BuOOH (3.3 mmol). The suspension was stirred vigorously at r.t., until TLC indicated that the reaction
was completed (ca. 3 h). The suspension was filtered through a Celiteꢃ and SiO2 pad, washed by CH2Cl2,
and evaporated to afford 4.
(1S,8aS)-1,2,3,4,6,8a-Hexahydro-8a-methyl-6-oxonaphthalen-1-yl Benzoate (4a). Yellow oil (76%).
Rf (hexane/AcOEt 7:3) 0.60. IR (film): 3050, 2977, 2942, 2869, 1732, 1660, 1600, 1560, 1492, 1450, 1368,
1314, 1249, 1177, 1071, 1027, 941, 812, 758, 720, 660. 1H-NMR: 8.08 (d, J ¼ 6.9, 2 Ho of Ph); 7.62 (t, J ¼ 7.3,
Hp of Ph); 7.48 (t, J ¼ 7.7, 2 Hm of Ph); 6.95 (d, J ¼ 9.9, HꢀC(8)); 6.25 (dd, J ¼ 9.9, 1.9, HꢀC(7)); 6.20 (d,
J ¼ 1.5, HꢀC(5)); 4.84 (dd, J ¼ 11.1, 4.9, HꢀC(1)); 2.51 (dd, J ¼ 5.1, 1.7, CH2(4)); 2.45–2.42 (m, CH2(2));
2.20–2.10 (m, CH2(3)); 1.47 (s, Me). 13C-NMR: 186.0 (C¼O); 165.3 (OC¼O); 163.5 (C(4a)); 152.8
(C(8)); 133.3 (C(7)); 133.1 (C(1) of Ph); 129.5 (C(4) of Ph); 128.5 (C(2) of Ph); 128.1 (C(3) of Ph); 126.3
(C(5)); 77.0 (C(1)); 44.4 (C(8a)); 31.7 (C(4)); 26.6 (C(2)); 23.9 (C(3)); 18.3 (Me). HR-ESI-MS: 283.1252
([MþH]þ , C18H19Oþ3 ; calc. 283.1256).
(1S,8aS)-1,2,3,4,6,8a-Hexahydro-5,7,8a-trimethyl-6-oxonaphthalen-1-yl Benzoate (4b). White crys-
tals (62%). M.p. 1318 (AcOEt/EtOH 9.5 :0.5). Rf (hexane/AcOEt 80 :20) 0.45. IR (film): 2980, 2948,
2939, 2867, 1720, 1670, 1633, 1601, 1451, 1395, 1369, 1314, 1273, 1111, 1098, 1070, 989, 810, 712, 690.
1H-NMR: 8.08 (dt, J ¼ 4.7, 1.0, 2 Ho of Ph); 7.59 (dt, J ¼ 4.5, 1.0, Hp of Ph); 7.41 (dt, J ¼ 4.5, 1.0, 2 Hm of
Ph); 6.71 (d, J ¼ 0.8, HꢀC(8)); 4.74 (dd, J ¼ 7.6, 3.1, HꢀC(1)); 2.22–2.17 (m, CH2(4)); 2.15–1.96 (m,

CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
1105
CH2(2)); 1.94 (d, J ¼ 0.8, MeꢀC(5)); 1.84 (d, J ¼ 1.9, MeꢀC(7)); 1.40 (s, MeꢀC(8a)); 1.26–1.23 (m,
CH2(3)). 13C-NMR: 186.2 (C¼O); 165.4 (OC¼O); 156.1 (C(4a)); 147.7 (C(8)); 133.3 (C(4) of Ph); 130.1
(C(1) of Ph); 130.7 (C(7)); 130.6 (C(5)); 129.6 (C(2) of Ph); 128.6 (C(3) of Ph); 77.6 (C(1)); 43.6 (C(8a));
29.7 (C(2)); 26.9 (C(4)); 26.8 (C(3)); 19.1 (MeꢀC(7)); 16.4 (MeꢀC(8a)); 11.1 (MeꢀC(5)). HR-ESI-MS:
311.1567 ([MþH]þ , C20H23Oþ3 ; calc. 311.1569).
(1S,8aS)-1,2,3,4,6,8a-Hexahydro-5-methoxy-8a-methyl-6-oxonaphthalen-1-yl Benzoate (4c). Color-
less oil (60%). Rf 0.23 (hexane/AcOEt 8 :2). IR (film): 3060, 2941, 2869, 1718, 1690, 1665, 1635, 1584,
1452, 1316, 1211, 1177, 1109, 1071, 1026, 846, 711, 680. 1H-NMR: 8.08 (d, J ¼ 5.6, 2 Ho of Ph); 7.61 (t, J ¼
5.0, Hp of Ph); 7.47 (t, J ¼ 5.3, 2 Hm of Ph); 6.94 (d, J ¼ 6.6, HꢀC(8)); 6.30 (d, J ¼ 6.6, HꢀC(7)); 4.85 (dd,
J ¼ 7.6, 3.1, HꢀC(1)); 3.75 (s, MeO); 2.10–2.07 (m, CH2(4)); 2.06–2.02 (m, CH2(2)); 1.90–1.84 (m,
CH2(3)); 1.47 (s, Me). 13C-NMR: 181.5 (C¼O); 171.9 (OC¼O); 165.4 (C(5)); 152.6 (C(8)); 147.9 (C(4a));
133.7 (C(4) of Ph); 130.2 (C(2) of Ph); 129.8 (C(1) of Ph); 129.6 (C(7)); 128.5 (C(3) of Ph); 76.8 (C(1));
60.5 (MeO); 45.1 (C(8a)); 26.7 (C(2)); 23.8 (C(4)); 22.8 (C(3)); 18.6 (Me).
(1S,8aS)-1,2,3,4,6,8a-Hexahydro-8a-(methoxymethyl)-6-oxonaphthalen-1-yl Benzoate (4d). White
solid (73%). M.p. 1208 (AcOEt). Rf (hexane/AcOEt 7:3) 0.26. IR (film): 2940, 2871, 1718, 1667, 1630,
1450, 1316, 1269, 1109, 1085, 1070, 1026, 986, 884, 751, 713. 1H-NMR: 8.03 (d, J ¼ 4.7, 2 Ho of Ph); 7.59 (t,
J ¼ 4.9, Hp of Ph); 7.46 (dt, J ¼ 4.9, 2 Hm of Ph); 6.96 (d, J ¼ 6.7, HꢀC(8)); 6.34 (d, J ¼ 5.5, HꢀC(7)); 6.27
(s, HꢀC(5)); 4.85 (dd, J ¼ 7.7, 3.2, HꢀC(1)); 4.13 (d, J ¼ 6.2, 1 H, MeOꢀCH2); 3.85 (d, J ¼ 6.2, 1 H,
MeOꢀCH2); 3.31 (s, MeOꢀCH2); 2.12–2.09 (m, CH2(4)); 1.90 (dq, J ¼ 7.9, 2.9, CH2(3)); 1.52 (tt, J ¼ 7.7,
3.2, CH2(2)). 13C-NMR: 186.4 (C¼O); 165.2 (OC¼O); 160.6 (C(4a)); 150.6 (C(8)); 133.5 (ArC(4)); 130.1
(ArC(1)); 130.6 (C(7)); 128.2 (C(5)); 129.6 (C(2) of Ph); 128.6 (C(3) of Ph); 77.4 (C(1)); 72.7
(CH2OMe); 59.8 (CH2OMe); 49.8 (C(8a)); 32.0 (C(4)); 27.2 (C(2)); 24.3 (C(3)). HR-ESI-MS: 313.1358
([MþH]þ , C19H21Oþ4 ; calc. 313.1362).
(1S,8aS)-1,2,3,4,6,8a-Hexahydro-6-oxo-8a-(prop-2-en-1-yl)naphthalen-1-yl Benzoate (4e). Pale yel-
low oil (76%). Rf (hexane/AcOEt 8 :2) 0.38. IR (film): 3072, 2948, 2868, 1718, 1666, 1451, 1315, 1268,
1110, 1070, 918, 750, 712. 1H-NMR: 8.09 (t, J ¼ 8.8, 2 Ho of Ph); 7.61 (dt, J ¼ 7.3, 1.5, 2 Hm of Ph); 7.48–
7.46 (m, Hp of Ph); 6.89 (d, J ¼ 10.1, HꢀC(8)); 6.35 (dd, J ¼ 10.1, 1.9, HꢀC(7)); 6.27 (s, HꢀC(5)); 5.37–
5.29 (m, CH2CH¼CH2); 5.11 (br. s, 1 H of CH2CH¼CH2); 5.03 (d, J ¼ 0.7, 1 H, CH2CH¼CH2); 4.91 (dd,
J ¼ 11, 4.9, HꢀC(1)); 2.93 (dd, J ¼ 14.0, 7.5, 1 H, CH2CH¼CH2); 2.74 (dd, J ¼ 14.0, 6.4, 1 H,
CH2CH¼CH2); 2.39 (dd, J ¼ 8.8, 3.2, CH2(4)); 2.16–2.12 (m, CH2(2)); 2.08–2.02 (m, CH2(3)).
13C-NMR: 186.3 (C¼O); 165.2 (OCO); 161.4 (C(4a)); 151.2 (C(8)); 133.4 (C(4) of Ph); 130.7
(CH2CH¼CH2); 129.6 (C(1) of Ph); 129.5 (C(7)); 130.0 (C(2) of Ph); 128.4 (C(3) of Ph); 128.1 (C(5));
118.4 (CH2CH¼CH2); 77.0 (C(1)); 48.6 (C(8a)); 34.7 (CH2CH¼CH2); 31.6 (C(4)); 26.5 (C(2)); 23.8
(C(3)).
(1S,8aS)-1,2,3,4,6,8a-Hexahydro-5,7-dimethyl-6-oxo-8a-(prop-2-en-1-yl)naphthalen-1-yl Benzoate
(4f). White solid (79%). M.p. 154.5–155.58 (AcOEt). Rf (hexane/AcOEt 9 :1) 0.44. IR (film): 3072,
2949, 2927, 2865, 1719, 1670, 1631, 1450, 1371, 1314, 1267, 1110, 1026, 997, 918, 712, 687. 1H-NMR: 8.09 (dt,
J ¼ 4.7, 1.0, 2 Ho of Ph); 7.49 (dt, J ¼ 4.9, 1.0, 2 Hm of Ph); 7.61 (dt, J ¼ 4.9, 1.0, Hp of Ph); 6.66 (d, J ¼ 0.8,
HꢀC(8)); 5.04–4.99 (m, 1 H, CH2CH¼CH2); 4.91 (dt, J ¼ 6.6, 0.8, 1 H, CH2CH¼CH2); 5.26–5.23 (m,
CH2CH¼CH2); 4.81 (dd, J ¼ 7.6, 3.3, HꢀC(1)); 2.90 (dd, J ¼ 9.4, 5.3, 1 H, CH2CH¼CH2); 2.69 (dd, J ¼
9.4, 4.1, 1 H, CH2CH¼CH2); 2.14–2.08 (m, CH2(4)); 2.07–2.02 (m, CH2(2)); 1.94 (d, J ¼ 0.6, MeꢀC(5));
1.87 (d, J ¼ 0.8, MeꢀC(7)); 1.48–1.38 (m, CH2(3)). 13C-NMR: 186.5 (C¼O); 165.4 (OC¼O); 133.3
(CH2CH¼CH2); 153.9 (C(4a)); 146.0 (C(8)); 131.7 (C(4) of Ph); 135.7 (C(7)); 132.7 (C(5)); 130.1 (C(1)
of Ph); 129.7 (C(2) of Ph); 128.6 (C(3) of Ph); 117.8 (CH2CH¼CH2); 78.0 (C(1)); 47.5 (C(8a)); 35.4
(CH2CH¼CH2); 26.9 (C(2)); 26.7 (C(4)); 23.6 (C(3)); 16.3 (MeꢀC(7)); 11.0 (MeꢀC(5)).
(1S,8aS)-1,2,3,4,6,8a-Hexahydro-4,8a-dimethyl-6-oxonaphthalen-1-yl Benzoate (4g). Oil (69%). Rf
(hexane/AcOEt 8 :2) 0.47. IR (film): 3060, 2962, 2870, 1720, 1664, 1603, 1580, 1450, 1315, 1270, 1108,
1093, 1070, 1030, 989, 898, 760, 713. 1H-NMR: 8.07 (d, J ¼ 4.7, 2 Ho of Ph); 7.60 (dt, J ¼ 4.8, 1.0, Hp of Ph);
7.48 (t, J ¼ 4.8, 2 Hm of Ph); 6.95 (d, J ¼ 6.6, HꢀC(8)); 6.26 (dd, J ¼ 6.6, 1.2, HꢀC(7)); 6.21 (s, HꢀC(5));
4.82 (dd, J ¼ 7.5, 3.2, HꢀC(1)); 2.59 (dd, J ¼ 4.2, 1.2, HꢀC(4)); 2.14–2.07 (m, CH2(2)); 1.96–1.88 (m,
CH2(3)); 1.48 (s, MeꢀC(8a)); 1.19 (d, J ¼ 4.2, MeꢀC(4)). 13C-NMR: 186.3 (C¼O); 166.8 (OC¼O); 165.4
(C(4a)); 153.5 (C(8)); 133.4 (C(7)); 129.9 (C(1) of Ph); 123.7 (C(5)); 129.6 (C(4) of Ph); 128.6 (C(2) of

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CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
Ph); 127.8 (C(3) of Ph); 76.9 (C(1)); 44.6 (C(8a)); 33.4 (C(4)); 32.5 (C(2)); 26.7 (C(3)); 19.0 (MeꢀC(4));
17.3 (MeꢀC(8a)). HR-ESI-MS: 319.1309 ([MþNa]þ , C19H20NaO3þ ; calc. 319.1310).
Synthesis of Hydroxyphenyl Aldehydes 5. To a soln. of 4 (1 mmol) in MeOH (50 ml), K2CO3
(4 mmol) was added, and the mixture was maintained with magnetic stirring at r.t. until complete. The
reaction was quenched with brine, and MeOH was evaporated in vacuo. The aq. layer was extracted with
Et2O (3ꢁ25 ml) and AcOEt (25 ml). The combined org. extracts were washed with brine, dried
(Na2SO4), filtered, and evaporated in vacuo to give a residue, which was purified by CC to afford 5.
4-(5-Hydroxy-2-methylphenyl)butanal (5a). Pale orange solid (94%). Rf (benzene/AcOEt 8 :2) 0.48.
IR (film) 3347, 3021, 2935, 2865, 1716, 1609, 1595, 1501, 1467, 1451, 1272, 1150, 1070, 1027, 813, 720.
1H-NMR: 9.76 (t, J ¼ 1.5, CHO); 7.20 (dd, J ¼ 5.7, 3.6, HꢀC(4’)); 6.98 (d, J ¼ 7.7, HꢀC(3’)); 6.61 (s,
HꢀC(6’)); 2.58 (t, J ¼ 7.3, CH2(4)); 2.49 (dt, J ¼ 7.2, 1.5, CH2(2)); 2.21 (s, Me); 1.90 (q, J ¼ 7.3, CH2(3)).
13C-NMR: 202.5 (C(1)); 153.8 (C(5’)); 140.6 (C(1’)); 131.1 (C(3’)); 126.5 (C(2’)), 115.7 (C(6’)); 112.9
(C(4’)); 43.2 (C(2)); 32.3 (C(4)); 22.1 (C(3)); 18.2 (Me). HR-ESI-MS: 179.0990 ([MþH]þ , C11H15O2þ ;
calc. 179.0994).
4-(3-Hydroxy-2,4,6-trimethylphenyl)butanal (5b). Colorless oil (80%). Rf (hexane/AcOEt 7:3) 0.51.
IR (film) 3474, 3007, 2949, 2882, 1716, 1480, 1456, 1410, 1386, 1246, 1212, 1094, 1012, 869. 1H-NMR: 9.81
(t, J ¼ 1.0, CHO); 6.80 (s, HꢀC(5’)); 4.71 (s, OH); 2.64 (t, J ¼ 5.4, CH2(4)); 2.54 (dt, J ¼ 4.7, 1.0, CH2(2));
2.24 (s, MeꢀC(6)); 2.23 (s, MeꢀC(2)); 2.21 (s, MeꢀC(4)); 1.79 (q, J ¼ 4.8, CH2(3)). 13C-NMR: 202.4
(CHO); 150.4 (C(3’)); 137.0 (C(1’)); 129.8 (C(5’)); 127.5 (C(6’)); 121.8 (C(2’)); 120.4 (C(4’)); 43.8 (C(2));
29.2 (C(4)); 21.9 (C(3)); 19.3 (MeꢀC(6)); 15.7 (MeꢀC(4)); 11.8 (MeꢀC(2)). HR-ESI-MS: 207.1377
([MþH]þ , C13H19Oþ2 ; calc. 207.1380).
4-(3-Hydroxy-2-methoxy-6-methylphenyl)butanal (5c). Pale yellow oil (63%). Rf (hexane/AcOEt
7:3) 0.56. IR (film): 3405, 2921, 2850, 1717, 1603, 1488, 1464, 1292, 1237, 1165, 1093, 1001, 810, 716, 628.
1H-NMR: 9.79 (t, J ¼ 1.0, CHO); 6.82 (dd, J ¼ 5.5, 0.4, HꢀC(5’)); 6.74 (d, J ¼ 5.5, HꢀC(4’)); 3.77 (s,
MeO); 2.67 (t, J ¼ 5.0, CH2(4)); 2.50 (dt, J ¼ 4.7, 1.0, CH2(2)); 2.24 (s, Me); 1.86 (q, J ¼ 4.7, CH2(3)).
13C-NMR: 202.5 (CHO); 146.9 (ArC(2)); 145.6 (ArC(3)); 133.0 (ArC(6)); 128.7 (ArC(1)); 126.5 (C(4’));
113.4 (C(5’)); 61.2 (MeO); 43.3 (C(2)); 26.1 (C(4)); 22.0 (C(3)); 18.8 (Me). HR-ESI-MS: 231.0994
([MþNa]þ , C12H16NaOþ3 ; calc. 231.0997).
4-[5-Hydroxy-2-(methoxymethyl)phenyl]butanal (5d). Colorless oil (87%). Rf (hexane/AcOEt 7:3)
0.28. IR (film): 3400, 2920, 2848, 1713, 1609, 1490, 1460, 1292, 1223, 1158, 1096, 1021, 815, 710, 627.
1H-NMR: 9.76 (s, CHO); 7.14 (d, J ¼ 5.4, HꢀC(3’)); 6.63 (s, HꢀC(6’)); 6.60 (d, J ¼ 5.5, HꢀC(4’)); 4.38 (s,
MeOꢀCH2); 3.36 (s, MeOꢀCH2); 2.64 (t, J ¼ 4.9, CH2(4)); 2.50 (t, J ¼ 4.9, CH2(2)); 1.92 (q, J ¼ 4.9,
CH2(3)). 13C-NMR: 202.7 (C¼O); 155.7 (C(5’)); 142.2 (C(1’)); 131.5 (C(2’)); 127.6 (C(3’)); 116.1 (C(4’));
112.8 (C(6’)); 72.3 (CH2OMe); 57.7 (CH2OMe); 43.2 (C(2)); 31.3 (C(4)); 23.1 (C(3)). HR-ESI-MS:
231.0996 ([MþNa]þ , C12H16NaOþ3 ; calc. 231.097).
4-[5-Hydroxy-2-(prop-2-en-1-yl)phenyl]butanal (5e). Pale yellow oil (94%). Rf (hexane/AcOEt
7:3) 0.56. IR (film): 3419, 3076, 3008, 2933, 2864, 1721, 1638, 1476, 1339, 1254, 1157, 991, 913, 820, 758,
1
667. H-NMR: 9.76 (s, CHO); 7.54 (d, J ¼ 8.2, HꢀC(3’)); 6.98 (d, J ¼ 8.2, HꢀC(4’)); 6.70 (s, HꢀC(6’));
6.01–5.98 (m, CH2CH¼CH2); 5.05 (d, J ¼ 1.3, 1 H, CH2CH¼CH2); 5.00 (br. s, 1 H, CH2CH¼CH2); 3.26
(d, J ¼ 6.2, CH2CH¼CH2); 2.63 (t, J ¼ 5.6, CH2(4)); 2.16–2.12 (m, CH2(2)); 1.95–1.75 (m, CH2(3)).
13C-NMR: 202.9 (C¼O); 154.8 (C(5’)); 140.8 (C(1’)); 137.0 (C(3’)); 131.0 (CH2CH¼CH2); 129.7 (C(6’));
129.4 (C(2’)); 115.4 (¼CH2); 113.4 (C(4’)); 43.4 (C(2)); 36.9 (C(4)); 32.4 (CH2CH¼CH2); 19.7 (C(3)).
HR-ESI-MS: 227.1048 ([MþNa]þ , C13H16NaOþ2 ; calc. 227.1041).
4-[3-Hydroxy-2,4-dimethyl-6-(prop-2-en-1-yl)phenyl]butanal (5f). White solid (80%). Rf (hexane/
AcOEt 8 :2) 0.30. IR (film): 3476, 3077, 2932, 2870, 1717, 1637, 1579, 1480, 1412, 1389, 1212, 1095, 912, 874,
684. 1H-NMR: 9.81 (t, J ¼ 0.8, CHO); 6.80 (s, HꢀC(5’)); 6.01–5.88 (m, CH2CH¼CH2); 5.04 (dd, J ¼ 6.3,
1.0, 1 H, CH2CH¼CH2); 4.96 (dd, J ¼ 2.0, 1.0, 1 H, CH2CH¼CH2); 4.69 (d, J ¼ 1.6, OH); 3.33 (d, J ¼ 4.1,
CH2CH¼CH2); 2.64 (t, J ¼ 5.5, HꢀC(4)); 2.62 (d, J ¼ 4.1, HꢀC(4)); 2.54 (dt, J ¼ 4.7, 0.8, CH2(2)); 2.24 (s,
MeꢀC(4’)); 2.22 (s, MeꢀC(2’)); 1.83–1.76 (m, CH2(3)). 13C-NMR: 202.3 (C¼O); 150.8 (C(3’)); 129.4
(C(6’)); 138.2 (CH2CH¼CH2); 137.0 (C(1’)); 129.4 (C(5’)); 121.9 (C(2’)); 120.6 (C(4’)); 115.6
(CH2CH¼CH2); 43.9 (C(2)); 37.3 (CH2CH¼CH2); 28.8 (C(4)); 22.6 (C(3)); 15.8 (MeꢀC(4)); 11.9
(MeꢀC(2)). HR-ESI-MS: 233.1542 ([MþH]þ , C15H21O2þ ; calc. 233.1537).

CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
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4-(5-Hydroxy-2-methylphenyl)pentanal (5g). Pale yellow oil (60%). Rf (hexane/AcOEt 8 :2) 0.25.
IR (film): 3386, 2961, 2930, 2868, 1716, 1610, 1585, 1497, 1460, 1258, 1238, 1026, 994, 870, 813, 716.
1H-NMR: 9.70 (t, J ¼ 1.0, CHO); 6.99 (d, J ¼ 5.3, HꢀC(3’)); 6.67 (d, J ¼ 1.8, HꢀC(6’)); 6.58 (dd, J ¼ 5.4,
1.8, HꢀC(4’); 2.98–2.95 (m, HꢀC(4)); 2.36 (dt, J ¼ 5.0, 1.1, CH2(2)); 2.22 (s, MeꢀC(2)); 1.91 (t, J ¼ 4.8,
CH2(3)); 1.21 (d, J ¼ 4.5, MeꢀC(4)). 13C-NMR: 202.6 (C¼O); 154.2 (C(5’)); 145.7 (C(1’)); 131.3 (C(3’));
127.5 (C(2’)); 112.8 (C(6’)); 112.2 (C(4’)); 42.1 (C(2)); 33.9 (C(4)); 29.5 (C(3)); 21.6 (MeꢀC(4)); 18.6
(MeꢀC(2’)). HR-ESI-MS: 193.1154 ([MþH]þ , C12H17O2þ ; calc. 193.1150).
Synthesis of 6. (Isopropyl)(triphenyl)phosphonium iodide (1.5–2 mmol) in THF (3.1 ml/mmol) was
stirred and cooled to ꢀ788. A soln. of BuLi was added dropwise (1.6m in THF, 1.5–2 mmol), and the
mixture was stirred for 0.5 h, and it was let to warm to r.t. A typical orange-red color was observed as
indication of deprotonation of the phosphonium salt. After 0.5 h, a soln. of the corresponding aldehyde
(1 mmol) in THF (0.94 ml/mmol) was added at ꢀ788 (0.5 h). The mixture was then kept warm for
another 0.5 h at r.t., and H2O was added. The mixture was extracted with Et2O (3ꢁ10 ml). The
combined org. extract was washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated
and the corresponding residues were purified by CC to afford pure alkenyl-phenols 6.
4-Methyl-3-(5-methylhex-4-en-1-yl)phenol (6a). Colorless oil (68%). Rf (hexane/AcOEt 9 :1) 0.56.
IR (film): 3347, 2935, 2865, 1609, 1595, 1467, 1376, 1221, 1150, 1070, 1027, 943, 867, 801. 1H-NMR: 6.97 (d,
J ¼ 8.1, HꢀC(5)); 6.63 (br. s, HꢀC(2)); 6.56 (dd, J ¼ 8.2, 2.2, HꢀC(6)); 5.16 (t, J ¼ 6.8, HꢀC(4’)); 2.52 (t,
J ¼ 7.8, CH2(1’)); 2.21 (s, MeꢀC(4)); 2.05 (q, J ¼ 7.5, CH2(3’)); 1.71 (s, MeꢀC(5’)); 1.61 (s, Me(6’)); 1.59–
1.54 (m, J ¼ 7.3, CH2(2’)). 13C-NMR: 153.7 (C(1)); 142.4 (C(3)); 130.9 (C(5)); 127.9 (C(4)); 112.4 (C(6));
115.7 (C(2)); 131.9 (C(5’)); 124.3 (C(4’)); 32.9 (C(1)); 30.2 (C(2)); 27.9 (C(3)); 25.7 (MeꢀC(5)); 17.7
(C(6)). HR-ESI-MS: 205.1516 ([MþH]þ , C14H21Oþ ; calc. 205.1514).
2,4,6-Trimethyl-3-(5-methylhex-4-en-1-yl)phenol (6b). Colorless oil (75%). Rf (hexane/AcOEt 8 :2)
0.74. IR (film): 3502, 2964, 2920, 1581, 1476, 1447, 1374, 1205, 1086, 1010, 865. 1H-NMR: 6.78 (s, HꢀC(5));
5.19 (t, J ¼7.1, 1.3, HꢀC(4)); 4.47 (br. s, OH); 2.58 (dd, J ¼ 8.3, 3.1, CH2(1)); 2.22 (s, MeꢀC(6)); 2.21 (s,
MeꢀC(4)); 2.20 (s, MeꢀC(2)); 2.10 (q, J ¼ 7.2, CH2(3’)); 1.72 (d, J ¼ 0.7, MeꢀC(5’)); 1.64 (s, Me(6’));
1.50–1.44 (m, CH2(2’)). 13C-NMR: 150.2 (C(1)); 138.4 (C(3)); 132.0 (C(5’)); 129.6 (C(4)); 127.5 (C(5));
124.3 (C(4’)); 121.5 (C(2)); 119.7 (C(6)); 29.6 (C(1’)); 29.5 (C(2’)); 28.5 (C(3’)); 25.7 (C(6’)); 19.3
(MeꢀC(6)); 17.8 (MeꢀC(5’)); 15.7 (MeꢀC(2)); 11.7 (MeꢀC(4)). HR-ESI-MS: 233.1902 ([MþH]þ
,
C16H25Oþ ; calc. 233.1827).
4-(Methoxymethyl)-3-(5-methylhex-4-en-1-yl)phenol (6d). Oil (78%). Rf (hexane/AcOEt 9 :1) 0.22.
IR (film): 3354, 2928, 2861, 1610, 1586, 1502, 1451, 1377, 1227, 1161, 1096, 1074, 956, 930, 825. 1H-NMR:
7.14 (d, J ¼ 8.4, HꢀC(5)); 6.64 (d, J ¼ 2.5, HꢀC(2)); 6.58 (dd, J ¼ 8.2, 2.6, HꢀC(6)); 5.32 (br. s, OH); 5.16
(tq, J ¼ 7.1, 1.4, HꢀC(4’)); 4.39 (s, MeOꢀCH2); 3.37 (s, MeOꢀCH2); 2.60 (t, J ¼ 7.9, CH2(1’)); 2.05 (q, J ¼
7.2, CH2(3’)); 1.71 (d, J ¼ 1.1, MeꢀC(5)); 1.61 (s, Me(6)); 1.61 (q, J ¼ 7.3, CH2(2’)). 13C-NMR: 155.5
(C(1)); 143.6 (C(3)); 131.9 (C(4)); 131.1 (C(5)); 127.7 (C(5’)); 124.3 (C(4’)); 116.2 (C(2)); 112.5 (C(6));
72.4 (CH2OMe); 57.8 (CH2OMe); 31.9 (C(1’)); 31.2 (C(2’)); 28.0 (C(3’)); 25.7 (C(6’)); 17.8 (MeꢀC(5’)).
HR-ESI-MS: 235.1624 ([MþH]þ , C15H23Oþ2 ; calc. 235.1620).
3-(1,5-Dimethylhex-4-en-1-yl)-4-methylphenol (6g). Colorless oil (64%). Rf (hexane/AcOEt 8 :2)
0.59. IR (film): 3355, 2956, 2920, 1606, 1580, 1494, 1458, 1375, 1288, 1226, 1006, 945, 869, 808. 1H-NMR:
6.97 (d, J ¼ 8.1, HꢀC(5)); 6.68 (d, J ¼ 2.7, HꢀC(2)); 6.55 (dd, J ¼ 8.1, 2.7, HꢀC(6)); 5.09 (t, J ¼ 7.0,
HꢀC(4)); 4.91 (br. s, OH); 2.91 (sext., J ¼ 6.9, HꢀC(1’)); 1.93 (dt, J ¼ 7.4, 6.6, CH2(3)); 1.67 (s,
MeꢀC(5’)); 1.51 (s, Me(6’)); 1.59 (dq, J ¼ 7.4, 1.2, CH2(2)). 13C-NMR: 154.0 (C(1)); 147.4 (C(3)); 131.6
(C(5’)); 131.0 (C(5)); 127.5 (C(4)); 124.5 (C(4’)); 112.3 (C(2)); 112.2 (C(6)); 37.7 (C(2)); 34.1 (C(1)); 26.1
(C(3)); 25.7 (MeꢀC(5)); 21.5 (MeꢀC(1’)); 18.6 (MeꢀC(4’)); 17.6 (C(6)). HR-ESI-MS: 219.1749 ([Mþ
H]þ , C15H23Oþ ; calc. 219.1671).
Synthesis of Hexahydro-naphthalenones 8. NH3 (70 ml) was condensed into a flame-dried three-
necked round-bottom flask, equipped with a dry-ice condenser and mechanical stirrer, and maintained at
ꢀ788 under a positive pressure of dry N2. A soln. of 7 (2.4 g, 16.4 mmol) and t-BuOH (2 ml, 19 mmol) in
Et2O (8 ml) was introduced via a double needle, and K (1.4 g, 36 mmol) was then added in small portions.
The resulting blue suspension was stirred during 20 more min. To this suspension, anh. LiBr (3.14 g,
36 mmol) was then added, and the mixture was stirred vigorously for 30 min, keeping the temp. at ꢀ788.
Finally, MeI (32 mmol) was added, and the mixture was stirred for 15 min. The cooling bath was

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CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
removed, and the NH3 was allowed to evaporate. The residue was diluted with brine (40 ml) and Et2O
(30 ml), and the pH of the soln. was adjusted to 7.5 by careful addition of 10% HCl. The aq. layer was
then separated and extracted with Et2O (4ꢁ25 ml) and AcOEt (4ꢁ25 ml). The combined Et2O extract
was washed with brine, dried (Na2SO4) filtered, and evaporated to afford the corresponding compounds
83).
Synthesis of Hexahydro-naphthalenols 9. 8 (8.1 mmol) was dissolved in MeOH (2 ml/mmol), and the
soln. was cooled to ꢀ788. NaBH4 (9.7 mmol) was added portionwise, and the mixture was stirred until
the reaction was completed (30 min; TLC). The excess of reducing agent was destroyed by addition of
H2O (4 ml) and brine (30 ml) at low temp. The MeOH was evaporated, and the aq. layer was extracted
with Et2O (3ꢁ30 ml) and AcOEt (30 ml). The combined org. layer was washed with brine, dried,
filtered, and evaporated, to afford the crude 9.
Synthesis of Benzoates 10. To a soln. of 9 (1.41 g, 8.7 mmol) in pyridine (5 ml) (cooled to 08) was
added PhCOCl (1.0 ml, 8.7 mmol) and cat. amount of DMAP. The mixture was stirred overnight, poured
into cold 10% HCl soln. (25 ml), and extracted with Et2O (3ꢁ30 ml) and AcOEt (1ꢁ30 ml). The
combined Et2O extract was washed with sat. soln. of NaHCO3, H2O, and a 10% CuSO4 soln., dried
(Na2SO4), filtered, and evaporated to afford the ester 10.
1,2,3,4,6,8a-Hexahydro-8a-methylnaphthalen-1-yl Benzoate (10a). Oil (94%). Rf (hexane/AcOEt
8 :2) 0.79. IR (film): 2935, 2862, 1717, 1602, 1451, 1315, 1272, 1174, 1114, 1099, 1070, 1026, 988, 937, 711.
1H-NMR: 8.07 (dd, J ¼ 8.4, 1.5, 2 Ho) 7.54 (t, J ¼ 7.1, Hp); 7.42 (t, J ¼ 7.7, 2 Hm); 6.29–6.26 (m, HꢀC(8));
6.02 (t, J ¼ 2.8, HꢀC(5)); 5.60–5.45 (m, HꢀC(7)); 4.96 (dd, J ¼ 11.0, 4.9, HꢀC(1)); 2.64 (br. s, CH2(6));
2.31–2.29 (m, CH2(4)); 2.07–2.02 (m, CH2(2)); 1.85–1.75 (m, CH2(3)); 1.34 (s, Me). 13C-NMR: 166.0
(CO); 139.4 (C(4a)); 132.8 (C(4) of Ph); 131.4 (C(1) of Ph); 129.6 (C(2) of Ph); 128.4 (C(3) of Ph); 126.1
(C(7)); 122.5 (C(8)); 119.3 (C(5)); 78.8 (C(1)); 40.0 (C(8a)); 31.4 (C(4)); 27.4 (C(6)); 26.8 (C(2)); 24.7
(Me); 20.1 (C(3)). HR-ESI-MS: 269.1461 ([MþH]þ , C18H21O2þ ; calc. 269.1463).
1,2,3,4,6,8a-Hexahydro-5,7,8a-trimethylnaphthalen-1-yl Benzoate (10b). White solid (98%). M.p.
119.58 (AcOEt). Rf (hexane/AcOEt 9 :1) 0.80. IR (film): 2969, 2932, 2863, 2810, 1717, 1601, 1451, 1368,
1315, 1269, 1174, 1115, 1101, 1070, 986, 910, 846, 712, 688. 1H-NMR: 8.09 (dd, J ¼ 8.5, 1.5, 2 Ho); 7.57 (tt,
J ¼ 7.3, 1.5, Hp); 7.46 (t, J ¼ 7.0, 1.2, 2 Hm); 5.33 (s, HꢀC(8)); 4.84 (dd, J ¼ 11.4, 4.6, HꢀC(1)); 2.50 (d, J ¼
6.1, CH2(6)); 1.99 (dd, J ¼ 11.1, 3.0, CH2(4)); 1.82 (dq, J ¼ 12.6, 2.1, HꢀC(2)); 1.74 (dd, J ¼ 12.3, 4.6,
HꢀC(2)); 1.69 (s, MeꢀC(5)); 1.61 (s, MeꢀC(7)); 1.42–1.36 (m, CH2(3)); 1.30 (s, MeꢀC(8a)). 13C-NMR:
166.0 (CO); 132.7 (C(8)); 131.7 (C(4a)); 131.0 (C(7)); 129.6 (C(4) of Ph); 129.2 (C(1) of Ph); 128.4 (C(2)
of Ph); 126.4 (C(3) of Ph); 123.9 (C(5)); 79.5 (C(1)); 41.7 (C(8a)); 38.2 (C(6)); 27.4 (C(2)); 24.2 (C(4));
24.1 (C(3)); 22.7 (Me(7)); 20.5 (Me(5)); 18.7 (Me(8a)). HR-ESI-MS: 297.1774 ([MþH]þ , C20H25O2þ ;
calc. 297.1776).
1,2,3,4,6,8a-Hexahydro-5-methoxy-8a-methylnaphthalen-1-yl Benzoate (10c). Oil (80%). Rf (hexane/
1
AcOEt 8 :2) 0.83. H-NMR: 8.06 (dd, J ¼ 8.4, 1.3, 2 Ho); 7.56 (tt, J ¼ 7.3, 1.3, Hp); 7.45 (tt, J ¼ 8.2, 1.3,
2 Hm); 5.59 (s, HꢀC(8)); 5.58 (s, HꢀC(7)); 4.94 (dd, J ¼ 11.5, 4.6, HꢀC(1)); 3.53 (s, MeO); 2.82–2.76 (m,
CH2(6)); 2.10–1.90 (m, CH2(4)); 1.90–1.78 (m, CH2(3)); 1.75–1.70 (m, CH2(2)); 1.33 (s, Me). 13C-NMR:
168.1 (OC¼O); 157.0 (MeO); 132.8 (C(4) of Ph); 129.9 (C(2) of Ph); 129.3 (C(1) of Ph); 128.6 (C(3) of
Ph); 126.4 (C(8)); 121.5 (C(7)); 109.1 (C(4a)); 72.4 (C(1)); 68.8 (C(8a)); 55.4 (MeO); 39.2 (C(6)); 28.7
(C(2)); 26.7 (C(4)); 25.6 (C(3)); 15.2 (Me). HR-ESI-MS: 299.1567 ([MþH]þ , C19H23O3þ ; calc.
299.1569).
1,2,3,4,6,8a-Hexahydro-8a-(methoxymethyl)naphthalen-1-yl Benzoate (10d). White solid (99%).
M.p. 898 (AcOEt). Rf (hexane/AcOEt 8 :2) 0.5. IR (film): 3064, 2933, 2863, 1787, 1723, 1599, 1452, 1272,
1213, 1173, 1040, 1017, 997, 778, 703. 1H-NMR: 8.05 (dd, J¼7.6, 1.5, 2 Ho); 7.68 (tt, J¼7.6, 2.1, Hp); 7.53 (t,
J¼7.9, 2 Hm); 5.83 (ddt, J¼8.5, 3.3, 1.8, HꢀC(7)); 5.70 (br. s, HꢀC(5)); 5.65 (dt, J¼7.6, 1.8, HꢀC(8)); 5.01
(dd, J¼11.4, 4.9, HꢀC(1)); 4.05 (d, J¼9.3, 1 H, MeOCH2); 3.61 (d, J¼9.4, 1 H, MeOCH2); 3.43 (s,
MeO); 2.71–2.68 (m, CH2(6)); 2.34 (t, J¼13.8, CH2(4)); 2.16–2.11 (m, CH2(3)); 1.89–1.86 (m, CH2(2)).
13C-NMR: 162.4 (OC(O)Ph); 136.1 (C(4a)); 134.6 (C(4) of Ph); 130.6 (C(1) of Ph); 129.6 (C(2) of Ph);
128.9 (C(3) of Ph); 128.4 (C(8)); 125.7 (C(7)); 121.9 (C(5)); 79.0 (C(1)); 73.7 (CH2OMe); 59.9 (MeO);
3
)
Compounds 8a, 8d, 8e and 9a, 9d, 9e are described in [26].

CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
1109
45.2 (C(8a)); 31.7 (C(4)); 27.7 (C(2)); 26.9 (C(3)); 24.9 (C(6)). HR-ESI-MS: 299.1565 ([MþH]þ
,
C19H23Oþ3 ; calc. 299.1569).
1,2,3,4,6,8a-Hexahydro-8a-(prop-2-en-1-yl)naphthalen-1-yl Benzoate (10e). Pale green oil (99%). Rf
(hexane/AcOEt 9 :1) 0.80. IR (film): 3072, 2941, 2863, 1790, 1722, 1668, 1452, 1417, 1316, 1270, 1113, 913,
780, 711. 1H-NMR: 8.07 (d, J ¼ 6.9, 2 Ho); 7.55 (t, J ¼ 7.1, Hp); 7.49 (t, J ¼ 7.9, 2 Hm); 5.78–5.74 (m,
CH2CH¼CH2); 5.73–5.69 (m, HꢀC(8)); 5.68–5.58 (m, HꢀC(7)); 5.52–5.50 (m, HꢀC(5)); 5.12 (br. s,
1 H, CH2CH¼CH2); 5.03 (br. s, 1 H, CH2CH¼CH2); 5.0 (d, J ¼ 1.3, HꢀC(1)); 2.80 (dd, J ¼ 14.2, 7.9, 1 H,
CH2CH¼CH2); 2.64 (t, J ¼ 2.1, CH2(6)); 2.40 (dd, J ¼ 14.2, 6.2, 1 H, CH2CH¼CH2); 2.30–2.10 (tm, J ¼
13.7, HꢀC(4)); 2.06–1.86 (m, CH2(2)); 1.87–1.78 (m, CH2(3)); 1.52 (tt, J ¼ 13.5, 4.5, HꢀC(4)).
13C-NMR: 165.8 (OC(O)Ph); 136.6 (C(4a)); 130.5 (C(1) of Ph); 130.4 (C(8)); 129.4 (C(4) of Ph); 129.2
(CH2CH¼CH2); 128.7 (C(2) of Ph); 128.2 (C(3) of Ph); 128.7 (C(7)); 124.6 (C(5)); 116.0
(CH2CH¼CH2); 78.9 (C(1)); 44.0 (C(8a)); 35.5 (CH2CH¼CH2); 31.2 (C(4)); 27.0 (C(6)); 26.8 (C(2));
24.5 (C(3)). HR-ESI-MS: 294.1616 ([MþH]þ , C20H23O2þ ; calc. 294.1620).
1,2,3,4,6,8a-Hexahydro-5,7-dimethyl-8a-(prop-2-en-1-yl)naphthalen-1-yl Benzoate (10f). Pale yellow
solid (95%). M.p. 82.58 (pentane/AcOEt 8 :2). Rf (hexane/AcOEt 9 :1) 0.72. IR (film): 3071, 2928, 2862,
1617, 1640, 1602, 1450, 1314, 1269, 1176, 1113, 1070, 1026, 989, 908, 869, 712, 688. 1H-NMR: 8.09 (dd, J ¼
8.4, 1.2, 2 Ho); 7.57 (tt, J ¼ 4.9, 1.2, Hp); 7.46 (dt, J ¼ 7.3, 1.2, 2 Hm); 5.60–5.58 (m, CH2CH¼CH2); 5.27 (s,
HꢀC(8)); 5.02 (dq, J ¼ 17.2, 1.5, 1 H, CH2CH¼CH2); 4.95 (s, 1 H, CH2CH¼CH2); 4.93 (dd, J ¼ 11.4, 4.9,
HꢀC(1)); 2.79 (dd, J ¼ 14.4, 8.2, 1 H, CH2CH¼CH2); 2.48 (d, J ¼ 7.6, CH2(6)); 2.58 (d, J ¼ 9.1, HꢀC(4));
2.38 (dd, J ¼ 14.4, 6.1, CH2CH¼CH2); 2.09–1.95 (m, HꢀC(4)); 1.95–1.80 (m, 3 H, CH2(2), CH2(3)); 1.69
(s, Me(5)); 1.64 (s, Me(7)); 1.44–1.36 (m, 1 H, CH2(3)). 13C-NMR: 165.9 (CO); 135.2 (CH2CH¼CH2);
132.8 (C(4) of Ph); 131.5 (C(4a)); 130.9 (C(7)); 129.0 (C(1) of Ph); 129.6 (C(2) of Ph); 128.4 (C(3) of
Ph); 126.0 (C(5)); 124.4 (C(8)); 115.6 (CH2CH¼CH2); 79.8 (C(1)); 45.7 (C(8a)); 36.2 (CH2CH¼CH2);
38.5 (C(6)); 27.2 (C(2)); 24.1 (C(4)); 24.0 (C(3)); 22.7 (MeꢀC(7)); 18.6 (MeꢀC(5)). HR-ESI-MS:
323.1930 ([MþH]þ , C22H26Oþ2 ; calc. 323.1933).
1,2,3,4,6,8a-Hexahydro-4,8a-dimethylnaphthalen-1-yl Benzoate (10g). Pale yellow oil (100%). Rf
(hexane/AcOEt 9 :1) 0.84. IR (film): 3025, 2962, 2933, 2873, 2858, 1718, 1601, 1585, 1491, 1452, 1376,
1335, 1313, 1173, 1109, 1039, 996, 985, 778, 710. 1H-NMR: 8.08 (d, J ¼ 5.6, 2 Ho; 7.68 (t, J ¼ 5.0, Hp); 7.45
(t, J ¼ 5.0, 2 Hm); 5.62 (s, HꢀC(8)); 5.72–5.56 (m, HꢀC(7)); 5.53–5.38 (m, HꢀC(5)); 4.94 (ddd, J ¼ 7.5,
6.3, 3.2, HꢀC(1)); 2.67 (d, J ¼ 11.1, CH2(6)); 2.48–2.32 (m, HꢀC(4)); 2.10–2.00 (m, CH2(2)); 1.92–1.76
(m, CH2(3)); 1.36 (s, MeꢀC(8a)); 1.06 (d, J¼4.3, MeꢀC(4)). 13C-NMR: 166.0 (CO); 142.8 (C(4a)); 132.8
(C(4) of Ph); 130.8 (C(1) of Ph); 129.6 (C(2) of Ph); 128.9 (C(8)); 128.4 (C(3) of Ph); 122.2 (C(7)); 116.2
(C(5)); 79.1 (C(1)); 40.0 (C(8a)); 33.3 (C(6)); 31.9 (C(4)); 27.2 (C(2)); 26.9 (C(3)); 20.8 (MeꢀC(4)); 18.0
(MeꢀC(8a)). HR-ESI-MS: 283.1618 ([MþH]þ , C19H23O2þ ; calc. 283.1620).
Syntheses of 11. To a suspension of (isopropyl)(triphenyl)phosphonium iodide (1 mmol) in THF
(3 ml/mmol) at ꢀ788, BuLi (1.6m in THF, 1 mmol) was added dropwise. The mixture was stirred at ꢀ788
for 1.5 h, and then it was slowly let to warm to r.t. After 1.5 h, the aldehyde 5 (1 mmol) dissolved in THF
(0.94 ml/mmol) was added at ꢀ788. After 0.5 h, the mixture was then left to warm to r.t. for 1–3 h, and
H2O was added. The mixture was extracted with Et2O (3ꢁ10 ml). The combined org. extract was washed
with brine, dried (Na2SO4), and finally filtered. The filtrate was concentrated in vacuo to afford 11a, 11e,
and 11h.
1,2,3,4-Tetrahydro-5-methylnaphthalene-1,8-diol (11a). Pale yellow oil (60%). Rf (hexane/AcOEt
7:3) 0.54. IR (film): 3306, 2934, 2863, 1719, 1594, 1473, 1318, 1272, 1172, 1157, 1027, 991, 921, 837, 813, 756,
735. 1H-NMR: 7.51 (s, OH); 6.98 (d, J ¼ 8.1, HꢀC(6)); 6.67 (d, J ¼ 8.4, HꢀC(7)); 5.05 (t, J ¼ 6.3,
HꢀC(1)); 2.57 (t, J ¼ 5.4, CH2(1)); 2.14 (s, Me); 1.92–1.83 (m, CH2(2)); 1.81–1.76 (m, CH2(3)).
13C-NMR: 154.5 (C(1)); 136.7 (C(4a)); 129.9 (C(2)); 27.6 (C(8a)); 123.9 (C(1)); 113.4 (C(3)); 67.9 (C(8));
32.5 (C(7)); 27.1 (C(5)); 19.7 (C(6)); 19.0 (Me).
1,2,3,4-Tetrahydro-5-(prop-2-en-1-yl)naphthalene-1,8-diol (11e). Pale yellow oil (69%). Rf (hexane/
AcOEt 8 :2) 0.51. IR (film): 3351, 3077, 3005, 2935, 2866, 1637, 1593, 1473, 1333, 1271, 1252, 1158, 1071,
993, 913, 819, 757, 713, 667. 1H-NMR: 7.58 (s, OH); 7.00 (d, J ¼ 8.1, HꢀC(6)); 6.71 (d, J ¼ 8.4, HꢀC(7));
5.91–5.85 (m, CH2CH¼CH2); 5.05–5.01 (m, HꢀC(1)); 4.99–4.94 (m, CH2CH¼CH2); 3.26 (d, J ¼ 6.0,
CH2CH¼CH2); 2.64 (t, J ¼ 5.6, CH2(1)); 2.17 (s, CH2(3)), 1.82–1.75 (m, CH2(2)). 13C-NMR: 155.0

1110
CHEMISTRY & BIODIVERSITY – Vol. 8 (2011)
(C(1)); 137.0 (CH2CH¼CH2); 136.7 (C(4a)); 129.8 (C(2)); 123.7 (C(8a)); 115.4 (CH2CH¼CH2); 114.3
(C(3)); 68.1 (C(8)); 36.9 (CH2CH¼CH2); 32.7 (C(7)); 26.6 (C(5)); 19.8 (C(6)).
1,2,3,4-Tetrahydro-8-methoxy-5-(methoxymethyl)naphthalen-1-ol (11h). Oil (61%). Rf (hexane/
AcOEt 7:3) 0.87. IR (film): 3305, 2930, 2860, 1594, 1471, 1318, 1272, 1173, 1156, 1117, 990, 921, 835, 812,
756, 735. 1H-NMR: 7.20 (d, J ¼ 8.4, HꢀC(6)); 6.72 (d, J ¼ 8.4, HꢀC(7)); 5.05 (t, J ¼ 4.4, HꢀC(1)); 4.38 (d,
J ¼ 0.7, MeOꢀCH2); 3.88 (s, MeO); 3.36 (s, MeOꢀCH2); 2.84 (dt, J ¼ 17.3, 5.0, 1 H, CH2(4)); 2.64–2.61
(m, 1 H, CH2(4)); 2.02–1.99 (m, CH2(2)); 1.83–1.77 (m, CH2(3)).
Antimicrobial Assays. All organisms were obtained from the American Type Culture Collection
(Manassas, VA), and include the fungi Candida albicans ATCC 90028, Candida glabrata ATCC 90030,
Candida krusei ATCC 6258, Cryptococcus neoformans ATCC 90113, and Aspergillus fumigatus ATCC
90906, and the bacteria Staphylococcus aureus ATCC 29213, methicillin-resistant Staphylococcus aureus
ATCC 43300 (MRSa), Escherichia coli ATCC 35218, Pseudomonas aeruginosa ATCC 27853, and
Mycobacterium intracellulare ATCC 23068. Susceptibility testing was performed using a modified version
of the CLSI methods [27][28] as described by Samoylenko et al [29]. All organisms were tested using
modified versions of the CLSI (formerly NCCLS) methods. For all organisms excluding M. intracellulare
and A. fumigatus, optical density was used to monitor growth [27][28]. Media supplemented with 5%
Alamar BlueTM (BioSource International, Camarillo, CA) was utilized for growth detection of M.
intracellulare [30][31] and A. fumigatus [32]. Samples (dissolved in DMSO) were serially diluted in 20%
DMSO/saline and transferred (10 ml) in duplicate to 96-well flat-bottom microplates. Inocula were
prepared by correcting the OD630 of microbe suspensions in incubation broth (RPMI 1640/0.2%
dextrose/0.03% glutamine/MOPS, pH 6.0 (Cellgro)) for Candida spp., Sabouraud Dextrose for C.
neoformans, cation-adjusted MuellerꢀHinton (Difco), pH 7.3, for Staphylococcus spp., E. coli, and P.
aeruginosa, 5% Alamar BlueTM (BioSource International, Camarillo, CA) in Middlebrook 7 H9 broth
with OADC enrichment, pH 7.0, for M. intracellulare, and 5% Alamar BlueTM/RPMI 1640 broth (0.2%
dextrose, 0.03% glutamine, buffered with 0.165m MOPS at pH 7.0) for A. fumigatus to afford an assay
volume of 200 ml, and final target inocula of Candida spp. and C. neoformans (1.5ꢁ103), M. intracellulare
(2.0ꢁ106), Staphylococcus spp., E. coli, P. aeruginosa (5.0ꢁ105 CFU/ml), and A. fumigatus (2.7ꢁ
104 CFU/ml). Final sample test concentrations were 1/100th of the DMSO stock concentration. Drug
controls (ciprofloxacin (ICN Biomedicals, Ohio) for bacteria and amphotericin B (ICN Biomedicals,
Ohio) for fungi) were included in each assay. All organisms were read at either 530 nm using the Biotek
Powerwave XS plate reader (Bio-Tek Instruments, Vermont), or 544ex/590em nm, (M. intracellulare, A.
fumigatus) using the Polarstar Galaxy Plate Reader (BMG LabTechnologies, Germany) prior to and after
incubation: Candida spp. at 358 for 46–50 h, Staphylococcus spp., E. coli, and P. aeruginosa at 358 for 16–
20 h, C. neoformans at 358 for 70–74 h, A. fumigatus at 358 for 46–50 h, and M. intracellulare at 378 and
10% CO2 for 70–74 h. IC50 Values (concentrations that afford 50% inhibition relative to controls) were
calculated using XLfit 4.2 software (IDBS, Alameda, CA) and fit model 201. The MIC value is defined as
the lowest test concentration that allows no detectable growth (for M. intracellulare and A. fumigatus, no
color change from blue to pink). Minimum fungicidal or bactericidal concentrations were determined by
removing 5 ml from each clear (or blue) well, transferring to agar and incubating as previously mentioned.
The MFC/MBC is defined as the lowest test concentration that kills the organism (allows no growth on
agar). Drug controls ciprofloxacin (ICN Biomedicals, Ohio) for bacteria and amphotericin B (ICN
Biomedicals, Ohio) for fungi were included in each assay.
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Received February 17, 2010