Diastereoselective Intramolecular Heck Reaction Assisted by an Acetate Group: Synthesis of the Decahydrobenzofluorene Derivative Dasyscyphin e

Article abstract of DOI:10.1021/acs.joc.7b01551

The first synthesis of antifungal sesquiterpene quinol dasyscyphin E was achieved starting from trans-communic acid. The process described involves the first diastereoselective synthesis of this type of compound by cyclization of an aryl bicyclosesquiterpene. The acid was efficiently transformed into a sesquiterpene synthon, which was converted into the corresponding bromoaryl sesquiterpene. The key step of synthetic sequence was the cyclization of the latter under Heck reaction conditions, which yielded the tetracyclic skeleton of the target compound with complete diastereoselectivity. The participation of an acetate group is decisive, both for the course of the Heck reaction and for the stereoselectivity of the process.

Full text of DOI:10.1021/acs.joc.7b01551

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Article
Diastereoselective Intramolecular Heck Reaction Assisted by an Acetate
Group: Synthesis of the Decahydrobenzofluorene Derivative Dasyscyphin E
Fermín Jiménez, Antonio Fernández, Ettahir Boulifa, Ahmed Ibn Mansour,
Ramon Alvarez-Manzaneda, Rachid Chahboun, and Enrique Alvarez-Manzaneda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01551 • Publication Date (Web): 15 Aug 2017
Downloaded from http://pubs.acs.org on August 15, 2017
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Diastereoselective Intramolecular Heck Reaction
Assisted by an Acetate Group: Synthesis of the
Decahydrobenzofluorene Derivative Dasyscyphin E
†
†
‡
‡
Fermín Jiménez, Antonio Fernández, Ettahir Boulifa,
Ahmed Ibn Mansour, Ramón
Alvarez-Manzaneda,§ Rachid Chahboun†* and Enrique Alvarez-Manzaneda†*
†Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología,
Universidad de Granada, 18071 Granada, Spain.
‡Laboratoire de Chimie Organique Appliquée, Département de Chimie, Faculté des Sciences,
Université Abdelmalek Essaâdi, Tetouan, Morocco.
§Area de Química Orgánica, Departamento de Química y Física, Universidad de Almería, 04120
Almería, Spain.
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OBn
Br
AcO
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CHO
H
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3 steps
(81%)
6 steps
(51%)
5 steps
(78%)
OH
H
H
H
H
H
H
H
OH
dasyscyphin E
COOMe
COOMe
COOMe
trans-communic acid
methyl ester
ABSTRACT
The first synthesis of antifungal sesquiterpene quinol dasyscyphin E has been achieved starting
from trans-communic acid. The process described involves the first diastereoselective synthesis
of this type of compound by cyclization of an aryl bicyclosesquiterpene. The acid was efficiently
transformed into a sesquiterpene synthon, which was converted into the corresponding
bromoaryl sesquiterpene. The key step of synthetic sequence was the cyclisation of the latter
under Heck reaction conditions, which yielded the tetracyclic skeleton of the target compound
with complete diastereoselectivity. The participation of an acetate group is decisive, both for the
course of the Heck reaction as for the stereoselectivity of the process.
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INTRODUCTION
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During the last decade,
a
series of compounds with
a
tetracyclic 6/6/5/6
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(decahydrobenzofluorene) skeleton exhibiting remarkable biological activity have been isolated
from different natural sources. Among these two main groups of compounds can be
distinguished: those presenting a trans B/C junction and those with a cis B/C union. Pelorol (1),1
which can activate the inositol 5-phosphatase (SHIP),2 belongs to the first group. Other examples
of trans B/C fused compounds are walsucochins A (2) and B (3), with significant protective
activity against H2O2-induced PC12 cell damage,3 and the neuroprotective walsucochinoids A
(4) and B (5).4 Compounds with a cis B/C union include akaol A (6),5 the cytotoxic dasyscyphin
B (7)6 and the antifungal dasyscyphins D (8) and E (9) (Figure 1).7
Only a few syntheses of this type of interesting compound have been reported, probably due to
the difficulty involved in obtaining them, particularly those with a cis B/C junction.
In 2005, Andersen et al reported the synthesis of the trans B/C fused metabolite pelorol A (1);
the construction of the C ring, a key step of the sequence, was achieved after the electrophilic
cyclisation of an aryl bicyclofarnesol, derived from (+)-sclareolide, after some difficulty.8 She et
al. reported a total synthesis of dasyscyphin D (8) by successive Robinson annulations of an
indanone prepared after a PtCl2-catalysed pentannulation.9 More recently, these authors
described an enantioselective total synthesis of (-)-walsucochin B (3), via a cationic polyolefin
cyclisation initiated by chiral epoxide.10 Our own group has previously reported enantiospecific
syntheses for akaol A (6) and dasyscyphin B (7), utilising Diels-Alder cycloadditions.11
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HO
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D
C
H
H
H
COOMe
O
OH
HO
O
A
H
H
B
H
3
2
1
O
R1
HO
R2
OR1
OH
R3
O
OH
H
H
H
R1
R
OH
O
H
R2
H
H
O
8 R1: OH, R2: H
9 R1: H, R2: OH
4 R: i-Pr; R1: Me
R1: H
6 R1: OH, R2:H, R3: MeOCH2
7 R1: H, R2: MeOCH2, R3: OH
5
R:
Figure 1. Some natural decahydrobenzofluorene derivatives.
In this paper we tackle the first synthesis of dasysycyphin E (9) by diastereoselective
cyclization of an aryl bicyclofarnesane.
RESULTS AND DISCUSSION
Although at first sight the cyclisation of aryl bicyclofarnesanes, as achieved by Andersen in the
synthesis of pelorol (1), would seem to be a suitable method to access this type of benzofluorene
derivative, this process has two main drawbacks that must be overcome. Firstly, constructing the
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cyclopentane C ring through intramolecular Friedel-Crafts processes of aryl bicyclic
sesquiterpenes is a very difficult task, as Andersen et al observed, requiring the use of activated
aromatic precursors. Furthermore, electrophilic cyclisations of aryl bicyclofarnesanes afford the
8R diastereoisomer as the main compound, as in the case of pelorol (1), and do not appear to be
suitable for synthesising compounds such as 6-9. The problem of constructing the cyclopentane
C ring can be circumvented by means of a highly reactive aryl allyl cation, which undergoes fast
cyclisation even when non-activated aromatic rings are used. This strategy has been utilised by
our group and others in the construction of the 6/5/6 taiwaniaquinoid skeleton.12 The possibility
of applying a similar procedure to the construction of the 6/6/5/6 skeleton of benzofluorene
derivatives was previously explored in our laboratory. For this purpose the aryldiene 15 was
prepared, starting from the sesquiterpene aldehyde 1213 (Scheme 1).14 The allyl alcohol 14,15 was
transformed into diene 15 after treatment with cationic resin. As expected, compound 15
underwent intramolecular Friede-Crafts alkylation to give the corresponding tetracyclic
compound 16, with the benzofluorene skeleton characteristic of target compounds.
Unfortunately, however, after assaying different acid conditions a mixture of 8-epimers, in which
the unwished-for 8R isomer 16a was the major constituent, was obtained. When the reaction was
performed with cationic resin at room temperature, a 3:1 mixture resulted; with SnCl4 at 0 ºC,
compound 16a was obtained as the only stereoisomer. Recently, Bisai et al. reported similar
results in the synthesis of akaol A (6).15 To explore the possibility of achieving the desired 8S
configuration through Se-induced cyclisation, the aryl diene 15 was subjected to cyclisation with
SnCl4 in the presence of N-phenylselenophthalimide (NPSP); however, under these conditions
the tetracyclic naphthalene derivative 17 was obtained (Scheme 1).
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Scheme 1. Attempts to synthesize benzofluorene derivatives.
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OMe
OMe
MeO
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MeO
HO
OMe
Br
OMe
1) n-BuLi, THF, -78 ºC
A-15 Amberlyst
CH2Cl2, rt
10 min (90%)
2) 12, THF, -78 ºC, 1h
H
H
14
(93%)
13
15
NPSP, SnCl4
CH2Cl2, -78 ºC
2 h (89%)
SnCl4, CH2Cl2
0 ºC, 1h (72%)
OMe
MeO
MeO
OMe
CHO
8
H
H
H
12
17
16a (8R)
A possible mechanism for the transformation of aryldiene 15 into the tetracyclic compound
17 is depicted in Scheme 2. The coordination of SnCl4 with the Se atom in the expected
intermediate II, resulting from diastereoselective cyclisation, promotes contraction of the B ring,
leading to the benzyl cation IV, the deprotonation of which finally yields the aromatic compound
17.
Scheme 2. A possible mechanism for the transformation of aryl diene 15 into compound 17.
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OMe
MeO
OMe
MeO
MeO
OMe
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NPSP
SnCl4
Se Ph
Se
Ph
H
H
H
II
I
15
SnCl4
MeO
OMe
MeO
OMe
OMe
Cl
MeO
-H+
H
H
Se Sn
H
Cl
H
17
Ph Cl
III
IV
The unsatisfactory diastereoselectivity of the above cationic cyclisation of aryl sesquiterpenes
prompted us to investigate new synthetic strategies towards benzofluorene derivatives with a 8S
configuration, such as compounds 6-9. We focus on the synthesis of dasyscyphin E (9), not yet
synthesised. The tetracyclic carbon skeleton of target compounds with the suitable 8S
configuration will be achieved after a Heck reaction-based cyclisation of an aryl sesquiterpene
obtained from an A ring functionalised sesquiterpene aldehyde and the suitable aryllithium. A
precedent could be found on the synthesis of taiwaniaquinoids, with a 6/5/6 skeleton. The
cyclopentane ring of this type of compound has previously been obtained by utilising an
intramolecular Heck reaction; although the reported processes were not diastereoselective.
Banerjee et al cyclised a benzyl methylenecyclohexene, obtaining the desired tricyclic compound
in moderate yield and low diastereoselectivity.16 Similarly, Node et al utilised an aryldiene as the
substrate, obtaining the corresponding dehydroderivative in good yield.17 Even though the Heck
cyclisation of aryldiene seems to be more favourable, its preparation is troublesome and the
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stereochemistry obtained after hydrogenation of the carbon-carbon double bond remains
impredictable.
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In this paper, we study the use of the Heck reaction in the construction of the 6/6/5/6 skeleton
of target compounds with the suitable 8S configuration. In a first approach, the A ring
functionalised bicyclofarnesane could be prepared starting from the suitable diterpene trans-
communic acid (10), after the side chain degradation. However, this process involves some
difficulties, because the exocyclic carbon-carbon double bond is also affected during the
oxidative degradation of the side chain, as previous studies revealed. This complication may
explain why, despite its accessibility, very little use has been made of this acid as a starting
product.18,19 Scheme 3 shows the synthetic sequence we have developed for obtaining gram-scale
formyl esters 23 and 24 from methyl ester 11.
Scheme 3. Scalable synthesis of sesquiterpene formyl esters 23 and 24.
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OAc
OH
I2/PPh3 (cat)
1) O3,
CH2Cl2-MeOH (5:1)
-78 ºC, 3 h
H
H
Ac2O,CH2Cl2,
rt, 1 day (93%)
2) NaBH4,
-78 ºC - rt
15 h (79%)
H
H
H
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COOR
COOMe
COOMe
18
10 R: H
11 R: Me
19
Na2CrO4, benzene
Ac2O - AcOH (1.3:1)
NaOAc, 75 ºC,13 h (91%)
OAc
O
OH
1) O3, CH2Cl2
-78 ºC, 1h
DBU, toluene
4 A molecular sieves
reflux, 3 days (92%)
O
H
H
2) NaBH4, -78 ºC - rt
14 h (93%)
OH
COOMe
H
COOMe
COOMe
21
20
22
BF3.OEt2
CH2Cl2, 0 ºC
30 min (92%)
BF3.OEt2
CH2Cl2-toluene (5:1)
-35 ºC, 1h (89%)
CHO
CHO
H
H
H
COOMe
COOMe
24
23
The reductive ozonolysis of ester 11 gave hydroxy ester 18, which was directly converted into
the tetrasubstituted acetoxy alkene 19, utilising a new acetylation procedure developed in our
laboratory, which involves treatment with Ac2O (1-2 equiv) in the presence of catalytic I2/PPh3
in dichloromethane. These reagents give rise to a first acetylation of the hydroxyl group, a
process not yet described, and the further known carbon-carbon double bond isomerization.20
Compound 19 was then oxidised to the α,β-enone 20 and then refluxed with DBU in benzene,
producing the dienone 21, which was converted into dihydroxy ester 22. Treatment of the latter
with BF3-OEt2 at -35 °C finally yielded ketoester 23 as the sole regioisomer. When the reaction
was carried out at 0 °C the α,β-unsaturated aldehyde 24 was obtained. Compounds 23 and 24
would seem to be suitable precursors of A ring functionalised aryl sesquiterpenes, such as
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adociaquinol and adociasulfate 11,21 inhibitors of the kinesin motor protein,22 and jaspic acid,
which inhibits human 15-lipoxygenase.23 Compound 23 is an immediate precursor of a series of
metabolites recently reported.24
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Next, aryl sesquiterpenes, such as compounds 30-32, were synthesised starting from ester 23.
The preparation of acetoxyester 30 is depicted in Scheme 4. Alcohol 26, after acetylation and
catalytic hydrogenolysis of the Bn group, led to acetoxyphenol 28, whose 12R configuration was
confirmed by X ray diffraction (Fig. 2). This was further brominated and O-benzylated, finally
affording compound 30.25
Scheme 4. Synthesis of aryl sesquiterpene 30 from ketoester 23
OBn
OBn
HO
H
AcO
H
Br
1) n-BuLi, THF, -78ºC
Ac2O/Pyr, CH2Cl2
H
H
2) 23, THF, -78ºC
10 min (93%)
cat. DMAP, rt
1 h (96%)
OBn
COOMe
COOMe
27
25
26
H2, Raney-Ni
THF, rt, 5 h
(98%)
OH
OH
OBn
Br
Br
AcO
AcO
AcO
NBS (1 eq), cat iPr2NH
K2CO3, BnBr
H
H
H
CH2Cl2, rt, 45 min
(91%)
acetone, reflux
12 h (98%)
H
H
H
COOMe
COOMe
COOMe
28
29
30
The next step in the process was to construct the cyclopentane C ring. Cyclisations of aryl
sesquiterpenes 30-32 under different Heck-reaction conditions, including Pd(OAc)2 or Pd(PPh3)4
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or PdCl2(PPh3)2, in the presence of PPh3 or Bu4NCl, utilising bases such as Cs2CO3 or K2CO3 or
Ag2CO3 in DMF, acetonitrile or toluene as a solvent, were assayed. Triflate 31 was recovered
unaltered under all the conditions applied, for example after treatment with Pd(OAc)2, PPh3 and
Cs2CO3 (entry 1, Table 1). In the view that the lack of reactivity might be caused by the bulky
triflate group, bromide 32 was then assayed. This substance presented a similar behaviour to that
of triflate 31, remaining unaltered in most cases (entry 2). Interestingly, and to our great
satisfaction, aryl sesquiterpene 30, bearing an acetyloxy group at C-11, underwent the desired
cyclisation with complete diastereoselectivity, thus affording the tetracyclic compound 34 under
all the conditions assayed; the best results are shown in Table 1 (entry 3) (Scheme 5). The
structure of compound 34 was established on the basis of 1D and 2D NMR experiments (HSQC,
gCOSY, gHMBC and NOESY). The above results seem indicate that substituents at C-11 cause
a steric hindrance which generates a conformational bias toward cyclization; moreover, the
coordination of the acetyloxy group located above the decaline carbon-carbon double bond with
the palladium atom should favour the coupling at the upper face (Fig. 3). It is significant that
when the reaction was carried out in the presence of HCO2Na, to promote the simultaneous
reduction of the expected carbon-carbon double bond of the final compound, no cyclisation took
place; instead, the reduction of bromide and benzyl ether occurred, and phenol 28 was obtained
(entry 4) (Scheme 5). Under the latter conditions, bromide 32 was partially reduced to compound
33 (entry 5).
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Figure 2. ORTEP drawing of acetoxyphenol 28 showing thermal ellipsoids at the 50%
probability level (CCDC 1549031).
Table 1. Attempts to achieve the cyclisation of aryl sesquiterpenes under different Heck-reaction
conditions
AcO 11
OBn
OMe
OMe
Br
OTf
R
H
H
H
H
H
H
COOMe
COOMe
COOMe
30
31
32 R: Br
33 R: H
Entry
1
Starting material
Conditions
Pd(OAc)2, PPh3, Cs2CO3 DMF, 105 °C, 30 h
Products
31
No reaction
2
32
Pd(OAc)2, PPh3, Cs2CO3 DMF, 105 °C, 27 h No reaction
3
4
5
30
30
32
Pd(OAc)2, PPh3, Cs2CO3 DMF, 100 °C, 12 h
Pd(OAc)2, PPh3, HCO2Na, DMF, 100 °C, 15 h
Pd(OAc)2, PPh3, HCO2Na, DMF, 100 °C, 13 h
34 (89%)
28 (71%)
32 (61%)
33 (18%)
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Figure 3. Possible participation of the acetyloxy group on the course of the Heck reaction
When diol 35, resulting from the reduction of compound 34 with LiAlH4, was treated with
hydrogen in the presence of Pd-C, no reaction occurred. When the hydrogenation was carried out
at 4 atmospheres in the presence of Adams’ catalyst, the simultaneous deprotection of the phenol
group and removal of benzylic alcohol took place, yielding dasyscyphin E (5). The over-
reduction compound 36 resulted when hydrogenation was carried out in the presence of HClO4
(Scheme 5). The synthetic dasyscyphin E (9) had identical physical properties to those
previously reported.7
Scheme 5. Synthesis of dasyscyphin E (9) from ester 30.
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OBn
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Br
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9
HO
H
AcO
AcO
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LiAlH4, Et2O
Table 1
OBn
H
H
OBn
H
(entry 3)
0 ºC -rt, 13 h
(97%)
H
H
OH
35
COOMe
COOMe
PtO2, AcOH,
HClO4, H2, 4 atm
14 h, rt (91%)
30
34
Table 1
(entry 4)
PtO2, EtOAc
H2, 4 atm
13.h, rt (94%)
H
AcO
H
OH
H
H
H
H
OH
H
H
OAc
COOMe
OH
dasyscyphin E (9)
36
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CONCLUSIONS
In summary, the first synthesis of dasyscyphin E (9) from trans-communic acid (10), via the
versatile sesquiterpene synthon 23, is reported. The key step of the synthesis sequence is the
diastereoselective cyclisation of a bromoaryl sesquiterpene under a Heck reaction assisted by an
acetate group.
EXPERIMENTAL SECTION
General Procedures
Unless stated otherwise, reactions were performed in oven-dried glassware under an
argon atmosphere using dry solvents. Solvents were dried as follows: Tetrahydrofuran (THF),
diethyl ether (Et2O), toluene and benzene over Na-benzophenone. Dichloromethane (DCM) and
methanol (MeOH) over CaH2. Dimethylformamide (DMF) and ethyl acetate (AcOEt) were dried
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over 4Å molecular sieves. Thin-layer chromatography (TLC) was performed using F254
precoated plates (0.25 mm) and visualized by UV fluorescence quenching and phosphomolybdic
acid solution in ethanol staining. Flash chromatography was performed on silica gel (230-400
mesh). Chromatography separations were carried out by conventional column on silica gel 60
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(230-400 Mesh), using hexanes-AcOEt (AcOEt-hexane) mixtures of increasing polarity. H and
13C NMR spectra were recorded at 600, 500 and 400 MHz, and at 150, 125 and 100 MHz,
respectively. CDCl3 was treated with K2CO3. Chemical shifts (δ H) are quoted in parts per
million (ppm) referenced to the appropriate residual solvent peak and tetramethylsilane. Data for
1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant
(Hz), integration), with the abbreviations s, br s, d, br d, t, q, sext and m denoting singlet, broad
singlet, doublet, broad doublet, triplet, quartet, sextet and multiplet, respectively. J = coupling
constant in Hertz (Hz). Data for 13C NMR spectra are reported in terms of chemical shift relative
to Me4Si (δ 0.0) and the signals were assigned utilizing DEPT-135 experiments (with CH and
CH3 signals in opposite phase to CH2 signals) and on the basis of heteronuclear correlations.
Infrared spectra (IR) were recorded as thin films or as solids on a FTIR spectrophotometer with
samples between sodium chloride plates or as potassium bromide pellets and are reported in
frequency of absorption (cm–1). Only selected absorbances (νmax) are reported. ([α]D)
measurements were carried out in a polarimeter; utilizing a 1dm length cell and CHCl3 as a
solvent. Concentration is expressed in mg/mL. HRMS were recorded on a spectrometer, utilizing
a Q-TOF analyzer, and ESI+ ionization.
Experimental Procedures
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(2,3-Dimethoxy-5-methylphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-
octahydronaphthalen-1-yl)methanol (14).
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To a solution of bromobenzene 13 (2.1 g, 9.54 mmol) in dry THF (20 mL) was carefully added
n-butyllithium (9.6 mmol) at -78 °C under an argon atmosphere, and the reaction mixture was
stirred at this temperature for 30 min. Then a precooled solution of aldehyde 12 (2.0 g, 9.00
mmol) in dry THF (15 mL) was syringed to the first solution and the reaction mixture was stirred
for a further 1 h at which time TLC showed no starting material. The reaction was quenched with
water (5 mL), the solvent was removed under vacuum, and the mixture was extracted with ether
(2 x 20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL),
dried over anhydrous Na2SO4 and the solvent was evaporated to give a crude product, which was
purified by flash chromatography on silica gel (20% ether/Hexane), affording 3.35 g of 14 (93%)
(a 1:1 mixture of diastereomers) as white solid.
(4aS,8aS,E)-5-(2,3-dimethoxy-5-methylbenzylidene)-1,1,4a,6-tetramethyl-1,2,3,4,4a,5,8,8a-
octahydronaphthalene (15).
To a solution of 14 (225 mg, 0.60 mmol) in dichloromethane (15 mL) was added amberlyst A-15
ion-exchange (200 mg) and the reaction mixture was stirred at room temperature for 10 min.
Filtration and concentration gave 191 mg of 15 (90%) as a colorless syrup. [α]D25= - 105.2 (c 1.0,
1
CHCl3). H NMR (500 MHz, Chloroform-d) δ (ppm) 0.84 (m, 1H), 0.89 (s, 3H), 0.95 (s, 3H),
1.04 (s, 3H), 1.17 – 1.26 (m, 2H), 1.43 – 1.50 (m, 2H), 1.54 – 1.72 (m, 3H), 1.84 (d, J = 11.8 Hz,
1H), 2.01 – 2.10 (m, 2H), 2.15 (s, 3H), 2.25 (m, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 5.53 (s, 1H), 6.20
(s, 1H), 6.60 (s, 1H), 6.63 (s, 1H). 13C NMR (125 MHz, Chloroform-d) δ (ppm) 19.5 (CH2), 19.7
(CH3), 20.3 (CH3), 22.1 (CH3), 23.3 (CH3), 25.3 (CH2), 32.8 (CH3), 34.0 (C), 38.4 (CH2), 38.8
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(C), 42.5 (CH2), 48.5 (CH), 56.0 (CH3), 56.3 (CH3), 112.7 (CH), 113.4 (CH), 119.3 (CH), 128.3
(C), 128.4 (CH), 131.9 (C), 132.3 (C), 146.5 (C), 147.5 (C), 151.3 (C). IR (film): 1718, 1685,
1617, 1560, 1454, 1261, 1219, 1109 cm-1. HRMS (APcl) m/z: calcd for C24H34O2Na (M+Na+)
377.2457, found: 377.2451.
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(4aS,6aR,11bS)-9,10-dimethoxy-4,4,6a,7,11b-pentamethyl-2,3,4,4a,5,6,6a,11b-octahydro-
1H-benzo[a]fluorene (16a).
Tin (IV) chloride (0.04 mL, 0.32 mmol) was added to a stirred solution of 15 (115 mg, 0.32
mmol) in dry dichloromethane (10 mL) cooled to 0 °C, and the reaction was further stirred for 60
min, at which time TLC showed no starting material. Then the reaction mixture was cooled to 0
°C and water (2 mL) was added dropwise. The mixture was concentrated in vacuo, ether - water
(25:10 mL) was added, and the mixture was washed with brine (3 x 10 mL). The organic phase
was dried over anhydrous Na2SO4 and the solvent was evaporated to give a crude product, which
was purified by flash chromatography on silica gel (5% ether/hexanes), affording 81 mg of 16a
(72%), as white solid; mp 95-97 ºC. [α]D25= - 56.3 (c 1.1, CHCl3). H NMR (500 MHz,
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Chloroform-d) δ (ppm) 0.86 (s, 3H), 0.94 (s, 3H), 1.19 (ddd, J = 20.3, 8.7, 5.0 Hz, 2H), 1.26 (s,
3H), 1.49 (s, 3H), 1.53 -1.90 (m, 8H), 2.34 (s, 3H), 2.54 (ddd, J = 10.3, 6.8, 3.6 Hz, 1H), 3.84 (s,
13
3H), 3.86 (s, 3H), 6.17 (s, 1H), 6.58 (s, 1H). C NMR (125 MHz, Chloroform-d) δ (ppm) 18.3
(CH3), 18.8 (CH2), 19.3 (CH2), 19.8 (CH3), 21.8 (CH3), 22.8 (CH3), 33.7 (CH3), 33.9 (C), 37.9
(CH2), 38.7 (CH2), 39.4 (C), 42.5 (CH2), 52.7 (C), 56.3 (CH3), 56.9 (CH3), 61.0 (CH), 112.7
(CH), 115.3 (CH), 124.6 (C), 135.0 (C), 143.5 (C), 145.9 (C), 150.5 (C), 166.4 (C). IR (KBr):
1719, 1654, 1560, 1542, 1489, 1253, 1114, 1056 cm-1. HRMS (APcl) m/z: calcd for C24H34O2Na
(M+Na+) 377.2457, found: 377.24552.
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(4aS,11aS)-6,7-dimethoxy-1,1,4a,9,10-pentamethyl-2,3,4,4a,11,11a-hexahydro-1H-
benzo[b]fluorene (17).
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To a solution of N-(phenylseleno)phathalimide (132 mg, 0.44 mmol) and tin(IV) chloride (0.05
mL, 0.40 mmol) in dry dichloromethane (15 mL) was added 15 (128 mg, 0.36 mmol) at -78 °C
and the resulting mixture was stirred for 2 h at the same temperature. The mixture was quenched
by addition of sat. aq. NaHCO3 and extracted by dichloromethane twice. The organic layer
combined was dried over anhydrous Na2SO4 and the solvent was evaporated to give a crude
product, which was purified by flash chromatography on silica gel (5% ether/hexanes), affording
113 mg of 17 (89%), as a colorless syrup. [α]D25= - 7.7 (c 1.0, CHCl3). H NMR (500 MHz,
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Chloroform-d) δ (ppm) 1.02 (s, 3H), 1.08 (s, 3H), 1.10 (s, 3H), 1.18 – 1.36 (m, 2H), 1.50 – 1.60
(m, 2H), 1.70 (m, 1H), 1.87 (ddt, J = 13.6, 7.6, 6.8 Hz, 1H), 2.18 (m, 1H), 2.62 (s, 3H), 2.71 (t, J
= 13.8 Hz, 1H), 2.83 (s, 3H), 2.89 (dd, J = 14.6, 6.3 Hz, 1H), 3.84 (s, 3H), 3.95 (s, 3H), 7.06 (s,
1H), 7.32 (s, 1H). 13C NMR (150 MHz, Chloroform-d) δ (ppm) 19.1 (CH3), 20.2 (CH2), 20.6
(CH3), 21.2 (CH3), 22.5 (CH3), 29.1 (CH2), 33.3 (C), 33.5 (CH3), 36.3 (CH2), 41.8 (CH2), 45.9
(C), 57.1 (CH3), 59.2 (CH3), 61.3 (CH), 112.3 (CH), 115.4 (CH), 127.6 (C), 128.9 (C), 129.4
(C), 130.6 (C), 141.6 (C), 144.4 (C), 148.7 (C), 152.3 (C). IR (film): 1735, 1605, 1578, 1558,
1419, 1361, 1152, 1039, 989 cm-1. HRMS (APcl) m/z: calcd for C24H32O2Na (M+Na+) 375.2300,
found: 375.2307.
(1S,4aR,5S,8aR)-methyl
5-(2-hydroxyethyl)-1,4a-dimethyl-6-
methylenedecahydronaphthalene-1-carboxylate (18).
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An ozone stream was bubbled into a solution of 11 (15 g, 47.40 mmol) into a 10 : 1 mixture of
CH2Cl2 and MeOH (400 : 40 mL) cooled at -78 ºC and the course of the reaction was monitored
by TLC. When the starting material was consumed (3 h), the solution was flushed out with an
argon stream for eliminating the ozone excess. Then, NaBH4 (5.49 g, 142.19 mmol) was added to
the cooled solution and stirred for 15 h letting the temperature increase to room temperature, at
which time TLC showed no ozonide remaining. The reaction was quenched with water (60 mL)
at 0 ºC, the phases were shaken and separated and the organic phase was washed with water (2 x
60 mL), brine (2 x 60 mL), dried over anhydrous Na2SO4 and filtered. Removal of the solvent
under vacuum afforded a crude product which was purified by flash chromatography on silica
gel (15 % AcOEt/Hexane) to yield alcohol 18 (10.50 g, 79 %) as a white solid; mp 88-90 ºC.
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[α]D25= + 45.1 (c 0.9, CHCl3). H NMR (500 MHz, Chloroform-d) δ (ppm) 0.52 (s, 3H), 1.01 –
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1.17 (m, 2H), 1.19 (s, 3H), 1.34 (dd, J = 12.6, 3.0 Hz, 1H), 1.44 (s, 1H), 1.50 – 1.57 (m, 1H),
1.61 – 2.06 (m, 8H), 2.18 (d, J = 13.3 Hz, 1H), 2.41 (dt, J = 9.9, 2.4 Hz, 1H), 3.49 – 3.56 (m,
1H), 3.62 (s, 3H), 3.69 – 3.77 (m, 1H), 4.55 (s, 1H), 4.86 (s, 1H). 13C NMR (125 MHz,
Chloroform-d) δ (ppm) 12.6 (CH3), 19.9 (CH2), 26.2 (CH2), 27.2 (CH2), 28.8 (CH3), 38.2 (CH2),
38.6 (CH2), 39.1 (CH2), 40.0 (C), 44.3 (C), 51.1 (CH), 52.1 (CH3), 56.3 (CH), 62.4 (CH2), 106.5
(CH2), 148.3 (C), 177.7 (C). IR (KBr): 3368, 2932, 2848, 1724, 1644, 1448, 1384, 1229, 1153,
1046, 889, 774 cm-1. HRMS (ESI) m/z: calcd for C17H29O3 (M+H+) 281.2117, found: 281.2120.
(1S,4aS,8aR)-methyl
5-(2-acetoxyethyl)-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalene-1-carboxylate (19).
To a solution of PPh3 (1.2 g, 4.6 mmol) in dry CH2Cl2 (20 mL) was added I2 (1.17 g, 4.6 mmol)
and the mixture was stirred at room temperature for 5 min. After that time, the mixture was
added via cannula over a solution of 18 (2.80 g, 10 mmol) in CH2Cl2 (60 mL) which it was
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previously added acetic anhydride (2 mL, 20 mmol). The resulting mixture was stirred at room
temperature for 24 h, the solvent was removed under vacuum and the crude product was directly
purified by flash chromatography on silica gel (95 % AcOEt/Hexane) to give the compound 19
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(3 g, 93 %) as a white solid; mp 70-72 ºC. [α]D25= + 103.5 (c 1.1, CHCl3). H NMR (500 MHz,
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Chloroform-d) δ (ppm) 0.76 (s, 3H), 1.00 (ddd, J = 13.7, 13.6, 4.7 Hz, 1H), 1.09 (ddd, J = 13.4,
13.2, 4.1 Hz, 1H), 1.20 (s, 3H), 1.30 (d, J = 1.8 Hz, 1H), 1.47 – 1.58 (m, 1H), 1.65 (s, 3H), 1.66
– 1.77 (m, 2H), 1.83 (dt, J = 13.8, 3.7 Hz, 1H), 1.88 (d, J = 13.3 Hz, 1H), 1.92 – 2.02 (m, 2H),
2.04 (s, 3H), 2.18 – 2.29 (m, 2H), 2.38 (td, J = 12.3, 11.8, 5.9 Hz, 1H), 3.63 (s, 3H), 4.00 (ddd, J
= 16.5, 10.8, 5.9 Hz, 1H) 4.01 (ddd, J = 16.6, 10.7, 5.8 Hz, 1H). 13C NMR (125 MHz,
Chloroform-d) δ (ppm) 17.6 (CH3), 19.5 (CH2), 19.9 (CH3), 20.7 (CH2), 21.0 (CH3), 27.3 (CH2),
28.4 (CH3), 34.3 (CH2), 37.1 (CH2), 37.6 (CH2), 39.2 (C), 43.9 (C), 51.1 (CH3), 53.4 (CH), 64.0
(CH2), 129.9 (C), 134.3 (C), 171.0 (C), 177.9 (C). IR (film): 2949, 1726, 1467, 1381, 1234,
1161, 1139, 1030 cm-1. HRMS (ESI) m/z: calcd for C19H31O4 (M+H+) 323.2222, found:
323.2216.
(1S,4aS,8aR)-methyl
5-(2-acetoxyethyl)-1,4a,6-trimethyl-7-oxo-1,2,3,4,4a,7,8,8a-
octahydronaphthalene-1-carboxylate (20).
To a solution of acetate 19 (4.0 g, 12.35 mmol) in benzene (60 mL) were added Na2CrO4 (3 g,
18.52 mmol), Ac2O (13 mL), AcOH (10 mL) and AcONa (4 g). The mixture was heated to 75 ºC
for 13 h until TLC showed no starting material. After cooling at 0 ºC, the reaction was quenched
with water (25 mL) and the solvent was removed under vacuum. The resulting mixture was
diluted with CH2Cl2 (70 mL) washed with water (5 x 30 mL), saturated aqueous NaHCO3
solution (3 x 20 mL), brine and dried over Na2SO4. Removal of the solvent in vacuum afforded a
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crude product which was purified by flash chromatography in silica gel (15 % AcOEt/Hexane) to
obtain the enone 20 (3.80 g, 91 %) as a white solid; mp 68-70 ºC. [α]D25= + 236.3 (c 1.1, CHCl3).
1H NMR (500 MHz, Chloroform-d) δ (ppm) 0.94 (s, 3H), 1.08 (ddd, J = 13.5, 13.5, 4.2 Hz, 1H),
1.20 (s, 3H), 1.31 (ddd, J = 13.1, 13.0, 4.2 Hz, 1H), 1.64 (dt, J = 14.6, 3.7 Hz, 1H), 1.83 (s, 3H),
1.87 (d, J = 3.5 Hz, 1H), 1.92 (dt, J = 13.9, 3.7 Hz, 1H), 1.99 – 2.04 (m, 1H), 2.06 (s, 3H), 2.27
(d, J = 13.5 Hz, 1H), 2.54 (ddd, J = 12.8, 10.3, 6.0 Hz, 1H), 2.62 (ddd, J = 12.8, 10.4, 6.0 Hz,
1H), 2.76 (dd, J = 17.5, 3.4 Hz, 1H), 2.91 (dd, J = 17.5, 14.7 Hz, 1H), 3.67 (s, 3H), 4.08 (ddd, J
= 10.6, 10.5, 6.0 Hz, 1H), 4.16 (ddd, J = 10.6, 10.5, 5.9 Hz, 1H). 13C NMR (125 MHz,
Chloroform-d) δ (ppm) 11.8 (CH3), 15.7 (CH3), 19.1 (CH2), 20.9 (CH3), 27.7 (CH3), 28.9 (CH2),
36.1 (CH2), 36.6 (CH2), 37.3 (CH2), 41.1 (C), 43.6 (C), 50.7 (CH), 51.5 (CH3), 62.3 (CH2), 132.6
(C), 160.4 (C), 170.8 (C), 177.0 (C), 199.4 (C). IR (film): 2942, 1739, 1726, 1667, 1465, 1380,
1334, 1231, 1192, 1161, 1035, 981, 773 cm-1. HRMS (ESI) m/z: calcd for C19H29O5 (M+H+)
337.2015, found: 337.2016.
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(1S,4aS,8aR)-methyl
1,4a,6-trimethyl-7-oxo-5-vinyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalene-1-carboxylate (21).
To a solution of 20 (2.00 g, 5.95 mmol) in dry toluene (40 mL) were added 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (1.8 mL, 11.89 mmol) and 4 Å molecular sieves (2 g).
The mixture was heated under reflux for 3 days, at which time TLC showed no starting material.
After the mixture was cooled, and toluene was removed under vacuum resulting in a crude that
was directly purified into silica gel (10 % AcOEt/Hexane) affording the unsaturated ketone 21
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(1.51 g, 92 %) as a yellow syrup. [α]D25= + 96.9 (c 0.9, CHCl3). H NMR (400 MHz,
Chloroform-d) δ (ppm) 0.94 (s, 3H), 1.03 (ddd, J = 13.6, 13.4, 4.1 Hz, 1H), 1.17 (s, 3H), 1.25
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(ddd, J = 13.4, 13.2, 4.2 Hz, 2H), 1.54 (d, J = 14.4 Hz, 1H), 1.76 (s, 3H), 1.86 (td, J = 13.7, 13.0,
3.6 Hz, 2H), 2.21 (d, J = 13.6 Hz, 1H), 2.73 (dd, J = 17.7, 3.5 Hz, 1H), 2.92 (dd, J = 17.7, 14.6
Hz, 1H), 3.64 (s, 3H), 5.07 (d, J = 17.7 Hz, 1H), 5.44 (d, J = 11.5 Hz, 1H), 6.25 (dd, J = 17.8,
11.7 Hz, 1H). 13C NMR (100 MHz, Chloroform-d) δ (ppm) 13.2 (CH3), 16.0 (CH3), 19.1 (CH2),
27.7 (CH3), 36.8 (CH2), 37.2 (CH2), 37.3 (CH2), 40.0 (C), 43.6 (C), 50.5 (CH), 51.4 (CH3), 120.8
(CH2), 129.3 (C), 133.2 (CH), 163.6 (C), 177.0 (C), 200.3 (C). IR (film): 2938, 1724, 1664,
1441, 1379, 1323, 1233, 1191, 1162, 1136, 1088, 984, 931, 773 cm-1. HRMS (ESI) m/z: calcd for
C17H25O3 (M+H+) 277.1804, found: 277.1798.
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(1S,4aS,7S,8aR)-methyl
7-hydroxy-5-(hydroxymethyl)-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalene-1-carboxylate (22).
An ozone stream was bubbled into a solution of 21 (2 g, 7.24 mmol) in CH2Cl2 (50 mL) cooled
at -78 ºC for 1 h. The solution was flushed out with an argon stream for eliminating the ozone
excess. Then, NaBH4 (1.71 g, 43.44 mmol) was added to the cooled solution and stirred for 14 h
letting the temperature increase to room temperature. The reaction was quenched with water (5
mL) at 0 ºC and the product was extracted with CH2Cl2 (2 x 15 mL). The combined organic
phases were washed with water (3 x 5 mL), brine (2 x 5 mL) and dried over anhydrous Na2SO4.
Removal of the solvent under vacuum afforded a crude product which was purified by flash
chromatography on silica gel (15 % AcOEt/Hexane) to yield diol 22 (1.90 g, 93%) as a white
solid; mp 195-197 ºC. [α]D25= + 79.1 (c 1.0, CHCl3). 1H NMR (400 MHz, Chloroform-d) δ
(ppm) 0.82 (s, 3H), 1.01 (ddd, J = 13.4, 13.3, 4.3 Hz, 1H), 1.10 (t, J = 5.3 Hz, 1H), 1.19 (s, 3H),
1.36 (d, J = 13.3 Hz, 1H), 1.52 (d, J = 7.0 Hz, 2H), 1.61 (s, 1H), 1.75 (dd, J = 13.2, 10.3 Hz, 1H),
1.83 (s, 3H), 2.21 (d, J = 13.7 Hz, 1H), 2.38 (dd, J = 13.1, 6.5 Hz, 1H), 3.62 (s, 3H), 4.01 (dd, J
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= 11.7, 5.3 Hz, 1H), 4.04 – 4.11 (m, 1H), 4.15 (dd, J = 11.6, 5.1 Hz, 1H). 13C NMR (100 MHz,
Chloroform-d) δ (ppm) 14.6 (CH3), 17.9 (CH3), 19.1 (CH2), 28.1 (CH3), 31.2 (CH2), 36.6 (CH2),
37.5 (CH2), 39.4 (C), 43.3 (C), 50.3 (CH), 51.2 (CH3), 58.3 (CH2), 72.9 (CH), 135.3 (C), 142.4
(C), 177.5 (C). IR (KBr): 3351, 2933, 1724, 1448, 1380, 1232, 1194, 1157, 1090, 1035, 992,
899, 755, 666 cm-1. HRMS (ESI) m/z: calcd for C16H27O4 (M+H+) 283.1909, found: 283.1915.
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(1S,4aS,5S,8aR)-methyl 5-formyl-1,4a,6-trimethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene-
1-carboxylate (23).
To a stirred solution of diol 22 (1.2 g, 4.25 mmol) in a 5 : 1 mixture of dry CH2Cl2 and toluene
(100 : 20 mL) cooled at -35 ºC was added dropwise BF3.OEt2 (1.1 mL, 8.50 mmol) and stirred
for 1 h, at which time TLC showed no starting material. Then, saturated aqueous NaHCO3 (20
mL) was added to the cooled mixture and was stirred for 10 minutes. Solvents were evaporated
under vacuum and then ethyl acetate (80 mL) was added. The phases were shaken and separated.
The organic layer was washed with water (3 x 20 mL), brine (2 x 20 mL), dried over Na2SO4 and
filtered. Removal of the solvent under vacuum afford a crude product that was purified by flash
chromatography on silica gel (30 % AcOEt/Hexane) to yield aldehyde 23 (1.00 g, 89%) as a
white solid; mp 105-107 ºC. [α]D25= + 4.9 (c 1.1, CHCl3). 1H NMR (500 MHz, Chloroform-d) δ
(ppm) 0.90 (s, 3H), 1.09 (ddd, J = 14.2, 12.9, 3.7 Hz, 1H), 1.21 (s, 3H), 1.32 (ddd, J = 13.6, 13.5,
4.2 Hz, 1H), 1.38 (dd, J = 12.1, 4.7 Hz, 1H), 1.46 – 1.53 (m, 1H), 1.61 (s, 3H), 1.72 (br d, J =
13.2 Hz, 1H), 1.86 (qt, J = 13.8, 3.3 Hz, 1H), 2.19 (br d, J = 13.5 Hz, 1H), 2.25 – 2.34 (m, 1H),
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2.50 – 2.58 (m, 1H), 2.61 (s, 1H), 3.67 (s, 3H), 5.72 (br s, 1H), 9.64 (d, J = 5.1 Hz, 1H). C
NMR (125 MHz, Chloroform-d) δ (ppm) 14.6 (CH3), 19.1 (CH2), 21.5 (CH3), 24.5 (CH2), 28.7
(CH3), 36.8 (C), 38.0 (CH2), 40.5 (CH2), 43.7 (C), 50.2 (CH), 51.4 (CH3), 66.8 (CH), 125.6
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(CH), 126.7 (C), 177.4 (C), 206.1 (CH). IR (KBr): 3351, 2933, 1724, 1448, 1380, 1232, 1194,
1157, 1090, 1035, 992, 899, 755, 666 cm-1. HRMS (ESI) m/z: calcd for C16H25O3 (M+H+)
265.1804, found: 265.1799.
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(1S,4aS,8aR)-methyl 5-formyl-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalene-1-
carboxylate (24).
To a stirred solution of diol 22 (1.2 g, 4.25 mmol) in dry CH2Cl2 cooled at 0 ºC was added
dropwise BF3.OEt2 (1.1 mL, 8.50 mmol) and stirred for 30 min, at which time TLC showed no
starting material. Then, saturated aqueous NaHCO3 (20 mL) was added to the cooled mixture and
was stirred for 10 minutes. Solvent was evaporated under vacuum and then ethyl acetate (80 mL)
was added. The phases were shaken and separated. The organic layer was washed with water (3
x 20 mL), brine (2 x 20 mL), dried over Na2SO4 and filtered. Removal of the solvent under
vacuum afford a crude product that was purified by flash chromatography on silica gel (30 %
AcOEt/Hexane) to yield aldehyde 24 (1.03 g, 92%) as a white solid; mp 91-93 ºC. [α]D25= +
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100.6 (c 1.1, CHCl3). H NMR (500 MHz, Chloroform-d) δ (ppm) 0.96 – 1.00 (m, 1H), 1.01 (s,
3H), 1.02 – 1.07 (m, 1H), 1.21 (s, 3H), 1.28 (dd, J = 12.6, 1.8 Hz, 1H), 1.50 (dt, J = 14.5, 3.6 Hz,
1H), 1.75 – 1.90 (m, 2H), 1.98 – 2.05 (m, 1H), 2.07 (s, 3H), 2.19 – 2.37 (m, 3H), 2.57 (d, J =
13.1 Hz, 1H), 3.64 (s, 3H), 10.05 (s, 1H). 13C NMR (125 MHz, Chloroform-d) δ (ppm) 17.4
(CH3), 19.2 (CH3), 19.4 (CH2), 20.0 (CH2), 28.6 (CH3), 36.2 (CH2), 37.3 (CH2), 37.7 (CH2), 38.1
(C), 43.6 (C), 51.2 (CH3), 53.4 (CH), 142.2 (C), 155.0 (C), 177.6 (C), 192.3 (CH). IR (KBr):
2950, 2870, 1724, 1670, 1610, 1465, 1376, 1229, 1191, 1161, 1140, 1037, 978, 829, 773, 701
cm-1. HRMS (ESI) m/z: calcd for C16H25O3 (M+H+) 265.1804, found: 265.1809.
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2-(benzyloxy)-4-bromo-1-methylbenzene (25).
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Benzyl bromide (0.7 mL, 5.88 mmol) was added to a stirred suspension of 5-bromo-2-
methylphenol (1.0 g, 5.35 mmol) and K2CO3 (0.96 g, 6.95 mmol) in acetone (50 mL) under
argon atmosphere. The mixture was heated under reflux overnight. Then, the solvent was
evaporated in vacuo, Et2O (100 mL) was added and the mixture was washed with water (2 x 30
mL) and brine (1 x 30 mL). The organic phase was dried over anhydrous Na2SO4 and
concentrated to give a crude product which was purified by flash chromatography (30 %
AcOEt/hexane) to give 25 (1.4 g, 92 %) as a colorless syrup. 1H NMR (500 MHz, Chloroform-d)
δ 2.24 (s, 3H), 5.07 (s, 2H), 7.03 – 7.04 (m, 2H), 7.04 (d, J = 1.0 Hz, 1H), 7.33 – 7.39 (m, 1H),
7.40 – 7.50 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 16.0 (CH3), 70.1 (CH2), 114.8 (CH),
119.5 (C), 123.5 (CH), 126.1 (C), 127.2 (CH x 2), 128.0 (CH), 128.6 (CH x 2), 131.7 (CH),
136.7 (C), 157.5 (C). IR (film): 3065, 3031, 2922, 1593, 1487, 1454, 1399, 1380, 1304, 1240,
1190, 1126, 1083, 1025, 879, 836, 801, 772, 736, 696, 631, 580 cm-1
(1S,4aS,5S,8aR)-methyl
5-((R)-(3-(benzyloxy)-4-methylphenyl)(hydroxy)methyl)-1,4a,6-
trimethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1-carboxylate (26).
To a solution of bromobenzene 25 (1.3 g, 4.54 mmol) in dry THF (15 mL) was carefully added
n-butyllitium (4.54 mmol) at -78 ºC under an argon atmosphere and the reaction mixture was
stirred at this temperature for 30 min, observing the formation of a white precipitate of the
aryllithium salt. Then a solution of aldehyde 23 (0.8 g, 3.03 mmol) in dry THF (10 mL) was
syringed to the first solution and the reaction mixture was stirred for a further 10 min at -78 ºC,
at which time TLC showed no starting material. The reaction was quenched with water (5 mL),
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the solvent was removed under vacuum, and the mixture was extracted with ether (2 x 15 mL).
The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over
anhydrous Na2SO4 and the solvent was evaporated to give a crude product, which was purified
by flash chromatography on silica gel (30 % AcOEt/hexane), affording 1.30 g of alcohol 26
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(93%) as a colorless syrup. [α]D25= - 46.5 (c 1.1, CHCl3). H NMR (500 MHz, Chloroform-d) δ
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(ppm) 0.94 (s, 3H), 1.14 (ddd, J = 13.4, 13.4, 3.7 Hz, 1H), 1.24 (s, 3H), 1.35 (s, 3H), 1.45 (dd, J
= 12.1, 4.2 Hz, 1H), 1.61 (dt, J = 14.2, 3.6 Hz, 1H), 1.79 (s, 1H), 2.00 (qt, J = 13.9, 3.3 Hz, 1H),
2.09 (d, J = 12.8 Hz, 1H), 2.18 – 2.26 (m, 2H), 2.29 (s, 3H), 2.40 – 2.48 (m, 2H), 3.69 (s, 3H),
5.03 (d, J = 4.4 Hz, 1H), 5.12 (s, 2H), 5.59 (br s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H), 7.10
(d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H).
13C NMR (125 MHz, Chloroform-d) δ (ppm) 14.5 (CH3), 16.0 (CH3), 19.7 (CH2), 23.9 (CH3),
24.3 (CH2), 28.9 (CH3), 37.0 (C), 38.2 (CH2), 40.8 (CH2), 43.9 (C), 51.3 (CH3), 51.5 (CH), 61.8
(CH), 69.5 (CH), 69.9 (CH2), 109.0 (CH), 117.0 (CH), 124.5 (C), 126.8 (CH), 127.1 (CH x 2),
127.6 (CH), 128.5 (CH x 2), 130.1 (CH), 131.4 (C), 137.6 (C), 145.7 (C), 156.5 (C), 177.8 (C).
IR (film): 3500, 2927, 1721, 1611, 1582, 1506, 1453, 1413, 1380, 1237, 1196, 1172, 1150, 1127,
1026, 986, 841, 812, 755, 696, 627 cm-1. HRMS (ESI) m/z: calcd for C30H39O4 (M+H+)
463.2848, found: 463.2851.
(1S,4aS,5S,8aR)-methyl
5-((R)-acetoxy(3-(benzyloxy)-4-methylphenyl)methyl)-1,4a,6-
trimethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1-carboxylate (27).
To a solution of alcohol 26 (0.9 g, 1.94 mmol) in pyridine (15 mL) at room temperature were
added DMAP (24 mg, 0.19 mmol) and Ac2O (2 mL, 10.88 mmol) and stirred for 1 h at room
temperature. The reaction was quenched with water (10 mL) at 0 ºC and the solution obtained
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was diluted with Et2O (50 mL), washed with water (1 x 15 mL), HCl 2M (4 x 15 mL), again with
water (1 x 15 mL), with saturated aqueous NaHCO3 (4 x 15 mL) and brine (1 x 15 mL). The
organic phase was dried with anhydrous Na2SO4, filtered, and evaporated under vacuum. The
crude obtained was purified by flash chromatography (10 % AcOEt/Hexane) affording acetate 27
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(942 mg, 96 %) as a colorless syrup. [α]D25= - 9.3 (c 1.0, CHCl3). H NMR (500 MHz,
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Chloroform-d) δ (ppm) 0.70 (s, 3H), 1.12 (ddd, J = 13.5, 13.4, 3.8 Hz, 1H), 1.16 – 1.21 (m, 1H),
1.23 (s, 3H), 1.40 (s, 3H), 1.44 (dd, J = 12.3, 4.3 Hz, 1H), 1.61 (dt, J = 14.1, 3.8 Hz, 1H), 1.96
(qt, J = 13.9, 3.3 Hz, 1H), 2.12 (s, 3H), 2.15 – 2.24 (m, 3H), 2.26 (s, 3H), 2.34 – 2.46 (m, 2H),
3.67 (s, 3H), 5.09 (s, 2H), 5.45 (br s, 1H), 6.13 (s, 1H), 6.60 (s, 1H), 6.66 (d, J = 7.7 Hz, 1H),
7.07 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.1 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.42 (d, J = 7.0 Hz,
2H). 13C NMR (125 MHz, Chloroform-d) δ (ppm) 13.2 (CH3), 16.0 (CH3), 19.7 (CH2), 21.2
(CH3), 23.7 (CH3), 24.1 (CH2), 28.9 (CH3), 37.0 (C), 38.1 (CH2), 40.7 (CH2), 43.9 (C), 51.3
(CH), 51.5 (CH3), 60.3 (CH), 70.1 (CH2), 71.5 (CH), 109.0 (CH), 117.0 (CH), 124.2 (CH), 125.2
(C), 126.9 (CH x 2), 127.7 (CH), 128.5 (CH x 2), 130.2 (CH), 131.9 (C), 137.5 (C), 141.4 (C),
156.5 (C), 170.3 (C), 177.6 (C). IR (film): 2926, 1721, 1583, 1508, 1453, 1414, 1372, 1233,
1150, 1128, 1077, 1024, 814, 753, 696, 666, 626 cm-1. HRMS (ESI) m/z: calcd for C32H41O5
(M+H+) 505.2954, found: 505.2955.
(1S,4aS,5S,8aR)-methyl
5-((R)-acetoxy(3-hydroxy-4-methylphenyl)methyl)-1,4a,6-
trimethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1-carboxylate (28).
70 % Raney - Nickel dispersion in water (1 mL) was added to a stirred solution of 27 (400 mg,
0.79 mmol) in THF (25 mL) with an H2 atmosphere provided by a balloon. The mixture was
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stirred at room temperature for 5 h, at which time TLC showed no remaining starting material.
Then, the resulting mixture was filtered through a silica gel (7.0 g) – anhydrous Na2SO4 (10.0 g)
pad and washed with AcOEt (50 mL). The solvent was evaporated to yield phenol 28 (322 mg,
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98 %) as a white solid; mp 176-178 ºC. [α]D25= - 6.9 (c 1.1, CHCl3). H NMR (500 MHz,
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Chloroform-d) δ (ppm) 0.70 (s, 3H), 1.10 (ddd, J = 13.7, 13.4, 3.9 Hz, 1H), 1.21 (s, 3H), 1.25 –
1.32 (m, 1H), 1.35 (t, J = 6.1 Hz, 1H), 1.44 (s, 1H), 1.45 (s, 3H), 1.58 (br d, J = 14.3 Hz, 1H),
1.94 (qt, J = 13.9, 3.3 Hz, 1H), 2.15 (s, 3H), 2.17 (s, 3H), 2.19 – 2.29 (m, 2H), 2.32 – 2.45 (m,
1H), 2.49 (s, 1H), 3.67 (s, 3H), 5.45 (br s, 1H), 6.12 (s, 1H), 6.56 (s, 1H), 6.60 (d, J = 7.9 Hz,
1H), 7.00 (d, J = 7.8 Hz, 1H). 13C NMR (125 MHz, Chloroform-d) δ (ppm) 13.3 (CH3), 15.4
(CH3), 19.6 (CH2), 21.3 (CH3), 23.7 (CH3), 24.1 (CH2), 28.9 (CH3), 37.0 (C), 38.1 (CH2), 40.6
(CH2), 43.9 (C), 51.4 (CH3), 51.5 (CH), 60.1 (CH), 71.6 (CH), 111.7 (CH), 116.7 (CH), 122.0
(C), 124.2 (CH), 130.5 (CH), 131.9 (C), 141.7 (C), 153.9 (C), 170.8 (C), 177.9 (C). IR (KBr):
3429, 2953, 2926, 2855, 1720, 1591, 1436, 1376, 1234, 1151, 1118, 1040, 1001, 943, 754, 667
cm-1. HRMS (ESI) m/z: calcd for C25H35O5 (M+H+) 415.2484, found: 415.2478.
(1S,4aS,5S,8aR)-methyl 5-((R)-acetoxy(2-bromo-3-hydroxy-4-methylphenyl)methyl)-1,4a,6-
trimethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1-carboxylate (29).
A solution of NBS (129 mg, 0.72 mmol) in CH2Cl2 (5 mL) was prepared and added via cannula
to a solution of phenol 28 (300 mg, 0.72 mmol) in CH2Cl2 (20 mL) and 2 drops of
diisopropylamine. The reaction mixture was stirred for 45 min at room temperature, at which
time TLC showed no starting material. Then, the solvent was removed, and the crude product
was purified by flash chromatography (30 % AcOEt/Hexane) to afford bromine derivative 29
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(325 mg, 91 %) as a colorless syrup. [α]D25= - 34.3 (c 1.0, CHCl3). H NMR (500 MHz,
Chloroform-d) δ (ppm) 0.77 (s, 3H), 1.12 (ddd, J = 13.5, 13.2, 3.8 Hz, 1H), 1.22 (s, 3H), 1.43 (s,
3H), 1.53 (dd, J = 12.2, 4.5 Hz, 1H), 1.60 – 1.74 (m, 2H), 1.93 (qt, J = 13.6, 3.5 Hz, 1H), 2.16 (s,
3H), 2.21 (br d, J = 13.6 Hz, 2H), 2.27 (s, 3H), 2.37 (br d, J = 11.8 Hz, 2H), 2.90 (s, 1H), 3.67 (s,
3H), 5.50 (br s, 1H), 6.19 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H). 13C NMR
(125 MHz, Chloroform-d) δ (ppm) 14.2 (CH3), 16.5 (CH3), 19.7 (CH2), 21.4 (CH3), 24.4 (CH2),
25.3 (CH3), 29.1 (CH3), 37.9 (CH2), 39.1 (C), 40.8 (CH2), 44.1 (C), 51.3 (CH3), 51.8 (CH), 54.8
(CH), 72.5 (CH), 109.0 (C), 120.5 (CH), 124.3 (C), 125.8 (CH), 129.0 (CH), 131.8 (C), 138.5
(C), 150.2 (C), 170.0 (C), 177.8 (C). IR (film): 3448, 2952, 2930, 2856, 1720, 1448, 1406, 1370,
1228, 1171, 1149, 1123, 1040, 1010, 945, 818, 753, 667 cm-1. HRMS (ESI) m/z: calcd for
C25H34BrO5 (M+H+) 493.1590, found: 493.1587.
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(1S,4aS,5S,8aR)-methyl
5-((R)-acetoxy(3-(benzyloxy)-2-bromo-4-methylphenyl)methyl)-
1,4a,6-trimethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1-carboxylate (30).
Benzyl bromide (0.05 mL, 0.45 mmol) was added to a stirred suspension of 29 (270 mg, 0.548
mmol) and K2CO3 (146 mg, 1.06 mmol) in dry acetone (10 mL) under argon atmosphere. The
mixture was heated under reflux overnight. Then, the solvent was evaporated in vacuo, Et2O (40
mL) was added and the mixture was washed with water (2 x 10 mL) and brine (1 x 10 mL). The
organic phase was dried over anhydrous Na2SO4 and concentrated to give a crude product which
was purified by flash chromatography (10 % AcOEt/hexane) to give 30 (313 mg, 98 %) as a
colorless syrup. [α]D25= - 39.9 (c 0.9, CHCl3). 1H NMR (400 MHz, Chloroform-d) δ (ppm) 0.76
(s, 3H), 1.09 (ddd, J = 13.4, 13.3, 3.8 Hz, 1H) 1.19 (s, 3H), 1.39 (s, 3H), 1.47 – 1.63 (m, 2H),
1.73 (td, J = 13.2, 3.7 Hz, 1H), 1.88 (td, J = 13.5, 3.1 Hz, 1H), 2.15 (s, 3H), 2.18 – 2.24 (m, 2H),
29
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