Total synthesis and structural confirmation of the antibacterial diterpene leubethanol

Article abstract of DOI:10.1016/j.tet.2013.05.082

We report the total synthesis of leubethanol (1), a serrulatane compound that has recently been reported as having considerable antibacterial activity against multidrug-resistant bacteria, such as Staphylococcus aureus, and is of interest for applications

Full text of DOI:10.1016/j.tet.2013.05.082

Tetrahedron 69 (2013) 6468e6473
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis and structural confirmation of the antibacterial
diterpene leubethanol
,
,
a
Jessica M.H. Lu a b, Michael V. Perkins b , Hans J. Griesser
*
a Ian Wark Research Institute, University of South Australia, Mawson Lakes, SA 5095, Australia
b School of Chemical and Physical Sciences, Flinders University, PO Box 2100, Adelaide 5001, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the total synthesis of leubethanol (1), a serrulatane compound that has recently been reported
as having considerable antibacterial activity against multidrug-resistant bacteria, such as Staphylococcus
aureus, and is of interest for applications in the control of bacterial biofilms in human medicine. Our
synthetic route begins with (ꢀ)-isopulegol (4) and key steps include substrate directed hydroboration to
Received 22 January 2013
Received in revised form 10 May 2013
Accepted 20 May 2013
Available online 24 May 2013
generate the C10 stereocentre and formation of the aromatic ring via the
a-oxoketene-S,S-acetal
intermediate 3. Overall the conversion of (ꢀ)-isopulegol (4) to leubethanol was achieved in 13 steps and
an overall yield of 7%. Comparison of our spectroscopic data with those reported for leubethanol (1),
isolated from Leucophyllum frutescens, verified the structure of the natural product.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Serrulatane
Leubethanol
Antimicrobial
Antibacterial
Natural product
1. Introduction
recently been shown to display potent antibacterial action against
multi-drug resistant M. tuberculosis.6 As part of our investigations
The serrulatanes are a class of diterpenes that have been
extracted from the leaves of a wide variety of Australian-native
Eremophila plants.1e5 In addition, the serrulatane natural product
leubethanol (1) was recently isolated6 from the root bark of the
evergreen shrub Leucophyllum frutescens used in Mexican tradi-
tional medicine. These natural products are part of a new class of
antimicrobial compounds that possess interesting biological ac-
tivity against Mycobacterium tuberculosis,6 Staphylococci2e4 and
Streptococci2e4 bacteria as well as anti-inflammatory properties.5
All biological studies to date involving serrulatanes have required
the compounds to be extracted from the plants. These desert plants
are not readily accessible and may not allow cropping of usable
material in drought years; moreover, extraction and purification
are tedious and provide only small amounts. This necessarily limits
the amounts of serrulatane compound that are available for the
study of biological activities and for the development of potential
practical applications, such as antibacterial coatings to protect
biomedical devices and implants from bacterial biofilm formation.7
The structure, including stereochemistry, of the methyl serru-
latane leubethanol (1) was determined6 by extensive NMR spec-
troscopy. Despite being one of the simplest serrulatanes it has
into the synthesis of various serrulatanes for biological evaluation
and future medical use we targeted leubethanol (1) as one of the
simpler structures of this class. Our proposed route (Scheme 1), as
well as confirming the structure of leubethanol (1), also enables
ready preparation of side-chain analogues.
Scheme 1. Retrosynthetic analysis of leubethanol (1).
A major challenge in the synthesis of the serrulatanes lies in the
control of all three stereocentres, especially considering the ab-
sence of functional groups near the stereocentres.8,9 Stereocontrol
in the synthesis of the closely-related pseudopterosins and seco-
pseudopterosins has been achieved using: a rhodium catalyzed
hydroboration,10 a rhodium catalyzed CeH activation/Cope rear-
rangement,9 an enantioselective copper catalyzed conjugate addi-
tion of an alkylzinc11 and conjugate addition to arene-Cr(CO)3
complexes.8,12 In contrast, our approach to the total synthesis of
leubethanol (1) utilized the inexpensive and readily available chiral
* Corresponding author. Tel.: þ61 8 8201 2496; fax: þ61 8 8201 2905; e-mail
address: mike.perkins@flinders.edu.au (M.V. Perkins).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.082

J.M.H. Lu et al. / Tetrahedron 69 (2013) 6468e6473
6469
pool starting material (ꢀ)-isopulegol (4) to provide two of the three
required stereocentres.
the presence of methanol leads to the annulated product 2, complete
with both the required oxygen functionality at C8 and the methyl
substituent on the aromatic ring. Conveniently, the Lewis acid
treatment removes the TBS protecting group, giving the C20 alcohol
and allowing for direct extension of the hydrocarbon tail.The final
phase of the synthesis involves building the hydrocarbon tail
(Scheme 4). Oxidation of the methoxy arene 2 gave the corre-
sponding aldehyde, which was immediately reacted with (carbe-
thoxymethylene)triphenylphosphorane in a Wittig reaction to afford
the unsaturated ester 10. Hydrogenation with Pd/C and H2 followed
by reduction of the ester to the alcohol with DIBAL-H and re-
oxidation to the aldehyde gave the saturated aldehyde 11.
The retrosynthetic analysis is depicted in Scheme 1, highlighting
the proposed annulation of the aromatic ring onto (ꢀ)-isopulegol (4)
via the key a-oxoketene-S,S-acetal intermediate 3. The commercially
available monoterpene (ꢀ)-isopulegol (4) bears two stereocentres in
common with leubethanol (C1 and C4) and the hydroxyl group can
be used to direct hydroboration and thus generate the required
configuration of the remaining methyl stereocentre.
2. Results and discussion
In the first step of the synthesis of leubethanol (1) (ꢀ)-isopulegol
(4) was treated with BH3$THF to give the diol 5 with good stereo-
selectivity13 and the diastereomeric ratio (C10 epimer) was de-
termined from the 1H NMR spectrum to be 12:1 (Scheme 2). The diol
5 was purified by recrystallization and the hydroborationwas readily
conducted on up to 15 g of starting material. The recrystallization of
diol 5 did not separate the minor isomer but after selective TBS
protection of the primary hydroxyl the minor isomer was readily
removed by column chromatography to give pure TBS ether 6. Swern
oxidation of the TBS ether 6 gave ketone 7, providing opportunity for
functionalisation at the position alpha to the ketone.
Scheme 4. Assembly of the hydrocarbon tail followed by demethylation.
The completion of the hydrocarbon tail was achieved through
another Wittig olefination, in this instance with the ylide derived
from isopropyltriphenyl phosphonium iodide, to install the iso-
prene moiety, thereby producing the methoxy serrulatane 12. Fi-
nally, demethylation17 of the methoxy serrulatane 12 with NaSEt in
Scheme 2. Formation of the methyl stereocentre.
A careful modification of the method of Kocienski et al.14 gave
the a-oxoketene-S,S-akcetal 8 as shown in Scheme 3. It was found
DMF afforded compound 1. The 1H and 13C NMR spectroscopic data
25
that the enolate needed to be initially formed in THF at ꢀ78 ꢁC and
the DMPU added immediately before addition of the CS2. The re-
action was then warmed to 0 ꢁC to allow reaction with the CS2 to
proceed before re-cooling to ꢀ78 ꢁC prior to the addition of the
second equivalent of base (LHMDS) and 1,3-dibromopropane. Using
these optimized conditions the one-pot, multistep reaction gave
compound 8 in 68% yield.
(Table 1) and optical rotation ([
a
]
ꢀ32 (c 0.15, CHCl3)) for syn-
D
thetic 1 were essentially identical to that reported ([
a
]
D ꢀ32 (c 0.15,
CHCl3))6 for the natural product leubethanol. This total chemical
synthesis thus offers definitive verification of the structural con-
figuration of leubethanol provided in the report of its isolation from
the natural source.6
3. Conclusions
We have synthesised the naturally occurring antimicrobial
compound leubethanol in 13 steps from commercially available
(ꢀ)-isopulegol with an overall yield of 7%. This total chemical syn-
thesis establishes a route for the preparation of larger amounts of
this compound for studies of its antimicrobial properties and po-
tential applications, and confirms the stereochemical configuration
of this natural product, as reported in its isolation6 from L. frutescens.
4. Experimental section
4.1. General experimental procedures
All reactions were carried out using anhydrous solvents under
a nitrogen atmosphere and performed in oven dried round bottom
flasks fitted with a rubber Suba Seal unless otherwise stated. Or-
ganic solutions were concentrated via rotary evaporation under
reduced pressure. Thin Layer Chromatography (TLC) was executed
with the indicated mobile phase solvents on silica gel plates (E.
Merck, 60 F254, 0.25 mm) with compounds visualised by exposure
Scheme 3. Construction of the keteneacetal 8 followed by benzannulation.
The 1,2-addition to the carbonyl of
followed by treatment with a Lewis acid has been reported as
controlled method for achieving benzannulation.14e16 Thus,
a-oxoketene-S,S-acetals
a
methallylmagnesium chloride was added to the keteneacetal 8, giv-
ing the sensitive intermediate carbinol 9. Exposure of 9 to BF3$OEt2 in
to a UV lamp (
l
¼254 nm) and developed by dipping in a KMnO4
solution or anisaldehyde solution, followed by rapid heating using

6470
J.M.H. Lu et al. / Tetrahedron 69 (2013) 6468e6473
Table 1
Comparison of the 1H and 13C NMR data for natural leubethanol and synthesised 1
Position
Natural producta
Synthesised product 1b
dH (m, J[Hz])c
dH (m, J[Hz])c
dC
dC
Ddd
0.02
0.06
ꢀ0.19
ꢀ0.09
ꢀ0.14
0.01
c
c
C1
C2
C3
C3Me
C4
153.01
113.25
134.83
20.96
122.30
42.37
152.99
113.19
135.02
21.05
122.44
42.38
6.448 (br d, 1.6, <0.20)
6.42 (s)
2.270 (s)
6.615 (dq, 1.64, <0.20)
2.24
6.59 (s)
2.58
C5
C6
2.59 (ddd, 6.23,5.21, 2.95)
a: 1.74 (ddd, 13.84, 5.00, 3.37, 2.95);
b: 1.870 (dddd, 13.84, 13.30, 6.23, 3.52)
a: 1.520 (dddd, 13.35, 5.20, 3.52, 2.58);
b: 1.967 (dddd, 13.25, 13.25, 6.16, 3.37)
3.078 (ddq, 6.97, 6.16, 2.58)
1.224 (d, 6.97)
19.43
a: 1.72 (m);
b: 1.92e1.85 (m)
a: 1.49e1.56 (m);
b: 1.96 (m)
3.06 (m)
19.41
0.02
C7
27.47
27.46
0.01
C8
C8Me
9
26.56
21.13
126.38
140.81
18.64
37.74
33.33
26.57
21.16
126.31
140.99
18.72
37.80
33.39
ꢀ0.01
ꢀ0.03
0.07
ꢀ0.18
ꢀ0.08
ꢀ0.06
ꢀ0.06
1.20 (d, 6.9)
10
C10
C20
C30
0.984 (d, 6.84)
0.96 (d, 6.9)
1.92e1.85 (m)
a: 1.06 (m);
b: 1.27e1.31 (m)
a: 1.98 (m);
b: 1.84e1.80 (m)
5.00 (t, 7.0)
1.902 (dddq, 10.02, 6.84, 5.21, 2.96)
a: 1.107 (dddd, 13.19, 10.02, 9.28, 4.86);
b: 1.314 (dddd, 13.9, 9.63, 6.94, 2.96)
a: 2.010 (ddddqq, 14.37, 9.63, 6.76, 4.86, 1.17, 0.89);
b: 1.834 (ddddq, 14.37, 9.28, 7.60, 6.94, 1.14, 0)
5.018 (ddqq, 7.60, 6.76, 1.38, 1.36)
C40
26.16
26.23
ꢀ0.07
C50
C60
C60Me
C70
124.91
130.95
17.49
124.92
131.11
17.61
ꢀ0.01
ꢀ0.16
ꢀ0.12
ꢀ0.11
1.582 (dd/br s, 1.36, 0.89, 0)
1.683 (ddd, 1.38, 1.18, 1.14)
1.55 (d, 1.3)
1.68 (d, 1.3)
25.59
25.70
a
Chemical shifts and coupling constants as reported in Molina-Salinas et al.6 (900 MHz).
b
c
Bruker 600 MHz NMR Spectrometer (CDCl3). Assignments assisted by 1He13C HMBC, 1He13C HMQC, 1He1H COSY.
Chemical shifts in ppm referenced to CHCl3 at 7.26 ppm and to CDCl3 at 77.00 ppm.
d
This is the difference in the 13C chemical shift of the isomer and that reported for the natural product.
a heat gun. Silica chromatography was performed using silica gel
(EM Merck, 230e400 mesh). When purifying compounds with acid
sensitivity, column chromatography was performed on buffered
silica as indicated. Buffered silica was prepared by spinning 100 g of
silica gel 60 (mesh size 0.040e0.063 mm) with 10 mL of pH 7
phosphate buffer on a rotary evaporator overnight at atmospheric
pressure.
added dropwise to a stirred solution of (ꢀ)-isopulegol (15 g,
16.5 mL, 97 mmol) in THF (390 mL) at 0 ꢁC. After stirring for 3 h, H2O
(14 mL) was slowly added to the reaction flask, followed by H2O2
(30 wt %, 21 mL) and NaOH (30 wt %, 21 mL) and the flask was
allowed to warm to room temperature over 30 min. The volume
was reduced by half, the product extracted with Et2O (3ꢂ55 mL)
and the organic layers were washed with brine (37 mL), dried over
MgSO4 and concentrated in vacuo to give the crude diol (5). The
crude diol was recrystallised with cyclohexane to give a mixture of
diol (5) and its C10 epimer (ratio 12:1) (15 g, 88 mmol, 91% yield) as
low melting white crystals. The spectroscopic data obtained for the
major isomer is consistent with that previously reported.13 Dis-
cernible signals attributed to the minor epimer are marked with an
asterisk (*). IR (nmax film/cmꢀ1) 3234, 2960, 2945, 2912, 1450, 1037;
1H NMR spectra were recorded on a Bruker Avance III 600 or
400 MHz asindicated. Chemical shifts are reported inparts per million
(ppm) downfield from tetramethylsilane and referenced to residual
protonium in the NMR solvent (CHCl3,
d
¼7.26). Data are reported
as follows: chemical shift, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, qt¼quintet, sx¼sextet, m¼multiplet, br¼broad,
app¼apparent), integration and coupling constant J (Hertz). 13C NMR
spectra were recorded on a Bruker Avance III 600 or 400 MHz as in-
dicated. Chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane and referenced to the carbon res-
1H NMR (400 MHz, CDCl3)
d
3.60 (1H, dd, J¼10.5 and 3.4 Hz, C20HA),
3.54 (1H, dd, J¼10.6 and 4.3 Hz, C20HB), 3.42 (1H, app. quintet,
J¼10.4 and 4.3 Hz, C1H), 2.04e1.99 (1H, m), 1.93 (1H, dd, J¼12.0 Hz),
1.81 (1H, br s, OH), 1.61 (1H, d, J¼12.3 Hz), 1.53 (1H, q, J¼13.0 and
3.3 Hz), 1.41e1.38 (1H, m), 1.32 (1H, dd, J¼9.7 and 3.1 Hz), 1.21 (1H,
dq, J¼12.2 and 3.4 Hz), 0.94 (3H, d, J¼7.3 Hz, C5H3) 0.89 (3H, d,
J¼6.5 Hz, C10CH3), 0.98e0.81 (2H, m); 13C NMR (100 MHz, CDCl3)
onances in the NMR solvent (CDCl3,
d
¼77.0, centre line). Optical ro-
tations were obtained using a PolAAR 21 polarimeter, referenced to
the sodium D line (589 nm) at 20 ꢁC, using the spectroscopic grade
solvents specified and at concentrations (c, g/100 mL) as indicated in
a cell with a 100 mm path length. High resolution mass spectra were
acquired with a Water Synapt HDMS unitin either positive or negative
ion mode.
d
71.5*, 69.9, 66.8, 66.4*, 48.5, 44.4, 45.5*, 45.0*, 38.5, 34.6, 31.4,
31.5*, 29.5, 22.1*, 22.0, 12.5*, 12.0.
4.2.2. (1R,2S,5R)-2-[((R)-20-tert-Butyldimethylsilyloxy)-10-methyl-
ethyl]-5-methylcyclohexan-1-ol (6). To a solution of diol 5 (12: 1
mixture of the two isomers, 15 g, 87 mmol) and imidazole (13.8 g,
203 mmol, 2.3 equiv) in dry DMF (65 mL) was added tert-butyldi-
methylsilyl chloride (TBSCl, 14 g, 97 mmol). After 15 min, the reaction
4.2. Preparative procedures
4.2.1. (1R,2S,5R)-2-[(R)-20-Hydroxy-10-methylethyl]-5-methylcyclohexan-
1-ol (5). BH3$THF (1 M solution in THF, 107 mL, 107 mmol) was

J.M.H. Lu et al. / Tetrahedron 69 (2013) 6468e6473
6471
mixture was quenched with saturated aqueous NH4Cl (100 mL) and
the product extracted into hexanes (3ꢂ100 mL). The combined or-
ganic layers were washed with brine (100 mL), dried over MgSO4 and
concentrated in vacuo. The crude oil was purified by column chro-
1.39 (1H, m),1.10 (3H, d, J¼6.9 Hz, C5H3), 0.90 (3H, d, J¼7.0 Hz, C10H3),
0.87 (s, 9H, t-Bu), 0.02 and 0.01 (s, 3H each, SiMe2); 13C NMR
(100 MHz, CDCl3) d 200.2,149.9,137.1, 65.8, 50.2, 37.1, 34.0, 28.9, 28.6,
28.5, 25.9, 25.8, 23.7, 19.9, 18.2, 15.1, ꢀ5.4, ꢀ5.5.
matography (SiO2, hexanes/EtOAc 6:1) to give the stereochemically
25
pure TBS ether 6 (19 g, 66 mmol, 76% yield) as a colourless oil. [
a
]
4.2.5. 2-(R)-(1S,4R,5-Methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-propan-1-ol (2). Methallylmagnesium chloride (105 mmol,
7 equiv) was prepared by the dropwise addition of methallyl chloride
(3.18 g, 3.43 mL, 35 mmol) in THF (140 mL) to Mg turnings (2.56 g,
105 mmol) in the presence of I2. The reaction was refluxed for 1 h and
cooled prior to cannulation of oxo-ketene S,S acetal 8 (2.01 g,
5.01 mmol) in THF (59 mL) at 0 ꢁC. The ice bath was removed and the
reaction continued at room temperature for 90 min before quenching
with saturated aqueous NH4Cl (100 mL). The product was extracted
with Et2O (3ꢂ30 mL) and the combined organic layers dried over
Na2SO4 then concentrated in vacuo to give the crude alcohol as an
orange oil. The crude alcohol, used without purification, was dissolved
in THF (6 mL) and added via cannula to a stirred solution of BF3$OEt2
(5 g, 4.95 mL, 35 mmol, 7 equiv) in MeOH (20 mL) at ꢀ40 ꢁC. The re-
action was left overnight then worked up with saturated aqueous
NaHCO3 (30 mL) diluted with brine (20 mL) and the product extracted
with Et2O (3ꢂ40 mL), dried over Na2SO4. The oil obtained upon con-
centration in vacuo was purified by column chromatography (buffered
D
ꢀ28.9 (c 2.3, MeOH); IR (nmax film/cmꢀ1) 3440, 2927, 2858, 1472,
1461; 1H NMR (400 MHz, CDCl3)
d 3.90 (1H, br s, OH), 3.42 (1H, dd, A
portion of an ABX system, JAB¼9.9 Hz, JBx¼5.4 Hz, C20HA), 3.36 (1H, dd,
B portion of an ABX system, JAB¼9.9 Hz, JBx¼3.8 Hz, C20HB), 3.17 (1H,
m, C1H), 1.76e1.73 (1H, m), 1.66 (1H, m), 1.42e1.31 (2H, m), 1.19e1.16
(3H, m), 0.94e0.84 (2H, m), 0.75 (3H, d, J¼6.5 Hz, C5H3), 0.67 (12H,
overlapping s, t-Bu and d, J¼6.5 Hz, C10H3) ꢀ0.16 (6H, s, SiMe2); 13C
NMR (100 MHz, CDCl3)
d 69.7, 67.7, 49.2, 43.8, 38.3, 34.7, 31.4, 29.1,
25.8, 22.1, 18.3, 12.3, ꢀ5.61, ꢀ5.65. HRESIMS m/z 309.2220 (MþNa)
(calcd for C16H34O2SiNa, 309.2226).
4.2.3. (2S,5R)-2-[((R)-20-tert-Butyldimethylsilyloxy)-10-methylethyl]-
5-methylcyclohexan-1-one (7). To a solution of DMSO (2.9 g, 2.6 mL,
37 mmol, 3 equiv) in CH2Cl2 (65 mL) at ꢀ78 ꢁC was added oxalyl
chloride (2.0 M solution in CH2Cl2, 9.3 mL,18.6 mmol,1.5 equiv). After
10 min, the alcohol 6 (3.56 g,12.4 mmol) in CH2Cl2 (15 mL) was added
via cannula. After 1 h, Et3N (7.5 g, 10.4 mL, 75 mmol, 6 equiv) was
added and the reaction mixture was warmed to room temperature
over 2 h. Saturated aqueous NH4Cl (65) was added to the vigorously
stirred suspensionandthe productextractedinto hexanes (3ꢂ40mL).
The combined organic layers were washed successively with HCl
(1.5 M, 25 mL) and brine (25 mL). The residue obtained on concen-
tration in vacuo was purified by column chromatography (SiO2,
CH2Cl2) to give the ketone 7 (3.07 g, 10.8 mmol, 87%) as a pale yellow
SiO2, CH2Cl2/hexanes 12:1) to give the methoxy arene 2 (616 mg,
25
2.5 mmol, 50% yield). [
a
]
ꢀ3.1 (c 55.6, CHCl3); IR (nmax film/cmꢀ1
)
D
2928, 2856, 1643, 1472, 1418, 1281, 1255, 1087, 837, 775, 668; 1H NMR
(400 MHz, CDCl3)
d 6.63 (1H, s, C8H), 6.53 (1H, s, C6H), 3.82 (3H, s,
OCH3), 3.53 (1H, dd, J¼10.7 and 5.7 Hz, C1HA), 3.45 (1H, dd, J¼10.7 and
5.9 Hz, C1HB), 3.17e3.20 (1H, m, C4CH3), 2.72 (1H, m, C10H), 2.32 (3H, s,
C7CH3), 1.94e1.91 (1H, m), 1.89e1.87 (1H, m), 1.77e1.75 (1H, m),
1.58e1.55 (1H, m), 1.54e1.51 (1H, m), 1.17 (3H, d, J¼6.9 Hz, C4CH3),1.01
oil. [
a
]
25ꢀ8.2 (c 1.5, MeOH); IR (nmax film/cmꢀ1) 2955, 2857, 1642,
D
1462,1382,1251,1084, 845, 774; 1H NMR (400 MHz, CDCl3)
d
3.62 (1H,
(3H, d, J¼6.9 Hz, C3H3); 13C NMR (100 MHz, CDCl3)
d 157.1,139.3,135.0,
128.4, 122.4, 108.8, 66.3, 55.1, 41.8, 39.7, 27.0, 26.3, 21.5, 21.2, 19.6, 16.7.
dd, A portion of an ABX system, JAB¼9.4 Hz, JBx¼5.4 Hz, C20HA) 3.58
(1H, dd, B portion of an ABX system, JAB¼9.4 Hz, JBx¼3.2 Hz, C20HB),
2.34e2.26 (3H, m), 2.10e2.05 (2H, m) 2.04e1.95 (2H, m), 1.94e1.80
(2H, m),1.01 (3H, d, J¼6.2 Hz, C5H3), 0.94 (3H, d, J¼6.7 Hz, C10H3), 0.87
(9H, s, t-Bu), 0.02 (6H, s, SiMe2); 13C NMR dC (100 MHz, CDCl3) 212.0,
65.4, 52.1, 51.1, 35.6, 34.8, 34.2, 29.6, 25.9, 22.3, 18.2, 15.1, ꢀ5.5.
HRESIMS m/z 271.1674 (MþNa) (calcd for C16H24O2Na, 271.1674).
4.2.6. Ethyl 4-(R)-(1S,4R,5-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-pent-2-enoate (10). DMSO (1.02 g, 0.93 mL, 3 equiv) in CH2Cl2
(20 mL) was stirred at ꢀ78 ꢁC and oxalyl chloride (2.0 M in CH2Cl2,
3.27 mL, 6.54 mmol, 1.5 equiv) was added dropwise. The reaction
mixture was stirred for 10 min prior to cannulation of the alcohol 2
(1.08 g, 4.3 mmol) in CH2Cl2 (5 mL). After 1.5 h, Et3N (3.64 mL,
26.2 mmol, 6 equiv) was added dropwise and the flask warmed to
room temperature over 1 h. The mixture was diluted with CH2Cl2
(50 mL) then washed successively with water (2ꢂ25 mL) and brine
(50 mL). The organic layers were combined and dried over Na2SO4,
and filtered into a round bottom flask. Carbethoxymethylene tri-
phenylphosphorane (3.13 g, 8.72 mmol, 2 equiv) was added into the
solution of crude aldehyde. The reaction was monitored by TLC. The
CH2Cl2 was evaporated and the crude reaction mixture was purified
by column chromatography (buffered SiO2, CH2Cl2/hexanes 4:1) to
4.2.4. (2S,5R)-2-[((R)-20-tert-Butyldimethylsilyloxy)-10-methylethyl]-
6-(1,3-dithian-2-ylidene)-5-methylcyclohexan-1-one (8). To a solution
of lithium bis(trimethylsilyl)amide (LHMDS, 1.0 M solution in THF,
1.11 mL, 1.11 mmol, 1.05 equiv) at ꢀ78 ꢁC was added the ketone 7
(0.30 g,1.05 mmol) in THF (1.6 mL) via cannulation. After 30 min,1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.27 g,
0.26 mL, 2.11 mmol, 2 equiv) was added to the reaction flask, fol-
lowed by rapid addition of CS2 (84 mg, 67 mL, 1.11 mmol, 1.05 equiv).
The reaction mixture was allowed to warm to 0 ꢁC over 1.5 h, stirred
at this temperature for an additional 1 h before returning to ꢀ78 ꢁC.
A second portion of LHMDS (1.0 M solution in THF, 1.11 mL,
1.11 mmol, 1.05 equiv) was added dropwise. After a further 30 min,
1,3 dibromopropane (0.22 g, 0.11 mL, 1.11 mmol, 1.05 equiv) in THF
(3.3 mL) was added and the solution was warmed to room temper-
ature overnight, then poured into saturated aqueous NH4Cl (10 mL).
The product was extracted with Et2O (3ꢂ5 mL) and the combined
organic layers were washed with brine (10 mL) and dried over
Na2SO4. The residue obtained upon concentration in vacuo was pu-
rified by column chromatography (buffered SiO2, CH2Cl2) to afford
the ketene-S,S-acetal 8 (0.284 g, 0.71 mmol, 68% yield) as a pale
give the unsaturated ester 10 as an oil (1.06 g, 3.35 mmol, 78%
25
yield). [
a
]
ꢀ82.1 (c 2.9, CHCl3); IR (nmax film/cmꢀ1) 2936, 2870,
D
1717, 1649, 1613, 1579, 1463, 1274, 1232, 1212, 1148, 1095, 1037, 998,
866, 833, 730; 1H NMR (400 MHz, CDCl3)
d
6.87 (1H, dd, J¼10.5 and
4.8 Hz, C3H), 6.56 (1H, s, C8H), 6.50 (1H, s, C6H), 5.69 (1H, d,
J¼15.6 Hz, C2H), 4.13 (2H, q, J¼7.1 Hz, OCH2CH3), 3.80 (3H, s, OCH3),
3.13e3.10 (1H, m, C40H), 2.65 (1H, m, C10H), 2.40 (1H, m), 2.31 (3H, s,
C7CH3) 1.87e1.80 (2H, m), 1.69e1.66 (1H, m), 1.44e1.40 (1H, m),
1.27 (3H, t, J¼7.1 Hz, OCH2CH3), 1.11 (3H, d, J¼6.9 Hz, C40CH3), 1.08
yellow oil. [
a
]
25 þ92.8 (c 0.7, MeOH); IR (nmax film/cmꢀ1) 2928, 2856,
(3H, d, J¼6.9 Hz, C5CH3); 13C NMR (151 MHz, CDCl3)
d 168.9, 157.1,
D
1643, 1471, 1418, 1281, 1257, 1089, 836, 775, 668; 1H NMR (600 MHz,
153.3, 138.3, 134.8, 128.4, 122.7, 119.7, 109.1, 60.1, 55.0, 50.3, 42.3,
26.1, 26.0, 21.4, 21.2, 19.6, 18.4, 14.1. HRESIMS m/z 339.1931 (MþNa)
(calcd for C20H28O3Na, 339.1936).
CDCl3)
d
3.51 (2H, dd, A portion of an ABX system, JAB¼7.1 Hz, C20HA),
3.21 (1H, app. sextet, J¼5.9 Hz, C5H), 3.02 (1H, ddd, J¼12.3, 8.3 and
4.3 Hz, SCHA), 2.1 (2H, ddd, J¼14.9, 12.6 and 4.7 Hz, SCH2), 2.72 (1H,
ddd, J¼13.9, 6.9 and 4.6 Hz, SCHB), 2.30 (1H, dd, J¼12.5 and 6.2 Hz),
2.15 (2H, m), 2.09 (1H, m), 2.00 (1H, m), 1.90 (1H, m), 1.69 (1H, m),
4.2.7. Ethyl 4-(R)-(1S,4R,5-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-pentanoate (13). The unsaturated ester 10 (450 mg,1.49 mmol)

6472
J.M.H. Lu et al. / Tetrahedron 69 (2013) 6468e6473
and catalytic amount of Pd/C (15 mg) were stirred in EtOAc (9 mL)
under H2 for 7 days, after which, the reaction mixture was filtered
through CeliteÓ and the solvent evaporated to give the crude oil.
Purification was achieved with column chromatography (buffered
SiO2, CH2Cl2) to afford the saturated ester 13 (412 mg,1.35 mmol, 91%
warmed to room temperature and stirred for a further 1 h. The
reaction mixture was diluted with pentane (5 mL) then quenched
with saturated aqueous NH4Cl (5 mL), the product extracted with
pentane (3ꢂ5 mL), the combined organic layers washed with brine
(5 mL) and concentrated in vacuo. The crude oil was purified by
column chromatography (buffered SiO2, pentane/Et2O 20:1) to af-
yield). [
a
]
25 ꢀ41.2 (c 2.6, CHCl3); IR (nmax film/cmꢀ1) 2955, 2870,1735,
D
1612, 1578, 1462, 1272, 1173, 1097, 1035, 832; 1H NMR (400 MHz,
ford the pure olefin 12 (48 mg, 0.16 mmol, 94%). [
a
]
25 ꢀ42.5 (c 0.4,
D
CDCl3)
d
6.57 (1H, s, C8H) 6.50 (1H, s, C6H), 4.07 (2H, q, J¼7.1 Hz,
MeOH), 1H NMR (600 MHz, CDCl3)
d
6.61 (1H, s, C4H), 6.51 (1H, s,
OCH2CH3), 3.80 (3H, s, OCH3), 3.15e3.13 (1H, m, C40H), 2.58 (2H, m),
2.30 (3H, s, C7CH3), 2.17 (1H, m), 2.17 (C10H), 1.90e1.85 (2H, m),
1.71e1.74 (2H, m), 1.50e1.42 (1H, m), 1.13 (3H, t, J¼7.1 Hz, CH2CH3),
0.96 (3H, d, J¼6.9 Hz, C40CH3), 0.94 (3H, d, J¼6.9 Hz, C5CH3); 13C NMR
C2H), 5.01 (1H, t, J¼7.0 Hz, C50H), 3.81 (3H, s, OCH3), 3.14 (1H, m,
C8H), 2.58 (1H, m, C5H), 2.31 (3H, s, C3CH3), 2.18e1.92 (2H, m),
1.91e1.87 (2H, m), 1.84e1.80 (1H, m), 1.72 (1H, m), [1.68 (3H, d,
J¼1.3 Hz) and 1.56 (3H, d, J¼1.3 Hz) C70H3 and C60CH3], 1.49e1.46
(1H, m), 1.31e1.27 (1H, m), 1.15 (3H, d, J¼6.9 Hz, C8CH3), 1.09 (1H,
(100 MHz, CDCl3) d 165.9, 157.0, 139.7, 134.7, 128.6, 122.2, 108.6, 60.1,
55.1, 42.2, 38.1, 33.0, 28.8, 27.2, 26.4, 21.3, 21.2, 19.3, 18.6, 14.2.
m), 0.97 (3H, d, J¼6.9 Hz, C10H3); 13C NMR (151 MHz, CDCl3)
d 157.0,
140.4, 134.6, 130.9, 128.6, 125.0, 122.1, 108.4, 53.5 42.4, 37.9, 33.4,
27.5, 26.5, 26.3, 25.7, 21.5, 21.4, 19.5, 18.8, 17.6.
4.2.8. 4-(R)-(1S,4R,5-Methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-pentan-1ol (14). To a stirred solution of the saturated ester 13
(300 mg, 0.99 mmol) in CH2Cl2 (10 mL) was added DIBAL-H (1 M in
toluene, 4.00 mL, 4.00 mmol, 4 equiv) at ꢀ78 ꢁC. After 1 h, sodium
potassium tartarate (15 mL) was added and the solution warmed to
room temperature. The product was extracted with CH2Cl2
(3ꢂ15 mL), the combined organic layers washed with brine (5 mL)
and dried over Na2SO4 and concentrated in vacuo. The crude oil was
purified by column chromatography (buffered SiO2, CH2Cl2/Et2O
4.2.11. (5S,8R)-3,8-Dimethyl-5-[60-methylhept-50-en-20-(R)-yl]-5,6,7,8-
tetrahydronaphthalen-1-ol (1). A solution of the methoxy serrula-
tane 12 (88 mg, 0.29 mmol) in DMF (3 mL) was degassed by stirring
under N2 for 30 min prior to the addition of NaSEt (246 mg,
2.9 mmol, 10 equiv). The mixture was refluxed for 2 h, cooled to
room temperature and a second portion of NaSEt (123 mg,
1.45 mmol, 5 equiv) added. The mixture was returned to reflux for
a further 3 h. After cooling to room temperature, the reaction was
quenched with HCl (1 M, 2 mL) and the product extracted in Et2O
(3ꢂ5 mL). The combined organic layers were washed with brine
(2ꢂ2 mL), dried over Na2SO4 and the solvent removed in vacuo. The
crude oil was purified by column chromatography (buffered SiO2,
CH2Cl2/MeOH 9:1) to afford leubethanol (1) (73 mg, 0.24 mmol,
10:1) to give the alcohol 14 (220 mg, 0.79 mmol, 80%). [
a
]
25 ꢀ52.2 (c
D
0.9, CHCl3); IR (nmax film/cmꢀ1 3424, 2955, 2870, 1724, 1612, 1578,
1462, 1343, 1272, 1097, 832); 1H NMR (400 MHz, CDCl3)
d 6.60 (1H,
s, C8H), 6.51 (1H, s, C6H), 3.81 (3H, s, OCH3), 3.53 (2H, dd, J¼10.7
and 4.4 Hz, CH2OH), 3.14 (1H, m, C40H), 2.60 (1H, m, C10H), 2.30 (3H,
s, C7CH3), 1.89e1.83 (3H, m), 1.74 (1H, m), 1.68e1.63 (1H, m), 1.47
(1H, m), 1.33e1.30 (3H, m), 1.13 (3H, d, J¼6.9 Hz, C40CH3), 0.98 (3H,
88%). [
a
]
D
25 ꢀ32 (c 0.15, CHCl3); IR nmax film/cmꢀ1 3461, 2925, 1618,
d, J¼6.9 Hz, C5H3); 13C NMR (151 MHz, CDCl3)
d
157.0, 140.3, 134.8,
1580, 1456; 1H NMR (600 MHz, CDCl3)
d
6.59 (1H, s, C4H), 6.42 (1H,
128.7, 122.0, 108.5, 63.4, 55.2, 42.3, 41.2, 31.2, 29.2, 27.4, 26.5, 21.7,
21.6, 20.3, 19.2. HRESIMS m/z 299.1990 (MþNa) (calcd for
C18H28O2Na, 299.1987).
s, C2H), 5.00 (1H, t, J¼7.0 Hz, C50H), 4.63 (1H, br s, OH), 3.06 (1H, m,
C8H), 2.58 (1H, m, C5H), 2.24 (3H, s, C3CH3), 1.98e1.95 (2H, m),
1.92e1.85 (2H, m), 1.84e1.80 (1H, m), 1.72 (1H, m), [1.68 (3H, d,
J¼1.3 Hz) and 1.55 (3H, d, J¼1.3 Hz) C70CH3 and C60CH3], 1.49e1.46
(1H, m), 1.31e1.27 (1H, m), 1.20 (3H, d, J¼6.9 Hz, C8CH3), 1.06 (1H,
4.2.9. 4-(R)-(1S,4R,5-Methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-pentanal (11). DMSO (79 mg, 72
m
L, 1.01 mmol, 3 equiv) in
m), 0.96 (3H, d, J 6.9, C10H3); 13C NMR (151 MHz, CDCl3)
d 153.0,
CH2Cl2 (2 mL) was stirred at ꢀ78 ꢁC and oxalyl chloride (2.0 M in
141.0, 135.0, 131.1, 126.3, 124.9, 122.4, 113.2, 42.4, 37.8, 33.4, 27.5,
26.6, 26.2, 25.7, 21.2, 21.1, 19.4, 18.7, 17.6. HRESIMS m/z 285.2220
(MꢀH) (calcd for C20H29O, 285.2212).
CH2Cl2, 253 mL, 0.50 mmol, 1.5 equiv) was added dropwise. The
reaction mixture was stirred for 10 min prior to cannulation of the
alcohol 14 (93 mg, 0.33 mmol) in CH2Cl2 (1.5 mL). After 1.5 h, Et3N
(282 mL, 2.02 mmol, 6 equiv) was added dropwise and the flask
Acknowledgements
warmed to room temperature over 1 h. The mixture was quenched
with saturated aqueous NH4Cl (5 mL) and the product extracted
with Et2O (3ꢂ15 mL). The combined organic layers were washed
successively with HCl (1.5 M, 5 mL) and brine (5 mL). The residue
obtained on concentration in vacuo was purified by column chro-
This work was supported by a Bio Innovation SA grant, by the
Robert Mathys Stiftung, Bettlach, Switzerland via a PhD scholarship
for J.M.H.L., and by the Australian Government via NHMRC grant
511349.
matography (SiO2, CH2Cl2) to give the aldehyde 11 (80 mg,
25
0.29 mmol, 87%). [
a
]
ꢀ54.3 (c 1.1, CHCl3); IR (nmax film/cmꢀ1
)
D
Supplementary data
2955, 2870, 1724, 1612, 1579, 1462, 1343, 1271, 1097, 832; 1H NMR
(400 MHz, CDCl3) d 9.63 (1H, s, C1HO), 6.57 (1H, s, C8H), 6.51 (1H, s,
Copies of the 1H NMR, 13C NMR and Accurate Mass Spectra are
C6H), 3.80 (3H, s, OCH3), 3.15e3.13 (1H, m, C40H), 2.61 (1H, m, C10H),
2.30 (3H, s, C7CH3), 2.17e2.16 (2H, m), 1.90e1.85 (2H, m), 1.71e1.74
(3H, m) 1.50e1.42 (2H, m), 1.13 (3H, d, J¼6.9 Hz, C40CH3), 0.97 (3H,
available for compounds 6, 2, 10 & 1. Copies of the 1H NMR and 13
C
NMR spectra are available for compounds 5, 7, 8, 14 & 12 and the 1H
NMR spectrum for compound 13 is available. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.05.082.
d, J¼6.9 Hz, C5H3); 13C NMR (151 MHz, CDCl3)
d 203.2, 157.0, 140.3,
135.0, 128.7, 122.0, 108.6, 55.1, 42.5, 41.2, 38.4, 27.3, 27.2, 26.5, 21.6,
21.5, 20.3, 18.7.
References and notes
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5,6,7,8-tetrahydronaphthalene (12). To a stirred suspension of iso-
propyltriphenyl phosphonium iodide (111 mg, 0.26 mmol,
1.5 equiv) in THF (2 mL) at 0 ꢁC was added n-BuLi (1.24 M in hex-
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