A chemoenzymatic total synthesis of the hirsutene-type sesquiterpene (+)-connatusin B from toluene

Article abstract of DOI:10.1016/j.tet.2010.07.059

The first total synthesis of the hirsutene-type sesquiterpenoid natural product (+)-connatusin B (2) is reported. The cis-1,2-dihydrocatechol 3, which is obtained in enantiomerically pure form via the enzymatic dihydroxylation of toluene, served as the starting material. Diels-Alder cycloaddition and oxa-di-π-methane rearrangement reactions represent key chemical steps in the reaction sequence leading to the cyclopropane ring-fused linear triquinane 14. Reductive cleavage of the three-membered ring within this framework and various functional group interconversions then provide the title compound 2.

Full text of DOI:10.1016/j.tet.2010.07.059

Tetrahedron 66 (2010) 7807e7814
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A chemoenzymatic total synthesis of the hirsutene-type sesquiterpene
(þ)-connatusin B from toluene
*
David J.-Y.D. Bon, Martin G. Banwell , Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2010
Received in revised form 28 June 2010
Accepted 20 July 2010
Available online 27 July 2010
The first total synthesis of the hirsutene-type sesquiterpenoid natural product (þ)-connatusin B (2) is
reported. The cis-1,2-dihydrocatechol 3, which is obtained in enantiomerically pure form via the enzy-
matic dihydroxylation of toluene, served as the starting material. DielseAlder cycloaddition and oxa-di-
p
-methane rearrangement reactions represent key chemical steps in the reaction sequence leading to
the cyclopropane ring-fused linear triquinane 14. Reductive cleavage of the three-membered ring within
this framework and various functional group interconversions then provide the title compound 2.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chemoenzymatic
Connatusin B
DielseAlder
Oxa-di-p-methane
Photochemistry
Sesquiterpene
H
H
OH
1. Introduction
O
OH
OH
In 2005 Rukachaisirikul and co-workers reported the isolation
of the hirsutene-type sesquiterpenoids connatusins A and B, 1 and
2, respectively, from the culture broth of the fungus Lentinus con-
natus BCC 8996.1 The structures of these compounds were initially
established using NMR techniques and that associated with con-
natusin A (1) was confirmed via single-crystal X-ray analysis. The
assigned absolute configurations are consistent with those de-
termined for related members of the linear triquinane family of
natural products.2 Compounds 1 and 2 were evaluated, alongside
various co-metabolites, as antimalarial and cytotoxic agents but
they proved to be inactive.2
HO H
HO H
OH
O
HO
HO
(+)-connatusin B (2)
(+)-connatusin A (1)
3
2. Results and discussion
2.1. Retrosynthetic analysis
The retrosynthetic analysis employed in establishing the pres-
ent synthesis of (þ)-connatusin B (2) is shown in Figure 1 and
follows from our earlier work in the area.3,4 Thus, we anticipated
that reductive cleavage of the carbonyl-conjugated cyclopropane
ring together with various functional group interconversions (FGIs)
would allow for the elaboration of the tetracyclic system 4 into the
target 2. Compound 4 would, in turn, be generated by a photo-
Recently, we have demonstrated that by using a combination of
DielseAlder cycloaddition and oxa-di-p-methane rearrangement
reactions it is possible to convert the readily available, enantio-
merically pure and toluene-derived cis-1,2-dihydrocatechol 3 into
the linear triquinane-type sesquiterpenoids (e)-complicatic acid,
(þ)-hirsutic acid, and (ꢀ)-phellodonic acid.3 We have also used
analogous chemistry to prepare the non-natural enantiomeric
form of the parent hydrocarbon hirsutene.4 Herein, we detail the
adaptation of such work to the first total synthesis of (þ)-con-
natusin B (2) and thereby confirming the assigned structure, in-
cluding absolute configuration, of this natural product.
chemically-promoted oxa-di-p-methane rearrangement of the
cycopenta-fused bicyclo[2.2.2]octenone 5,5 itself the product of
elaboration of the DielseAlder adduct arising from the enantio-
merically pure diene 3 and the dienophile 6. Compounds 3 and 6
are both commercially available with the former being obtained, on
large scale and in enantiomerically pure form, through the whole-
cell biotransformation of toluene using micro-organisms that pro-
duce the responsible enzyme, namely toluene dioxygenase (TDO).6
It is noteworthy that the carbonyl group within dienophile 6 acts in
* Corresponding author. Tel.: þ61 2 6125 8202; fax: þ61 2 6125 8114; e-mail
address: mgb@rsc.anu.edu.au (M.G. Banwell).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.059

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D.J.-Y.D. Bon et al. / Tetrahedron 66 (2010) 7807e7814
several different roles. First of all, it activates the cyclopentene
residue in the cycloaddition reaction and assists in controlling the
regiochemical outcome of this process. It then provides the means
by which the gem-dimethyl group associated with target 2 is in-
troduced and, finally, it serves as the progenitor to the isolated
hydroxy group associated with connatusin B. The successful re-
action sequence arising from this analysis is presented in the
following sections.
Accordingly, compound 10 was treated with acetic anhydride in the
presence of triethylamine and 4-(N,N-dimethylamino)pyridine
(DMAP)9 and in this manner the expected acetate 11 was obtained
in 99% yield. As has been the case with various closely related
substrates,3 hydrolysis of the acetonide unit within compound 11
proved difficult but could be accomplished by treating it with
activated DOWEX-50 resin in refluxing methanol/water mixtures
for 20 h. In this manner, diol 12 was obtained in 90% yield at 53%
conversion. Selective oxidation of the hydroxyl group remote from
the bridgehead methyl group within substrate 12 was effected
using the sterically demanding oxammonium salt derived from
reaction of 1-oxy-4-acetamido-2,2,6,6-tetramethylpiperidine (4-
AcNH-TEMPO) with p-TsOH$H2O10 and the resulting acyloin was
immediately subjected to O-benzoylation using benzoyl chloride in
the presence of triethylamine and DMAP. By this means the sub-
strate, 13, required for the pivotal oxa-di-p-methane rearrange-
ment was obtained in 86% yield (from 12) and all the spectral data
obtained on this compound were in accord with the assigned
structure. In particular, the appearance of a one-proton singlet at
d
5.11 in the 1H NMR spectrum of compound 13, which is attributed
to the oxymethine proton adjacent to the ketone unit, clearly in-
dicated that the mono-oxidation of diol 12 had taken place in the
anticipated manner.
X
O
6
6
Y
5
iii
i
O
R
+
O
O
O
O
O
Figure 1. Retrosynthetic analysis of (þ)-connatusin B (2).
O
8 X = Y = H
9 X = Y = Me
10 R = OH
11 R = OAc
ii
iv
7
2.2. The DielseAlder cycloaddition and oxa-di-p-methane
rearrangement steps
v
As a result of our earlier observations regarding the facial se-
lectivity of DielseAlder cycloaddition reactions involving diene 3
and its derivatives,3,4,7 this compound was first converted into the
corresponding and well-known3b acetonide 7 under standard
conditions. Microwave irradiation of a 1:5 mixture of compounds 6
and 7 (no solvent) at 200 ꢁC for 0.25 h using a reactor supplying
w200 W of power provided the required and previously reported
DielseAlder adduct 8 in 75% yield (Scheme 1).8 Using conditions
applied to a related compound,4 adduct 8 was treated with lithium
hexamethyldisilazide (LiHMDS) and the resulting enolate inter-
cepted with methyl iodide. Repeating this deprotonation/methyl-
ation sequence on the mono-methylated ketone so formed gave the
required gem-dimethylated ketone 9, which was obtained in 56%
yield. Reduction of compound 9 with lithium aluminum hydride in
diethyl ether at ꢀ30 ꢁC then afforded a chromatographically sepa-
rable mixture of compound 10 (79%) and its epimer (19%). Various
NOE experiments carried out on the former product suggested the
correct stereochemistry had been established at the newly created
stereogenic center and confirmation of this followed from single-
crystal X-ray analyses of derivatives obtained after the photo-
chemical rearrangement step. The origins of the reasonably high
levels of stereoselectivity associated with the conversion 9/10
remain unclear at the present time. Given the nature of the con-
versions that had to be undertaken to complete the synthesis of
target 2 from this point, protection of the newly introduced hy-
droxy group associated with compound 10 was necessary. Earlier
work associated with the synthesis of (ꢀ)-phellodonic acid3b sug-
gested that an ester group might serve the required purpose.
H
H
H
AcO
AcO
O
vi, vii
viii
1
OH
OH
AcO
O
OBz
13
X
14 X = OBz
15 X = H
12
ix
x
H
H
H
H
H
xi
H
AcO
AcO
O
O
NMe2
16
17
Scheme 1. Reagents and conditions: (i) see ref. 3b; (ii) LiHMDS (1.1 mol equiv), THF,
ꢀ15/18/ꢀ15 ꢁC, 1.25 h then MeI (1.2 mol equiv), 0.75 h then ꢀ15/18 ꢁ
C (over
1.25 h) then repeat procedure; (iii) LiAlH4 (1.5 mol equiv), Et2O, ꢀ30/18 ꢁC, 6.5 h;
(iv) Ac2O (3 mol equiv), DMAP (cat.), Et3N, 0/18 ꢁC, 16 h; (v) Hþ-DOWEX-50, MeOH/
H2O, reflux, 20 h; (vi) 4-AcNH-TEMPO (2.2 mol equiv), p-TsOH$H2O (2.2 mol equiv),
CH2Cl2, 0/18 ꢁC, 7 h; (vii) BzCl (2.5 mol equiv), DMAP (3.3 mol equiv), Et3N (excess),
CH2Cl2, 0/18 ꢁC, 16 h; (viii) acetophenone (1.4 mol equiv), acetone, photolysis, 18 ꢁC,
3.5 h; (ix) SmI2 (2.2 mol equiv), THF/MeOH, ꢀ78 ꢁC, 0.16 h; (x) LiHMDS (1.2 mol equiv),
THF, ꢀ78 ꢁC, 1 h then Eschenmoser’s salt (3 mol equiv), ꢀ78/18 ꢁC, 16 h; (xi) MeI
(12 mol equiv), Et2O/CH2Cl2, 18 ꢁC, 16 h then Al2O3 (basic), CH2Cl2, 18 ꢁC, 0.5 h.

D.J.-Y.D. Bon et al. / Tetrahedron 66 (2010) 7807e7814
7809
A solution of compound 13 in acetone containing acetophenone
was placed in QuartexÔ immersion-well photo-reactor equipped
with a PyrexÔ filter and irradiated with a 450 W medium-pressure
mercury vapor lamp for 3.5 h. As a result, and in keeping with
outcomes observed in related cases,3 a ca. 1:1 mixture of the epi-
meric forms of compound 14 was obtained in 95% combined yield
(at 76% conversion). While these epimers could be separated
chromatographically and then characterized independently, for the
purposes of continuing the synthesis a THF solution of the mixture
was treated with samarium iodide at ꢀ78 ꢁC in order to effect re-
ductive removal of the benzoyloxy group. In this manner com-
pound 15 was obtained in 81% yield and as a crystalline solid. While
all of the spectral data obtained on this material were in full accord
with the assigned structure, final confirmation of this was obtained
by single-crystal X-ray analysis, details of which are provided in the
Experimental section.
As a prelude to installing the vicinal diol unit associated with
(þ)-connatusin B (2), the enolate derived from ketone 15 was
trapped with Eschenmoser’s salt (Me2N]CH2I)11 and the resulting
tertiary amine 16 (71%) was subjected to a one-pot N-methylation/
Hoffman elimination sequence using methyl iodide then basic
alumina. By such means enone 17 was obtained in 87% yield. The
final steps associated with the elaboration of this pivotal compound
into target 2 are detailed in the following section.
Confirmation of this assignment followed from a single-crystal
X-ray analysis of the corresponding acetonide 19 that was obtained
in 98% yield under standard conditions. Details of the X-ray analysis
are presented in the Experimental section.
With the acetonide 19 in hand attention turned to the final re-
quirement for completion of the synthesis, namely installation of the
cyclopentenone subunit associated with connatusin B. While com-
pound 19 is isomeric with the enone (21) being sought all attempts,
including those involving various metal catalysts, to effect the rele-
vant isomerization were unsuccessful. As a result a reduction/oxi-
dation sequence was needed to effect the necessary conversion.
Thus, treatment of a benzene solution of the carbonyl-conjugated
cyclopropane 19 with 8 molar equivalents of tri-n-butyltin hydride
and the free-radical initiator 1,10-azobisisobutyronitrile (AIBN) and
then heating the resulting mixture at reflux for 6 h resulted in the
smooth cleavage of the three-membered ring and formation of the
linear triquinane 20, which was obtained in 98% yield as a white,
crystalline solid. In order to install the required enone moiety, the
enolate anion derived from ketone 20 using LiHMDS was trapped
with o-nitrophenylselenocyanide.13 The resulting
a-arylselenoke-
tone, which was obtained as a single diastereoisomer, was then
subjected to reaction with m-chloroperbenzoic acid (m-CPBA) and
the selenoxides so formed exposed to diethylamine and oxygen. In
this manner the enone 21 was obtained in 75% overall yield from
precursor 20.14 Finally, exposure of compound 21 to activated
DOWEX-50 resin in refluxing methanol/water mixtures for 16 h
afforded target 2 in 77% yield.
The spectroscopic data obtained on the synthetically-derived
samples of compound 2 were in full accord with the assigned
structure and in good agreement with those reported1 for the
natural product (þ)-connatusin B. In particular, the specific rota-
tions of the two materials were of the same sign and very similar in
2.3. The endgame: installation of the vicinal diol
and enone moieties
Compound 17 would appear to contain all the functionality
necessary for its elaboration into connatusin B (2). As the first step
in such a process (Scheme 2), enone 17 was subjected to reaction
with AD-mix-a
containing added K2OsO4$2H2O.12 After 16 h at 0 ꢁC
magnitude {[
a
]
D þ12.3 (c 0.4, CHCl3) (synthetic) vs [ D þ14 (c 0.44,
a
]
CHCl3) (natural)1}. A comparison of the two sets of 13C NMR spec-
troscopic data is shown in Table 1. The only minor discrepancy in
chemical shifts (Dd>0.2 ppm) is observed for those resonances due
to the carbonyl unit (Dd¼0.4 ppm) and this could be attributed to
the effects of intra- and/or inter-molecular hydrogen bonding in
this polyhydroxylated compound. Certainly, when 13C NMR spectra
of synthetically derived connatusin B (2) were recorded at two
different concentrations (ca. 1 mg/mL and 10 mg/mL) then varia-
tions in the chemical shifts of these signals of up to Dd¼0.4 ppm
were observed. The relevant comparison of the 1H NMR spectral
data sets is also shown in Table 1 and reveals an excellent match
the reaction mixture worked up and after chromatographic puri-
fication diol 18 was obtained in 81% yield. The illustrated config-
uration was assigned to the newly created stereogenic center
within product 18 on the basis that electrophilic attack at the
double-bond within precursor 17 would take place at the more
accessible convex face.
H
H
H
H
H
H
H
H
H
i
ii
other than that the multiplet observed at
the natural product (which is assigned to H-10
d
1.90 in the spectrum of
) is not seen in the
AcO
AcO
AcO
O
O
O
b
HO
O
one derived from the synthetic material. An inspection of the
300 MHz 1H NMR spectrum of the natural product kindly provided
to us by Professor Rukachaisirikul shows a doublet of doublets at
HO
O
17
18
19
d
1.90 but no multiplet at this same position. Interestingly, while
not reported in the original paper, a one-proton triplet can be seen
iii
at ca. d 1.30 in the same spectrum. An equivalent signal is observed
in the 800 MHz 1H NMR spectrum of the synthetically-derived
material (see Table 1). Accordingly, we believe that the multiplet
H
H
H
H
H
10
13
12
H
v
reportedly appearing at
d 1.90 in the spectrum of the natural
iv
7
1
3
product is not real. Final confirmation of the structure of the syn-
thetically-derived sample of connatusin B was secured through
a single-crystal X-ray analysis of its mono-hydrate. The derived
ORTEP is shown in Figure 2 while other details are provided in the
Experimental section. The melting range recorded for the mono-
hydrate of the synthetic material was 116e120 ꢁC while that
reported1 for the natural product is 85.3e85.6 ꢁC. Given the man-
ner in which the natural product was isolated (extraction with
methanol/dichloromethane) these varying melting ranges are
probably attributable to differences in the degree of hydration of
the two samples.
5
H
AcO
HO
AcO
O
15 O
O
O
HO
O
O
HO
O
2
21
20
Scheme 2. Reagents and conditions: (i) AD-mix-
a (excess), K2OsO4$2H2O (excess),
tert-BuOH/H2O, MeSO2NH2 (excess), 0 ꢁC, 16 h; (ii) (MeO)2CMe2 (5 mol equiv),
p-TsOH$H2O (cat.), THF, 0/18 ꢁC, 18 h; (iii) n-Bu3SnH (8 mol equiv), AIBN (cat.), C6H6,
80 ꢁC, 6 h; (iv) (a) LiHMDS (1.05 mol equiv), THF, ꢀ78 ꢁC, 1 h then o-O2NC6H4SeCN
(1.05 mol equiv), ꢀ78/18 ꢁC, 16 h; (b) m-CPBA (1 mol equiv), CH2Cl2, ꢀ78 ꢁC, 0.5 h
then Et2NH, O2, ꢀ78/18 ꢁC, 3 h; (v) Hþ-DOWEX-50, MeOH/H2O, reflux, 16 h.
3

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D.J.-Y.D. Bon et al. / Tetrahedron 66 (2010) 7807e7814
Table 1
Comparison of the 13C and 1H NMR data recorded for naturally-occurring and synthetically-derived (þ)-connatusin B (2)
13C NMR Data (dC
)
1H NMR Data (dH
)
Synthetic 2a
Natural 2b
Synthetic 2c
Natural 2d
209.4
194.1
119.2
84.4
79.6
65.9
54.4
51.5
47.2
45.9
38.9
32.9
26.8
22.6
20.3
209.0
194.2
119.2
84.6
79.5
65.8
54.5
51.1
47.2
45.8
38.9
33.1
26.8
22.6
20.3
5.79 (1H, d, J¼2.1 Hz)
3.83 (1H, d, J¼7.8 Hz)
3.69 (1H, d, J¼12.0 Hz)
3.50 (1H, d, J¼12.0 Hz)
2.83 (1H, dd, J¼16.1 and 8.4 Hz)
2.77e2.70 (1H, m)
2.50 (1H, dd, J¼12.0 and 7.8 Hz)
2.31 (1H, ddd, J¼16.1, 7.8 and 2.1 Hz)
1.91 (1H, dd, J¼12.6 and 7.8 Hz)
Not observed
5.78 (1H, d, J¼2.1 Hz)
3.80 (1H, d, J¼7.8 Hz)
3.67 (1H, d, J¼12.0 Hz)
3.49 (1H, d, J¼12.0 Hz)
2.83 (1H, dd, J¼15.6 and 7.2 Hz)
2.72 (1H, m)
2.51 (1H, dd, J¼12.0 and 7.8 Hz)
2.30 (1H, ddd, J¼15.6, 7.8 and 2.1 Hz)
1.90 (1H, dd, J¼12.6 and 7.5 Hz)
1.90 (1H, m)
See text
1.18 (3H, s)
1.09 (3H, s)
0.98 (3H, s)
d
1.30 (1H, t, J¼12.0 Hz)
1.19 (3H, s)
1.09 (3H, s)
0.98 (3H, s)
d
a
Data recorded in CDCl3 at 100 MHz.
Data obtained from ref. 1 and recorded in CDCl3 at 75 MHz.
Data recorded in CDCl3 at 800 MHz.
b
c
d
Data obtained from ref. 1 and recorded in CDCl3 at 300 MHz.
Unless otherwise specified, spectra were acquired at 20 ꢁC in deu-
terochloroform (CDCl3) that had been stored over anhydrous so-
dium carbonate. Chemical shifts are recorded as
d values in parts
per million (ppm). Infrared spectra (nmax) were normally recorded
on a PerkineElmer 1800 Series FTIR Spectrometer and samples
were analyzed as thin films on KBr plates (for liquids) or as a KBr
disk (for solids). Low-resolution ESI mass spectra were recorded in
positive-ion mode on a MicromasseWaters LC-ZMD single quad-
rupole liquid chromatograph-mass spectrometer while low- and
high-resolution EI mass spectra were recorded on a Fisons VG
AUTOSPEC instrument. Melting points were measured on a Stan-
ford Research Systems Optimelt-Automated Melting Point System
and are uncorrected. Optical rotations were measured at the
sodium-D line (
l
¼589 nm) between 17 and 20 ꢁC and at the con-
centrations (c, in g/100 mL) indicated using spectroscopic grade
chloroform (CHCl3) as solvent. Analytical thin layer chromatogra-
phy (TLC) was performed on aluminum-backed 0.2 mm thick silica
gel 60 F254 plates as supplied by Merck. Eluted plates were visu-
alized using a 254 nm UV lamp and/or by treatment with a suitable
dip followed by heating. These dips included a mixture of vanil-
lin:sulfuric acid:ethanol (1 g:1 g:18 mL) or phosphomolybdic
Figure 2. Molecular structure of compound 2 (C15H22O4) with labeling of non-hy-
drogen atoms. Anisotropic displacement ellipsoids show 30% probability levels. Hy-
drogen atoms are drawn as circles with small radii. Associated water molecule not
shown.
acid:ceric
sulfate:sulfuric
acid
(concd):water
(37.5 g:7.5 g:37.5 g:720 mL). The retardation factor (Rf) values cited
here have been rounded to the first decimal point. Flash chro-
matographic separations were carried out following protocols de-
fined by Still et al.15 using silica gel 60 (0.040e0.0063 mm) as the
stationary phase and the AR- or HPLC-grade solvents indicated.
Starting materials and reagents were generally available from the
SigmaeAldrich, Merck, TCI, Strem or Lancaster Chemical Compa-
nies and were either used as supplied or, in the case of liquids,
distilled when required. Drying agents and other inorganic salts
were purchased from the AJAX, BDH or Unilab Chemical Compa-
nies. THF, dichloromethane and benzene were dried using a Glass
Contour solvent purification system that is based upon a technol-
ogy originally described by Grubbs et al.16 Spectroscopic grade
solvents were used for all analyses. Where necessary, reactions
were performed under a nitrogen or argon atmosphere.
3. Conclusions
The first total synthesis of the hirsutene-type sesquiterpene
(þ)-connatusin B (2) has been achieved and served to confirm the
structure, including absolute configuration, originally assigned to
this natural product. The reaction sequence used further empha-
sizes the utility of the starting material 3 in terpenoid synthesis and
the effectiveness of combinations of DielseAlder cycloaddition and
oxa-di-p-methane rearrangement reactions in providing usefully
functionalized linear triquinanes. Efforts are now focused on
adapting the chemistry presented here to the development of
a total synthesis of connatusin A (1).1 Results will be reported in due
course.
4. Experimental section
4.2. Specific chemical transformations
4.1. General experimental procedures
4.2.1. Compound 9. Lithium hexamethyldisilazide (2.15 mL of a 1 M
solution in THF, 2.15 mmol) was added, dropwise, to a magneti-
cally stirred solution of compound 83a (485 mg, 1.95 mmol) in THF
(15 mL) maintained at ꢀ15 ꢁC under a nitrogen atmosphere. The
Proton (1H) and carbon (13C) NMR spectra were recorded on
a Varian Gemini machine operating at 300 or 75 MHz, respectively.

D.J.-Y.D. Bon et al. / Tetrahedron 66 (2010) 7807e7814
7811
resulting mixture was stirred at ꢀ15 ꢁC for 0.75 h then warmed to
was allowed to warm to 18 ꢁC, stirred at this temperature for 16 h
then quenched with water (20 mL) and extracted with ethyl acetate
(5ꢂ15 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure to give acetate 11
(85 mg, 99%) as a white, crystalline solid, mp¼77e78 ꢁC, Rf¼0.75
18 ꢁC over a period of 1.25 h. Iodomethane (134
mL, 2.15 mmol)
was then added, dropwise, to the solution which had been re-
cooled to ꢀ15 ꢁC and the resulting mixture was stirred at this
temperature for 0.75 h then warmed to 18 ꢁC over a period of
1.25 h. This methylation process was then repeated once more and
thereafter the reaction mixture left to stir at 18 ꢁC overnight then
quenched with ammonium chloride (20 mL of a saturated aque-
ous solution) and extracted with dichloromethane (3ꢂ20 mL). The
combined organic extracts were dried (MgSO4), filtered, and
concentrated under reduced pressure and the light-yellow oil thus
obtained was subjected to flash column chromatography (silica
gel, 1:13.3/1:9 v/v ethyl acetate/hexane gradient elution) to
afford two fractions, A and B.
(in 3:7 v/v ethyl acetate/hexane), [
a
]
D
þ12.3 (c 1.1, CHCl3) [Found:
(MꢀHꢃ)þ, 319.1918. C19H28O4 requires (MꢀHꢃ)þ, 319.1909]. 1H NMR
(CDCl3, 400 MHz)
d
6.08e6.02 (m, 1H), 5.86e5.82 (dm, J¼8.4 Hz,
1H), 4.69 (d, J¼8.4 Hz, 1H), 4.24e4.18 (m, 1H), 3.82e3.78 (dm,
J¼7.2 Hz, 1H), 2.72e2.66 (m, 1H), 2.30e2.18 (m, 1H), 2.05 (s, 3H),
1.80 (dd, J¼10.8 and 8.8 Hz, 1H), 1.52 (dd, J¼12.4 and 8.0 Hz, 1H),
1.31 (s, 3H) 1.27 (s, 3H), 1.14 (t, J¼10.8 Hz, 1H), 1.12 (s, 3H), 0.88 (s,
6H); 13C NMR (CDCl3, 100 MHz)
d 170.3, 135.5, 130.9, 108.7, 82.8,
81.6, 79.4, 48.4, 41.9, 41.8, 40.6, 38.7, 37.5, 25.9, 25.4, 24.8, 22.1, 21.2,
Concentration of fraction A (Rf¼0.3 in 3:7 v/v ethyl acetate/
hexane) gave compound 93a (300 mg, 56%) as a white, crystalline
solid that was identical, in all respects, with an authentic sample.3a
Concentration of fraction B [Rf¼0.2(5) in 3:7 v/v ethyl acetate/
hexane] gave the previously reported3a mono-methylated de-
rivative of compound 8 (109 mg, 21%) as a white, crystalline solid
that was identical, in all respects, with an authentic sample.3a
18.5; nmax (KBr) 2934, 1738, 1454, 1371, 1239, 1202, 1054, 1039, 87þ8,
þ
722 cmꢀ1; MS (EI, 70 eV) m/z 319 [(MꢀHꢃ) , 16%], 305 [(MꢀCH3 ) ,
16], 276 (27), 234 (21), 216 (49), 202 (49), 187 (59), 173 (22), 160
(48), 145 (50), 119 (42), 43 (100).
ꢃ
4.2.4. Compound 12. A magnetically stirred solution of compound
11 (881 mg, 2.75 mmol) in methanol/water (30.6 mL of 5:1 v/v
mixture) was treated with DOWEX-50 resin (1.38 g of material
that had been rinsed successively with 1 M hydrochloric acid,
water, saturated sodium bicarbonate solution and water). The
resulting suspension was heated at reflux for 20 h then cooled and
filtered. The solids thus retained were rinsed with dichloro-
methane (3ꢂ25 mL) and methanol (3ꢂ50 mL) and the combined
filtrates concentrated under reduced pressure to give an off-white
solid. Subjection of this material to flash column chromatography
(silica gel, 1:1 v/v ethyl acetate/hexane elution) afforded two
fractions, A and B.
4.2.2. Compound 10. A magnetically stirred solution of ketone 9
(584 mg, 2.11 mmol) in diethyl ether (15 mL) was cooled to ꢀ30 ꢁC
then treated with lithium aluminum hydride (3.17 mL of a 1 M
solution in THF, 3.17 mmol) over a period of 0.5 h. The ensuing
mixture was left to stir at 18 ꢁC for 6 h then treated with sodium
sulfate (10 drops of a saturated aqueous solution), stirred at 18 ꢁC
for a further 16 h then filtered through CeliteÔ, which was rinsed
with ethyl acetate (15 mL). The combined filtrates were concen-
trated under reduced pressure to give a light-yellow oil and this
was subjected to flash column chromatography (silica gel,
1:13.3/1:1 v/v ethyl acetate/hexane gradient elution) to afford
two fractions, A and B.
Concentration of fraction A (Rf¼0.3) gave the title diol 12
(371 mg, 90% at 53% conversion) as an off-white and waxy solid,
mp¼59e62 ꢁC, [
a]
D
þ5 (c 1.0, CHCl3) [Found: (MþNa)þ, 303.1563.
Concentration of fraction A (Rf¼0.3 in 3:7 v/v ethyl acetate/
C16H24O4 requires (MþNa)þ, 303.1572]. 1H NMR (CDCl3, 400 MHz)
hexane) gave alcohol 10 (464 mg, 79%) as a white, crystalline solid,
d
6.16 (t, J¼8.0 Hz, 1H), 5.91 (d, J¼8.0 Hz, 1H), 4.61 (d, J¼8.0, Hz,
mp¼102e107 ꢁC, [
a
]
D
þ32.1 (c 1.0, CHCl3) [Found: (MꢀHꢃ)þ,
1H), 3.84 (dd, J¼7.2 and 2.4 Hz, 1H), 3.38 (d, J¼7.2 Hz, 1H), 3.10 (br
s, 1H), 2.98 (br s, 1H), 2.64e2.58 (m, 1H), 2.30e2.20 (m, 1H), 2.02
(s, 3H), 1.84e1.77 (m, 1H) 1.48 (dd, J¼12.4 and 8.0 Hz, 1H), 1.09
(s, 3H), 1.10e1.00 (m, 1H), 0.84 (s, 6H); 13C NMR (CDCl3, 100 MHz)
277.1804. C17H26O3 requires (MꢀHꢃ)þ, 277.1804]. 1H NMR (CDCl3,
300 MHz)
d
6.00 (t, J¼8.1 Hz, 1H), 5.78 (d, J¼8.1 Hz, 1H), 4.19 (dd,
J¼7.2 and 3.0 Hz, 1H), 3.80 (d, J¼7.2 Hz, 1H), 3.27 (d, J¼9.0 Hz, 1H),
2.68e2.60 (m, 1H), 2.24e2.08 (m, 1H), 1.57e1.42 (m, 2H), 1.31 (s,
3H), 1.30 (s, 3H), 1.38e1.18 (m, 1H), 1.25 (s, 3H), 1.04e0.92 (m, 1H),
d
170.8, 136.8, 132.3, 82.2, 74.3, 71.3, 49.5, 42.1, 42.0, 41.7, 41.5, 38.2,
26.0, 22.3, 21.4, 18.3; nmax (KBr) 2928, 2873, 1738, 1454, 1373, 1240,
1039, 740, 619 cmꢀ1; MS (ESI, þve ion) m/z 583 [(2MþNa)þ, 100%],
303 [(MþNa)þ, 48].
0.90 (s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 135.9, 131.1,
108.9, 83.4, 82.5, 79.8, 51.4, 41.9, 41.8, 41.0, 39.1, 37.8, 26.1, 25.7, 25.0,
21.2, 19.6; nmax (KBr) 3491, 2957, 2897, 2870, 1457, 1377, 1255, 1207,
Concentration of fraction B (Rf¼0.75 in 3:7 v/v ethyl acetate/
hexane) gave the starting acetonide 11 (410 mg, 47% recovery) as
a white, crystalline solid that was identical, in all respects, with an
authentic sample.
1165, 1080, 1057, 1025, 884, 734 cmꢀ1; MS (EI, 70 eV) m/z 278 (Mþ
,
ꢃ
5%), 277 [(MꢀHꢃ)þ, 10], 263 (20), 220 (35), 178 (55), 119 (65), 106
(75), 43 (100).
Concentration of fraction B (Rf¼0.5 in 3:7 v/v ethyl acetate/
hexane) afforded alcohol C5-epi-10 (115 mg, 20%) as a white,
4.2.5. Compound 13. Step i: A magnetically stirred solution of diol 12
(230 mg, 0.82 mmol) in dichloromethane (15 mL) was cooled to
0 ꢁC then treated with p-toluenesulfonic acid monohydrate
(343 mg, 1.81 mmol). 4-Acetamido-TEMPO (416 mg, 1.81 mmol)
was then added, portionwise over 2 h, and the ensuing mixture
stirred at 0 ꢁC for 2 h then at 18 ꢁC for 3 h before being quenched
with sodium bicarbonate (10 mL of a saturated aqueous solution)
and extracted with dichloromethane (5ꢂ10 mL). The combined
organic extracts were dried (MgSO4), filtered, and concentrated
under reduced pressure to give a light-orange/yellow oil that was
subjected to flash column chromatography (silica gel, 1:4 v/v ethyl
acetate/hexane elution). Concentration of the appropriate fractions
(Rf¼0.6 in 1:1 v/v ethyl acetate/hexane) gave the expected acyloin
crystalline solid, mp¼113e117 ꢁC, [
a
]
ꢀ274 (c 1.0, CHCl3) [Found:
D
(MꢀHþ)ꢀ, 277.1808. C17H26O3 requires (MꢀHþ)ꢀ, 277.1804]. 1H
NMR (CDCl3, 400 MHz)
d
6.08e5.99 (m, 2H), 4.22 (dd, J¼7.2 and
2.8 Hz, 1H), 3.83 (d, J¼7.6 Hz, 1H), 3.56e3.48 (m, 1H), 2.80e2.74 (m,
1H), 2.26e2.16 (m, 1H), 2.01 (dd, J¼10.4 and 5.6 Hz, 1H), 1.45e1.36
(m, 1H), 1.38 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.28e1.22 (m, 1H), 1.10
(t, J¼11.2 Hz, 1H), 0.94 (s, 3H), 0.87 (s, 3H); 13C NMR (CDCl3,
100 MHz)
d 138.1, 130.3, 109.0, 83.8, 81.7, 80.3, 51.1, 45.0, 41.0, 40.9,
40.8, 38.4, 25.8, 25.6, 25.1, 22.6, 19.8; nmax (KBr) 3552, 3043, 2958,
2935, 2901, 2857, 1462, 1383, 1369, 1256, 1160, 1078, 872 cmꢀ1; MS
(ESI, ꢀve ion) m/z 277 [(MꢀHþ)ꢀ, 10%], 255 (60),161 (78),145 (100).
4.2.3. Compound 11. A magnetically stirred solution of alcohol 10
(73 mg, 0.27 mmol) and 4-(N,N-dimethylamino)pyridine (3 mg,
0.02 mmol) in triethylamine (3 mL) was cooled to 0 ꢁC then treated
(214 mg, 94%) as a white, crystalline solid, mp¼96e97 ꢁC, [
a]
D
þ192.4 (c 0.7, CHCl3) (Found: Mþꢃ, 278.1513. C16H22O4 requires Mþ
,
ꢃ
278.1518). 1H NMR (CDCl3, 400 MHz)
d 6.18e6.10 (m, 2H), 4.76 (d,
with acetic anhydride (75
mL, 0.80 mmol). The resulting mixture
J¼8.8, Hz, 1H), 3.34 (s, 1H), 3.08e3.03 (m, 1H), 2.81 (br s, 1H),

7812
D.J.-Y.D. Bon et al. / Tetrahedron 66 (2010) 7807e7814
2.73e2.63 (m, 1H), 2.22 (dd, J¼11.2 and 8.8 Hz,1H), 2.07 (s, 3H),1.63
(dd, J¼12.8 and 8.0 Hz, 1H), 1.19 (s, 3H) 1.19e1.08 (m, 1H), 0.91
J¼10.4 and 5.2 Hz, 1H), 2.05 (s, 3H), 2.06e1.97 (m, 1H), 1.84 (dd,
J¼10.0 and 6.0 Hz, 1H), 1.39 (dd, J¼13.6 and 6.4 Hz, 1H), 1.17 (s, 3H),
(s, 3H), 0.90 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d
211.4, 170.7, 140.3,
1.02 (s, 3H), 0.90 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 209.5, 170.8,
127.0, 81.5, 74.1, 50.9, 50.5, 44.2, 41.5, 41.3, 36.3, 25.8, 22.1, 21.2, 17.1;
165.7, 133.5, 130.0, 129.4, 128.6, 84.8, 80.1, 61.2, 50.8, 44.5, 43.5, 41.1,
39.7, 39.1, 38.7, 26.8, 22.0, 21.3, 14.1; nmax (KBr) 2962, 1734, 1602,
1451, 1369, 1266, 1242, 1095, 711 cmꢀ1; MS (ESI, þve ion) m/z 787
[(2 MþNa)þ, 8%], 405 [(MþNa)þ, 100%], 383 [(MþH)þ, 15], 173 (38).
Concentration of fraction C (Rf¼0.4 in 1:4 v/v ethyl acetate/
hexane) gave the starting keto-benzoate 13 (102 mg, 24% recovery)
as a white, crystalline solid that was identical, in all respects, with
an authentic sample.
nmax (KBr) 3401, 2961, 2873, 1736, 1464, 1373, 1241, 1036, 725 cmꢀ1
;
MS (EI, 70 eV) m/z 278 (Mþꢃ, 11%), 218 (73), 203 (67), 175 (42), 161
(68), 159 (55), 145 (74), 105 (67), 95 (60), 43 (100).
Step ii: A magnetically stirred solution of the acyloin (90 mg,
0.32 mmol, formed in step i), triethylamine (1 mL) and 4-(N,N-
dimethylamino)pyridine (129 mg, 1.06 mmol) in dichloro-methane
(5 mL) was cooled to 0 ꢁC then treated with benzoyl chloride (92
mL,
0.79 mmol). The resulting mixture was allowed to warm to 18 ꢁC,
stirred at this temperature for 16 h then treated with HCl (20 mL of
a 1 M aqueous solution) and extracted with dichloromethane
(4ꢂ15 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure to give a light-
yellow oil that was subjected to flash column chromatography
(silica gel, 1:13.3/1:9 v/v ethyl acetate/hexane gradient elution).
Concentration of the relevant fractions (Rf¼0.4 in 1:4 v/v ethyl ac-
etate/hexane) then gave the keto-benzoate 13 (111 mg, 91%) as
4.2.7. Compound 15. A magnetically stirred solution of either epi-
meric form of compound 14 (161 mg, 0.42 mmol), or a mixture
thereof, in THF/methanol (8 mL of a 2:1 v/v mixture) was cooled to
ꢀ78 ꢁC and, while being maintained under an argon atmosphere,
was treated with samarium(II) iodide (9.27 mL of a 0.1 M solution
in THF, 0.93 mmol) by dropwise addition until a blue color persisted
for w10 min. After this time the reaction mixture was quenched
with potassium carbonate (10 mL of saturated aqueous solution)
and extracted with diethyl ether (3ꢂ2 mL). The combined organic
extracts were then washed with water (1ꢂ5 mL) and brine
(1ꢂ5 mL) before being dried (Na2SO4), filtered, and concentrated
under reduced pressure to give a light-yellow oil that was subjected
to flash column chromatography (silica gel, 1:4 v/v ethyl acetate/
hexane elution). Concentration of the relevant fractions (Rf¼0.3 in
1:3 v/v ethyl acetate/hexane) then gave the title compound 15
a white, crystalline solid, mp¼111e114 ꢁC, [
D þ170.4 (c 1.1, CHCl3)
a
]
(Found: Mþꢃ, 382.1772. C23H26O5 requires Mþꢃ, 382.1780). 1H NMR
(CDCl3, 400 MHz)
d
8.02e7.97 (m, 2H), 7.58e7.53 (tm, J¼7.6 Hz, 1H),
7.45e7.39 (m, 2H), 6.30e6.20 (m, 2H), 5.11 (s, 1H), 4.80 (d, J¼8.4 Hz,
1H), 3.20e3.14 (m, 1H), 2.86e2.76 (m, 1H), 2.44 (dd, J¼10.8 and
8.8 Hz, 1H), 2.07 (s, 3H), 1.69 (dd, J¼12.8 and 8.0 Hz, 1H), 1.27e1.18
(m, 1H), 1.10 (s, 3H), 0.96 (s, 3H), 0.94 (s, 3H); 13C NMR (CDCl3,
75 MHz)
d
205.1, 170.7, 166.2, 139.5, 133.4, 130.0, 129.3, 128.5, 127.8,
(90 mg, 81%) as a white, crystalline solid, mp¼126e129 ꢁC, [
a]
D
81.5, 73.7, 51.6, 50.3, 43.4, 41.6, 41.4, 36.7, 25.9, 22.2, 21.3, 17.2; nmax
(KBr) 2965, 2873, 1738, 1693, 1451, 1375, 1270, 1241, 1109, 1043,
771 cmꢀ1; MS (EI, 70 eV) m/z 382 (Mþꢃ, 4%), 226 (29), 200 (68), 198
(57), 160 (70), 145 (63), 122 (100), 121 (75), 106 (83), 105 (98), 77
(90), 51 (93), 50 (64), 43 (64).
þ68.1 (c 0.8, CHCl3) [Found: (MþH)þ, 263.1642. C16H22O3 requires
(MþH)þ, 263.1647]. 1H NMR (CDCl3, 400 MHz)
5.03 (d, J¼10.0 Hz,
d
1H), 2.60e2.54 (m, 1H), 2.41 (t, J¼5.2 Hz, 1H), 2.33 (dd, J¼17.6 and
1.2 Hz, 1H), 2.26 (dd, J¼10.0 and 7.6 Hz, 1H), 2.05 (s, 3H), 2.00e1.94
(m, 3H), 1.69e1.62 (m, 1H), 1.34 (dd, J¼13.6 and 6.4 Hz, 1H), 1.25 (s,
3H), 0.98 (s, 3H), 0.83 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 214.3,
4.2.6. Compound 14. A deoxygenated solution of compound 13
(428 mg, 1.12 mmol) and acetophenone (180 mL, 1.54 mmol) in ac-
170.7, 80.5, 64.3, 57.7, 46.9, 44.7, 43.0, 39.7, 39.5, 38.9, 38.5, 26.9,
22.1, 21.3, 21.1; nmax (KBr) 2942, 1716, 1378, 1244, 1041, 961,
886 cmꢀ1; MS (ESI, þve ion) m/z 285 [(MþNa)þ, 15%], 263 [(MþH)þ,
<1], 102 (100).
etone (200 mL) was placed in a QuartexÔ immersion well photo-
reactor (500 mL reactor from Ace Glass Inc.) equipped with
a PyrexÔ filter. The solution was subjected to irradiation with
a Hanovia 450 W medium pressure mercury-vapor lamp for 3.5 h
and then cooled and concentrated under reduced pressure to give
a pale-yellow oil. Subjection of this material to flash column
chromatography (silica gel, 1:20/1:4 v/v ethyl acetate/hexane
gradient elution) afforded three fractions, A, B and C.
4.2.8. Compound 16. A magnetically stirred solution of ketone 15
(86 mg, 0.33 mmol) in THF (4.4 mL) maintained at ꢀ78 ꢁC under an
argon atmosphere was treated, dropwise, with LiHMDS (394 mL of
a 1 M THF solution, 0.39 mmol) and the resulting mixture left to stir
at ꢀ78 ꢁC for 1 h. After this time, Eschenmoser’s salt (182 mg,
0.98 mmol) was added, in one portion, to the reaction mixture,
which was then allowed to warm to 18 ꢁC over 16 h before being
quenched with HCl (10 mL of a 3 M aqueous solution) and, after
5 min., extracted with diethyl ether (3ꢂ10 mL). The separated
aqueous phase was basified, to pH 14, then extracted with
dichloromethane (3ꢂ10 mL). The combined organic extracts were
dried (Na2SO4), filtered, and concentrated under reduced pressure
to afford the title amine 16 (75 mg, 71%) as a white, crystalline solid,
Concentration of fraction A (Rf¼0.25 in 1:4 v/v ethyl acetate/
hexane) gave the C1-b epimeric form of compound 14 (165 mg, 51%
at 76% conversion) as a white, crystalline solid, mp¼135e136 ꢁC,
[
a
]
þ14.9 (c 1.0, CHCl3) [Found: (MþH)þ, 383.1858. C23H26O5 re-
D
quires (MþH)þ, 383.1858]. 1H NMR (CDCl3, 400 MHz)
d 8.08e8.04
(m, 2H), 7.60 (t, J¼8.0, Hz, 1H), 7.50e7.46 (m, 2H), 5.35 (d, J¼4.0 Hz,
1H), 5.13 (d, J¼12.0 Hz, 1H), 2.75 (dd, J¼12.0 and 8.0 Hz, 1H),
2.58e2.50 (m, 1H), 2.35 (t, J¼4.0 Hz, 1H), 2.06e2.00 (m, 1H), 2.01
(s, 3H), 1.98e1.94 (m, 1H), 1.82 (dd, J¼12.0 and 8.0 Hz, 1H), 1.42 (dd,
J¼12.0 and 6.4 Hz, 1H), 1.36 (s, 3H), 1.01 (s, 3H), 0.90 (s, 3H); 13C
mp¼110e114 ꢁC, Rf¼0.7 in 1:3 v/v ethyl acetate/hexane, [
D ꢀ64.3
a
]
(c 1.0, CHCl3) [Found: (MþH)þ, 320.2224. C19H29NO3 requires
NMR (CDCl3, 75 MHz)
d
205.6, 170.7, 165.4, 133.5,130.0, 129.5, 128.6,
(MþH)þ, 320.2226]. 1H NMR (CDCl3, 400 MHz)
5.04 (d, J¼13.2 Hz,
d
83.7, 80.0, 55.7, 49.4, 44.3, 43.1, 38.9, 36.0, 33.7, 32.1, 26.7, 21.8, 21.3,
19.6; nmax (KBr) 2960, 2929, 2873, 1727, 1452, 1370, 1269, 1241, 1110,
1042, 710 cmꢀ1; MS (ESI, þve ion) m/z 405 [(MþNa)þ, 100%] 383
[(MþH)þ, 11].
1H), 2.60e2.52 (m, 1H), 2.46e2.35 (m, 2H), 2.28e2.20 (m, 2H), 2.18
(s, 6H), 2.08e1.98 (m, 1H), 2.03 (s, 3H), 1.96e1.86 (m, 2H), 1.63 (dd,
J¼10.4 and 6.0 Hz, 1H), 1.25 (dd, J¼13.2 and 6.8 Hz, 1H), 1.16 (s, 3H),
0.95 (s, 3H) 0.80 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 214.7, 170.5,
Concentration of fraction B (Rf¼0.35 in 1:4 v/v ethyl acetate/
80.2, 64.7, 62.2, 59.8, 49.6, 45.6, 44.2, 42.9, 38.6, 38.4, 37.7, 36.4,
26.6, 21.6, 21.2, 15.9; nmax (KBr) 2960, 2866, 2822, 2768, 1732, 1455,
1369, 1241, 1040, 900, 819, 736 cmꢀ1; MS (ESI, þve ion) m/z 320
[(MþH)þ, 25%], 58 (97), 57 (100).
hexane) gave the C1-a epimeric form of compound 14 (143 mg, 44%
at 76% conversion) as a white, crystalline solid, mp¼139e150 ꢁC,
[
a
]
þ18.6 (c 1.0, CHCl3) [Found: (MþNa)þ, 405.1671. C23H26O5 re-
D
quires (MþNa)þ, 405.1678]. 1H NMR (CDCl3, 400 MHz)
d 8.06e8.02
(m, 2H), 7.58 (t, J¼7.6 Hz, 1H), 7.47e7.41 (m, 2H), 5.14 (d, J¼9.6 Hz,
1H), 4.97 (s, 1H), 2.70e262 (m, 1H), 2.60e2.50 (m, 2H), 2.22 (dd,
4.2.9. Compound 17. A magnetically stirred solution of tertiary
amine 16 (195 mg, 0.61 mmol) in diethyl ether/dichloromethane

D.J.-Y.D. Bon et al. / Tetrahedron 66 (2010) 7807e7814
7813
(15 mL of a 3:1 v/v mixture), maintained at 18 ꢁC under a nitrogen
atmosphere, was treated with iodomethane (456 L, 7.33 mmol)
26.6, 26.4, 26.1, 21.6, 21.3, 13.0; nmax (KBr) 2930, 2858, 1738, 1462,
1379, 1238, 1158, 1043, 946, 867 cmꢀ1; MS (ESI, þve ion) m/z 371
[(MþNa)þ, 100%], 331 (97).
m
and the resulting solution stirred at the same temperature for 16 h
then concentrated under reduced pressure to give a yellow oil. This
oil was dissolved in dichloromethane (15 mL) and the solution
so-obtained treated with basic alumina (ca. 500 mg of
0.063e0.200 mesh material, activity grade 1). The resulting sus-
pension was stirred at 18 ꢁC for 0.5 h then concentrated under re-
duced pressure. The ensuing solid was loaded onto the top of
4.2.12. Compound 20. A magnetically stirred solution of cyclopropyl
ketone 19 (118 mg, 0.34 mmol) in benzene (10 mL) maintained at
18 ꢁC under an argon atmosphere was treated with AIBN (1 mg,
0.003 mmol) and tri-n-butyltin hydride (197 mL, 0.68 mmol). The
resulting solution was heated at reflux for 1.5 h then allowed to cool
to 18 ꢁC. The addition of further aliquots of AIBN and tri-n-butyltin
hydride and subsequent heating of resulting solution at reflux was
repeated three times and with the result that all of the starting
material was then consumed. The cooled reaction mixture was
concentrated under reduced pressure and the residue subjected to
flash column chromatography (silica gel, 1:9 v/v ethyl acetate/
hexane elution). Concentration of the relevant fractions (Rf¼0.6 in
1:3 v/v ethyl acetate/hexane) gave compound 20 (117 mg, 98%) as
a
column of TLC-grade alumina and this was eluted with
dichloromethane. Concentration of the relevant fractions (Rf¼0.6 in
1:3 v/v ethyl acetate/hexane) gave the title compound 17 (146 mg,
87%) as a white, crystalline solid, mp¼122e127 ꢁC, [
D ꢀ61.0 (c 1.0,
a
]
CHCl3) (Found: Mþꢃ, 274.1566. C17H22O3 requires Mþꢃ, 274.1569). 1H
NMR (CDCl3, 400 MHz)
d
5.83 (d, J¼1.6 Hz, 1H), 5.12e5.06 (m, 2H),
2.50e2.40 (m, 2H), 2.28e2.20 (m, 1H), 2.16e2.10 (m, 1H), 2.10
(s, 3H), 1.95 (dd, J¼13.2 and 9.6 Hz, 1H), 1.85 (dd, J¼10.0 and 6.0 Hz,
1H), 1.35 (dd, J¼14.0 and 6.0 Hz, 1H), 1.30 (s, 3H), 1.00 (s, 3H) 0.83
a white, crystalline solid, mp¼58e61 ꢁC, [
a
]
þ42.4 (c 1.0, CHCl3)
D
(s, 3H); 13C NMR (CDCl3, 75 MHz)
d
203.2, 170.8, 156.6, 114.0, 80.4,
[Found: (MþNa)þ, 373.1997. C20H30O5 requires (MþNa)þ,
66.3, 50.8, 44.6, 43.3, 42.1, 39.5, 38.6, 38.1, 27.1, 22.2, 21.4, 18.4; nmax
(KBr) 2925, 2853, 1739, 1715, 1633, 1464, 1374, 1322, 1240, 1093,
1043, 956, 852, 801 cmꢀ1; MS (EI, 70 eV) m/z 274 (Mþꢃ, 4%), 259
(11), 214 (78), 199 (81), 171 (54), 145 (58), 43 (100).
373.1991]. 1H NMR (CDCl3, 400 MHz)
d
5.11 (d, J¼8.8 Hz, 1H), 4.13
(d, J¼8.8 Hz, 1H), 3.60 (d, J¼8.8 Hz, 1H), 2.76e2.60 (m, 2H),
2.60e2.50 (m, 1H), 2.05 (s, 3H), 2.02e1.92 (m, 1H), 1.86e1.68
(m, 3H), 1.58e1.48 (m, 1H), 1.36 (s, 3H), 1.30 (s, 3H), 1.25e1.17
(m, 1H), 1.14 (s, 3H), 0.96 (s, 3H), 0.86 (s, 3H); 13C NMR (CDCl3,
4.2.10. Compound 18. A magnetically stirred solution of enone 17
(74 mg, 0.27 mmol) in toluene (3 mL) and tert-butanol/water
(2.7 mL of a 1:1 v/v mixture) maintained at 0 ꢁC was treated with
100 MHz) d 215.7, 170.4, 111.3, 89.6, 80.4, 65.2, 51.6, 51.5, 47.9, 46.8,
45.8, 39.6, 39.4, 36.7, 26.9, 26.5, 25.9, 21.3, 21.2, 16.3; nmax (KBr)
2927, 2855, 1742, 1464, 1378, 1233, 1031 cmꢀ1; MS (ESI, þve ion)
m/z 373 [(MþNa)þ, 100%].
methane sulfonamide (13 mg, 13 mmol) and AD mix-
a (378 mg
with added K2OsO4$2H2O such that the total osmium tetroxide
content was 1 mg). The resulting solution was left to stir at 0 ꢁC
for 16 h then subjected to flash column chromatography (silica
gel, 1:1 v/v ethyl acetate/hexane). Concentration of the relevant
4.2.13. Compound 21. Step i: A magnetically stirred solution of tri-
quinane 20 (55 mg, 0.16 mmol) in THF (5 mL) maintained at ꢀ78 ꢁC
under a nitrogen atmosphere, was treated, dropwise, with LiHMDS
fractions (Rf¼0.4) gave the title compound 18 (67 mg, 81%) as
(173 mL of a 1.0 M solution in THF, 0.17 mmol) and the resulting
ꢀ68.1 (c 1.1, CHCl3) (Found: Mþ
,
solution was stirred at this temperature for 1 h. After this time o-
nitrophenyl selenocyanate (39 mg, 0.17 mmol) was added and the
ensuing mixture allowed to warm to 18 ꢁC and stirred for at this
temperature for 16 h then quenched with ammonium chloride
(5 mL of a saturated aqueous solution) and extracted with ethyl
acetate (3ꢂ5 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure to give
a light-yellow oil that was subjected to flash column chromatog-
raphy (silica gel, 1: 9 v/v ethyl acetate/hexane elution) to afford two
fractions, A and B.
ꢃ
a clear, colorless oil, [
a
]
D
308.1623. C17H24O5 requires Mþꢃ, 308.1624). 1H NMR (CDCl3,
400 MHz)
d
5.06 (d, J¼9.6 Hz, 1H), 3.84 (d, J¼12.0 Hz, 1H), 3.74 (br
s, 1H), 3.35 (d, J¼12.0 Hz, 1H), 2.94 (br s, 1H), 2.44 (t, J¼5.6 Hz,
1H), 2.42e2.34 (m, 1H), 2.18e2.14 (m, 1H), 2.14e2.08 (m, 1H), 2.09
(s, 3H), 1.97e1.88 (m, 1H), 1.76 (dd, J¼10.4 and 6.0 Hz, 1H) 1.35
(dd, J¼13.6 and 6.0 Hz, 1H), 1.22 (s, 3H), 0.98 (s, 3H), 0.82 (s, 3H);
13C NMR (CDCl3, 75 MHz)
d 215.2, 170.6, 81.8, 80.3, 61.7, 55.7, 52.7,
44.4, 43.1, 39.8, 38.8, 38.5, 34.9, 26.9, 22.2, 21.3, 12.5; nmax (KBr)
3460, 2959, 2927, 2871, 1731, 1465, 1370, 1241, 1042 cmꢀ1; MS (EI,
70 eV) m/z 308 (Mþꢃ, 7%), 279 (30), 167 (35), 149 (100), 71 (34), 57
(51), 43 (73).
Concentration of fraction A (Rf¼0.3 in 1:3 v/v ethyl acetate/
hexane) gave the expected o-nitrophenylselenide (25 mg, 76% at 38%
conversion) as a waxy, yellow oil, [
a
]
D ꢀ150.0 (c 1.0, CHCl3) [Found:
4.2.11. Compound 19. A magnetically stirred solution of diol 18
(MþNa)þ, 574.1320. C26H33NO7Se requires (MþNa)þ, 574.1320]. 1H
(67 mg, 0.22 mmol) in THF (5 mL) maintained at 0 ꢁC was treated
NMR (CDCl3, 400 MHz) d 8.30e8.20 (m, 2H), 7.60e7.50 (m, 1H),
with 2,20-dimethoxypropane (133
m
L, 1.09 mmol) and p-toluene-
7.40e7.30 (m, 1H), 5.16 (d, J¼8.0 Hz, 1H), 4.23 (d, J¼8.8 Hz, 1H), 3.59
(d, J¼8.8 Hz, 1H), 3.44 (d, J¼6.8 Hz, 1H), 2.86e2.76 (m, 1H), 2.54 (t,
J¼6.4 Hz, 1H), 2.08 (s, 3H), 2.11e2.02 (m, 1H), 1.98e1.91 (m, 1H),
1.82e1.74 (m, 1H),168e1.57 (m, 2H), 1.40 (s, 3H),1.32 (s, 3H), 1.24 (s,
sulfonic acid monohydrate (2 mg, 0.01 mmol) and the resulting
solution was stirred at 0 ꢁC for 2 h before being allowed to warm to
18 ꢁC and then left to stand at this temperature for 16 h. The en-
suing mixture was quenched with sodium hydrogen carbonate
3H), 0.99 (s, 3H), 0.91 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 214.7,
(5 mL of
a
saturated aqueous solution) and extracted with
170.4, 146.4, 134.5, 134.2, 131.2, 126.4, 126.2, 112.1, 89.6, 80.1, 64.7,
56.1, 51.8, 50.7, 47.2, 46.0, 44.3, 39.9, 35.3, 26.8, 26.5, 25.8, 21.3, 21.1,
16.0; nmax (KBr) 2925, 2854, 1741, 1591, 1567, 1514, 1463, 1379, 1332,
1306, 1232, 1035, 853, 730 cmꢀ1; MS (ESI, þve ion) m/z 574
[(MþNa)þ, 26%], 373 (39), 357 (100).
dichloromethane (3ꢂ10 mL). The combined organic extracts were
washed with brine (1ꢂ10 mL) then dried (MgSO4), filtered, and
concentrated under reduced pressure to give the acetonide 19
(74 mg, 98%) as a colorless, crystalline solid, mp¼145e152 ꢁC,
Rf¼0.5 in 1:3 v/v ethyl acetate/hexane, [
a
]
ꢀ38.6 (c 1.0, CHCl3)
Concentration of fraction B (Rf¼0.6 in 1:3 v/v ethyl acetate/
hexane) gave the starting ketone 20 (34 mg, 62% recovery) as
a white, crystalline solid that was identical, in all respects, with an
authentic sample.
D
[Found: (MþNa)þ, 371.1829. C20H28O5 requires (MþNa)þ, 371.1834].
1H NMR (CDCl3, 400 MHz)
d
5.08 (d, J¼9.6 Hz, 1H), 4.11 (d, J¼9.2 Hz,
1H), 3.64 (d, J¼9.2 Hz, 1H), 2.44e2.35 (m, 2H), 2.13 (dd, J¼10.0 and
4.8 Hz, 1H), 2.06 (s, 3H), 1.90e1.78 (m, 2H), 1.75 (dd, J¼10.4 and
6.0 Hz, 1H), 1.38 (s, 3H), 1.35 (s, 3H), 1.42e1.30 (m, 1H), 1.22 (s, 3H),
Step ii: A magnetically stirred solution of the selenide (25 mg,
0.05 mmol) prepared via step i in dichloromethane (3 mL) main-
tained under argon at ꢀ78 ꢁC was treated with m-CPBA (12 mg of
ca. 70% technical grade material, 0.05 mmol) and the resulting
0.97 (s, 3H), 0.80 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d
209.7, 170.5,
111.2, 93.4, 80.4, 64.3, 57.0, 51.3, 44.1, 43.5, 39.4, 39.2, 37.3, 34.0,

7814
D.J.-Y.D. Bon et al. / Tetrahedron 66 (2010) 7807e7814
solution was stirred at this temperature for 0.5 h. After this time
diethylamine (100 L, 0.97 mmol) was added and the resulting
4.3.4. Structure determinations. Images were measured on a Nonius
Kappa CCD diffractometer (MoKa, graphite monochromator,
m
mixture allowed to warm to 18 ꢁC then stirred at this temperature
in the presence of atmospheric oxygen for 3 h. The reaction mixture
was quenched with sodium bicarbonate (5 mL of a saturated
aqueous solution) then extracted with ethyl acetate (3ꢂ5 mL). The
combined organic extracts were washed with brine (1ꢂ5 mL) then
dried (MgSO4), filtered, and concentrated under reduced pressure
to give a light-yellow oil. Subjection of this material to flash column
chromatography (silica gel, 1:9 v/v ethyl acetate/hexane elution)
and concentration of the relevant fractions (Rf¼0.7 in 1:1 v/v ethyl
acetate/hexane) afford enone 21 (15 mg, 95%) as a white, crystalline
l
¼0.71073 Å) and data extracted using the DENZO package.17
Structure solution was by direct methods (SIR92).18 The struc-
tures of compounds 15, 19 and 2 were refined using the CRYSTALS
program package.19 Atomic coordinates, bond lengths and angles,
and displacement parameters have been deposited at the Cam-
bridge Crystallographic Data Center (CCDC nos. 775438, 775439
and 775437 for 15, 19 and 2, respectively). These data can be
obtained free-of-charge via www.ccdc.cam.ac.uk/data_request/cif,
by emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Center, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: þ44 1223 336033.
solid, [
a
]
D þ2.9 (c 0.5, CHCl3) [Found: (MþNa)þ, 371.1834. C20H28O5
requires (MþNa)þ, 371.1834]. 1H NMR (CDCl3, 400 MHz)
d 5.82
(d, J¼2.0 Hz, 1H), 5.24 (d, J¼8.0 Hz, 1H), 3.98 (d, J¼8.8 Hz, 1H), 3.79
(d, J¼8.8 Hz, 1H), 2.86e2.62 (m, 3H), 2.33 (ddd, J¼15.6, 8.4 and
2.0 Hz,1H), 2.06 (s, 3H),1.97 (dd, J¼12.8 and 8.0 Hz,1H),1.55 (s, 3H),
1.43 (s, 3H), 1.28e1.22 (m, 1H), 1.19 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H);
Acknowledgements
We thank the Australian Research Council and the Institute of
Advanced Studies for generous financial support. DJ-YDB is the
grateful recipient of an ANU PhD Scholarship. We thank Professor
Vatcharin Rukachaisirikul (Prince of Songkla University, Songkhla,
Thailand) for providing copies of the 1H and 13C NMR spectra
recorded on naturally-derived connatusin B.
13C NMR (CDCl3, 100 MHz)
d 191.6, 170.6, 120.8, 111.7, 92.1, 80.2,
70.2, 54.0, 48.1, 46.5, 46.2, 39.6, 34.9, 29.9, 27.1, 26.6, 25.7, 23.8, 21.8,
21.4; nmax (KBr) 2929, 1729, 1708, 1629, 1369, 1248, 1048 cmꢀ1; MS
(ESI, þve ion) m/z 371 [(MþNa)þ, 28%], 74 (100).
4.2.14. Compound 2. A magnetically stirred solution of enone 21
(12 mg, 0.03 mmol) in methanol/water (1 mL of a 5:1 v/v mixture)
was treated with DOWEX-50 resin [ 24 mg of material that had
been rinsed successively with 1 M hydrochloric acid, water, satu-
rated sodium bicarbonate solution and water] and the resulting
suspension was heated at reflux for 16 h. The cooled reaction
mixture was filtered and the solids thus retained were rinsed with
dichloromethane (3ꢂ10 mL) and methanol (3ꢂ25 mL). The com-
bined filtrates were concentrated under reduced pressure to give
an off-white solid. Subjection of this material to flash column
chromatography (silica gel, ethyl acetate elution) and concentration
of the appropriate fractions (Rf¼0.4) afforded connatusin B (2)
References and notes
1. Rukachaisirikul, V.; Tansakul, C.; Saithong, S.; Pakawatchai, C.; Isaka, M.;
Suvannakad, R. J. Nat. Prod. 2005, 68, 1674.
2. For reviews on triquinanes, including natural products embodying this
framework, see: (a) Paquette, L. A. Top. Curr. Chem. 1979, 79, 41; (b) Trost, B. M.
Chem. Soc. Rev. 1982, 11, 141; (c) Paquette, L. A. Top. Curr. Chem. 1984, 119, 1; (d)
Paquette, L. A.; Doherty, A. M. Polyquinane Chemistry: Synthesis and Reactions;
SpringereVerlag: Berlin, 1987; (e) Mehta, G.; Srikrishna, A. Chem. Rev. 1997,
97, 671.
3. (a) Banwell, M. G.; Austin, K. A. B.; Willis, A. C. Tetrahedron 2007, 63, 6388;
(b) Reekie, T. A.; Austin, K. A. B.; Banwell, M. G.; Willis, A. C. Aust. J. Chem.
2008, 61, 94.
4. Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A. Tetrahedron 2004,
60, 535.
(7 mg, 77%) as a white, crystalline solid, mp¼116e120 ꢁC, [
a]
D
5. Singh, V. In CRC Handbook of Organic Photochemistry and Photobiology, 2nd ed.;
Horspool, W. M., Lenci, F., Eds.; CRC LLC: Boca Raton, FL, 2004; p 78/1.
6. For reviews on methods for generating cis-1,2-dihydrocatechols by microbial
dihydroxylation of the corresponding aromatics, as well as the synthetic ap-
plications of these metabolites, see: (a) Hudlicky, T.; Gonzalez, D.; Gibson, D. T.
Aldrichimica Acta 1999, 32, 35; (b) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.;
Jolliffe, K. A.; McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vogtle, M. Pure Appl.
Chem. 2003, 75, 223; (c) Johnson, R. A. Org. React. 2004, 63, 117; (d) Hudlicky, T.;
Reed, J. W. Synlett 2009, 685.
þ12.3 (c 0.4, CHCl3), [Found (MþNa)þ, 289.1417. C15H22O4 requires
(MþNa)þ, 289.1416]. 1H NMR (CDCl3, 800 MHz)
d
see Table 1; 13C
d see Table 1; nmax (KBr) 3397, 2922, 2853,
NMR (CDCl3, 100 MHz)
1705, 1630, 1463, 1119 cmꢀ1; MS (ESI, þve) m/z 331 [(MþNa)þ, 8%],
€
289 (100).
7. Austin, K. A. B.; Elsworth, J. D.; Banwell, M. G.; Willis, A. C. Org. Biomol. Chem.
2010, 8, 751.
4.3. Single-crystal X-ray analyses of compounds 15, 19 and 2
8. For a useful review on microwave-promoted reactions, including DielseAlder
cycloaddition reactions, see: Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
9. Hofle, G.; Steglich, W.; Vorbrüggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569.
10. This protocol is based on one first described by Ma and Bobbitt: Ma, Z.; Bobbitt,
J. M. J. Org. Chem. 1991, 56, 6110. For examples of related oxidations see Refs. 3
and 7.
11. Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int. Ed.
Engl. 1971, 10, 330.
4.3.1. Data for Compound 15. C16H22O3, M¼262.35, T¼200 K, or-
thorhombic, space group P212121, Z¼4, a¼6.7923(1), b¼12.3722(4),
c¼17.4495(5) Å, V¼1466.38(7) Å3, Dx¼1.188 g cmꢀ3, 1934 unique
€
data (2qmax¼55ꢁ), R¼0.037 [for 1399 reflections with I>2.0
Rw¼0.091 (all data), S¼0.86.
s(I)];
12. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
13. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
14. For a recent example of the application of this protocol see: Lin, A.; Willis, A. C.;
Banwell, M. G. Tetrahedron Lett. 2010, 51, 1044.
15. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
16. Pangaborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
17. DENZOeSMN: Otwinowski, Z.; Minor, W. Processing of X-ray diffraction data
collected in oscillation mode. In Methods in Enzymology: Macromolecular Crys-
tallography, Part A; Carter, C. W., Jr., Sweet, R. M., Eds.; Academic: New York, NY,
1997; Vol. 276, p 307.
18. SIR92: Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.;
Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
19. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl.
Crystallogr. 2003, 36, 1487.
4.3.2. Data for Compound 19. C20H28O5, M¼348.44, T¼200 K, or-
thorhombic, space group P212121, Z¼4, a¼7.6564(1), b¼11.6410(2),
c¼21.4772(3) Å, V¼1914.22(5) Å3, Dx¼1.209 g cmꢀ3, 3157 unique
data (2qmax¼60ꢁ), R¼0.035 [for 2537 reflections with I>2.0
Rw¼0.088 (all data), S¼0.89.
s(I)];
4.3.3. Data for Compound 2$H2O. C15H22O4$H2O M¼284.35,
T¼200 K, monoclinic, space group C2, Z¼4, a¼10.0661(2),
b¼8.9993(2), c¼16.7001(4) Å,
b
¼105.6552(16)ꢁ, V¼1456.70(6) Å3,
Dx¼1.296 g cmꢀ3, 1766 unique data (2qmax¼55ꢁ), R¼0.030 [for 1688
reflections with I>2.0
s
(I)]; Rw¼0.080 (all data), S¼1.01.