The enantiocontrolled synthesis of a highly functionalized cyclohexenone related to the A-ring of the furanosteroid viridin

Article abstract of DOI:10.1071/CH09283

A seven-step reaction sequence has been used to convert the enantiomerically pure cis-1,2-dihydrocatechol 10 into the cyclohexenone 17a. A near equivalent sequence involving the same starting material has allowed for the synthesis of the regioisomeric sys

Full text of DOI:10.1071/CH09283

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2009, 62, 1173–1180
The Enantiocontrolled Synthesis of a Highly Functionalized
Cyclohexenone Related to the A-Ring of the
Furanosteroid Viridin
Alison D. Findlay,A Antje Gebert,A Ian A. Cade,A and Martin G. BanwellA,B
AResearch School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra, ACT 0200, Australia.
BCorresponding author. Email: mgb@rsc.anu.edu.au
A seven-step reaction sequence has been used to convert the enantiomerically pure cis-1,2-dihydrocatechol 10 into the
cyclohexenone 17a. A near equivalent sequence involving the same starting material has allowed for the synthesis of the
regioisomeric system 17b. Compound 17a is related to the A-ring of ent-viridin (ent-1), the non-natural enantiomer of
the furanosteroid viridin (1).
Manuscript received: 15 May 2009.
Manuscript accepted: 11 June 2009.
Introduction
as certain analogues.[6–8] Nevertheless, and despite a range of
elegant studies conducted by various groups, the first and thus
far single total synthesis of virdin was only reported in 2004.[7]
It was obtained in racemic form. Thus, Sorensen and cowork-
ers first constructed the CD-ring subunit of virdin (1) using a
Vollhardt-type cyclotrimerization process that involved an open-
chain triyne. Their end-game involved assembly of the A-ring
through a ring-closing metathesis reaction and then exploit-
ing the ensuing cyclohexene double bond for the purposes of
introducing the relevant oxygenation pattern within this part of
viridin (1).
As part of an ongoing program within our laboratories that
hasbeendirectedtowardstheexploitationofmicrobially-derived
and enantiomerically pure cis-1,2-dihydrocatechols in the syn-
thesisofbiologicallyactivesystems,[9] wehavesoughttoprepare
compounds related to the A-ring of viridin (1) and the same ring
of its enantiomer ent-1 (Fig. 1). The outcomes of some of our
preliminary efforts in this area are now described.
The approach we have been taking as part of our effort to
develop total syntheses of both viridin and its enantiomer is
shown in retrosynthetic form in Fig. 2. The pivotal final step that
leads to ent-viridin would require an intramolecular Friedel–
Crafts acylation reaction of compound 2 and thus lead to the
formation of the non-aromatic B-ring of ent-1. Subsequent and
selective deprotection and oxidation steps should then deliver the
target. In what is likely to be the most challenging aspect of the
synthesis, the tetracyclic system 2 would, itself, be assembled
through the diastereoselective conjugate addition of a metal-
lated indanone of the general form 4 to a β-methoxylated and
trioxygenated cyclohexenone such as 3. Furannulation of the
resulting enolate using protocols of the type introduced by Garst
andSpencer[10] shouldthendeliversubstrate 2.Theindan-1-one-
based building block 4, which incorporates a suitable directed
metallating group (DMG), was expected to be accessible from
the known indan-1-one-4-carboxylic acid 5,[11] while enone 3
was considered likely to be available through manipulation of
The viridins are a well known but structurally unusual class
of steroids produced by various microorganisms.[1] They fea-
ture a furan ring fused between C-4 and C-6 of the normal
steroidal framework and have thus been labelled as furano-
steroids. These compounds display, among other things, potent
anti-fungal, anti-proliferative, as well as immunosuppressive
properties. As such they have considerable potential as thera-
peutic agents.[1] A prominent and representative member of the
class is viridin (1, Fig. 1) which was first isolated from the mould
Gliocladium virens in1945.[2] Biogenetically speaking, the com-
pound is derived by the tail-to-tail condensation of two farnesyl
residues with the non-ring-fused furan carbon thought likely to
arise from the methyl group of mevalonate.[3] On this basis the
illustrated absolute configuration of viridin was assigned. Its
structure, including relative configuration, was confirmed by
single-crystal X-ray analysis in 1972.[4] It is related to wort-
mannin (another furanosteroid), which was first isolated from
culture filtrates of Penicillium wortmanni Klocker and which
interacts with a range of important biological targets. In vitro it
binds most strongly to PI-3 kinase.[1b,5]
The fascinating structural and biological features of furano-
steroids has prompted significant effort, over the past decade or
so, directed towards the total synthesis of these systems as well
O
O
OH
A
OH
C
D
MeO
O
MeO
O
B
O
O
O
O
1
ent-1
Fig. 1. Structures of viridin (1) and ent-viridin (ent-1).
© CSIRO 2009
10.1071/CH09283
0004-9425/09/091173

1174
A. D. Findlay et al.
O
(iv) 1,4-Addition
(v) Furannulation
(vi) FGIs
OP
OP
(O)
(vii) F-C acylation
(viii) FGIs
MeO
MeO
ent-1
ϩ
CO2Me
PЈO
M
PЈO
O
DMG
O
2
3
4
DMG ϭ directed metallating group
M ϭ metal, P and PЈ ϭ OH protecting group
FGI ϭ functional group interconversion
(ii) FGIs
(iii) FGIs
(i) Enzymatic
dihydroxylation
of 8
(ii) H2, Pd on C
(i) Enzymatic
dihydroxylation
of 7
OH
OH
O
HO
HO
X
CO2H
ent-6
7 X ϭ H
8 X ϭ I
6
5
Fig. 2. Retrosynthetic analysis of approaches to developing total syntheses of viridin and its enantiomer.
PMP
the cis-1,2-dihydrocatechol 6. This last compound is readily
obtained on a large scale and in the illustrated enantiomeric form
through the whole-cell-mediated biotransformation of toluene
(7) using a genetically engineered microorganism that overex-
presses the responsible enzyme, toluene dioxygenase (TDO).[12]
Significantly, it is possible to obtain the enantiomer of diol
6 (i.e., ent-6) by subjecting p-iodotoluene (8) to dihydroxyla-
tion with TDO and then subjecting the ensuing metabolite to
de-iodination with dihydrogen in the presence of palladium on
carbon.[13] Accordingly, any preparation of a compound such as
3 would also constitute a synthesis of its enantiomer, as would be
required in developing approaches to the natural enantiomeric
form of viridin. The syntheses of a suitably protected form of
compound 3 as well as a regio-isomeric system are detailed in
the following section.
p-MBDMA,
(ϩ)-camphor
sulfonic acid
OPMB
HO
O
O
DIBAL-H
CH2Cl2,
6
CH2Cl2,
Ϫ30°C, 1 h
Ϫ78 to 0°C, 3.5 h
8
9
Scheme 1.
compound 10 are often more stable than the equivalent sys-
tems derived from congener 6. As a result, it also seemed
prudent to delay the methyl-for-bromine substitution process
for as long as possible. Accordingly, compound 10 was con-
verted, under standard conditions, into the previously reported
acetal 11.[14a] A solution of the latter compound in t-butyl methyl
ether (TBME) was cooled to −78◦C and then treated with a
1.0 M solution of DIBAL-H in hexane. After workup a ∼2:1
and chromatographically separable mixture of the desired mono-
ether 12a (57%) and its regio-isomer 12b (24%) was obtained.
The assignment of structures to each of these mono-ethers fol-
lows from 2D NMR experiments and from a single-crystal
X-ray analysis (see below) of a derivative of compound 12b.
O-Methylation of the free hydroxy group within compound
12a was readily effected with trimethyloxonium tetrafluoro-
borate in the presence of 1,8-bis(dimethylamino)naphthalene
(Proton Sponge)[15] and the resulting bis-ether 13a (99%) was
then subjected to cis-1,2-dihydroxylation using the UpJohn
protocol.[16] In keeping with expectations, this second reac-
tion took place with good levels of regio- and diastereo-
control and such that the diol 14a was obtained as the major
product (69%). Selective oxidation of the allylic hydroxy
group within compound 14a was best effected by using the
sterically demanding oxoammonium salt derived from the
p-toluenesulfonic acid (p-TsOH)-promoted disproportionation
of the 4-acetamido-TEMPO (TEMPO = 2,2,6,6-tetramethyl-l-
piperidyloxyl) radical.[17] The remaining hydroxy group within
Results and Discussion
In seeking to follow the retrosynthetic analysis shown in Fig. 2,
which would involve the methyl group of toluene ultimately
becomingtheangularsubstituent betweenandtheA- andB-rings
of ent-viridin, metabolite 6 was converted into the correspond-
ing p-methoxyphenyl (PMP)-acetal 8 (Scheme 1) by reacting
the former compound with p-methoxybenzaldehyde dimethyl
acetal (p-MBDMA) in the presence of catalytic quantities of
(+)-camphor sulfonic acid. Unfortunately, and despite our pos-
itive experiences with related systems,[14] this unstable acetal
failed to engage in the hoped-for reductive cleavage reaction
with diisobutylaluminium hydride (DIBAL-H) such that none
of the required cis-1,2-dihydrocatechol monobenzyl ether 9 was
observed. Rather, acomplexmixtureofproducts, whichincluded
aromatized ones, was obtained.
As a result of the difficulties outlined immediately above,
we turned to using the bromo-analogue, 10 (Scheme 2) of com-
pound 6 as the starting point for the synthesis on the basis
that the halogen could be replaced by a methyl group at some
point in the reaction sequence. A further motivation for pur-
suing this approach was our observation that derivatives of

Enantiocontrolled Synthesis of a Highly Functionalized Cyclohexenone
1175
OPMB
HO
Br
PMP
DIBAL-H
TBME or
CH2Cl2
p-MBDMA,
(ϩ)-camphor
sulfonic acid
OH
O
OP
12a
Me3OBF4,
proton sponge
HO
O
PЈO
57 or 10% (from 10)
Br
Br
Br
ϩ
CH2Cl2,
Ϫ30°C, 1 h
CH2Cl2,
0 to 18°C, 2 h
Ϫ78°C, 6 h
OH
PMBO
Br
10
13a 99%
13b 89%
11
12b
OsO4, NMO
acetone/water
24 or 72% (from 10)
Series a: P ϭ PMB, PЈ ϭ Me
Series b: P ϭ Me, PЈ ϭ PMB
0 to 18°C, 16 h
OP
OP
OP
OP
OH
4-(AcNH)TEMPO,
p-TsOH·H2O
PЈO
PЈO
PЈO
PЈO
TBDMSOTf,
2,6-lutidine
Br
Br
Br
MeLi, CuSPh
THF,
Ϫ78 to 0°C, 1 h
CH2Cl2,
Ϫ78 to 18°C, 1 h
CH2Cl2,
0 to 18°C, 3 h
TBDMSO
HO
TBDMSO
HO
O
O
O
15a 88%
15b 61%
14a 69%
14b 52%
17a 89%
17b 80%
16a 91%
16b 82%
Scheme 2.
compound 17b. Thus, by treating acetal 11 with DIBAL-H in
CH2Cl2, rather than TBME as used before, a ∼1:6 mixture
of the mono-p-methoxybenzyl (mono-PMB) ether 12a[19] and
regio-isomer 12b[19] was obtained (see Series b, Scheme 2).This
change in regioselectivity of the reductive cleavage of acetal 11
asafunctionofreactionmediumisattributedtotheco-ordinating
or non-co-ordinating effects of the relevant solvent. Thus, in the
reductive cleavage reaction carried out in TBME that leads to
mono-ether 12a as the major product of reaction, it is presumed
that the solvent coordinates to the reducing agent and that steric
effects thus direct, in a preferential but not an exclusive sense,
the complexed DIBAL-H to the acetal oxygen of substrate 11
that is remote from the bulky bromine. As a result the C–O bond
remote from this same bromine undergoes preferential cleavage
and thus leads to a predominance of mono-ether 12a. In contrast,
when the weakly co-ordinating CH2Cl2 is used as solvent, the
bromine within substrate 11 now has a capacity to coordinate
with the DIBAL-H and thereby direct acetal cleavage so as to
deliver regio-isomer 12b preferentially.[20] Now, following the
previously established synthetic sequence, compound 12b was
O-methylated using trimethyloxonium tetrafluoroborate in the
presence of Proton Sponge and thus afforded the mixed bis-ether
13b (89%). Reaction of this last compound under the UpJohn
conditions[16] then gave diol 14b in 52% yield. Selective oxi-
dation of compound 14b under conditionsꢀessentially identical
to those applied to congener 14a gave α -hydroxyenone 15b
(61%) that was O-silylated using TBDMSOTf in the presence
of 2,6-lutidine. In this manner the tris-ether 16b was obtained
in 82% yield. The crystalline nature of this material allowed it
to be subjected to a single-crystal X-ray analysis that served to
confirm the illustrated structure (including absolute stereochem-
istry) and, thereby, those of all of its precursors. The derived
ORTEP plot is shown in Fig. 3.
Fig. 3. ORTEP plot derived from the single-crystal X-ray analysis of
compound 16b (thermal ellipsoids shown at 30% probability level).
the product enone 15a (88%) was converted into the corre-
sponding t-butyldimethylsilyl (TBDMS)-ether 16a (91%) using
t-butyldimethylsilyltriflate(TBDMSOTf)inthepresenceof2,6-
lutidine. In the final step of the reaction sequence, compound 16a
was reacted with the cuprate derived from methyl lithium
(MeLi) and CuSPh.[18] By such means, a nucleophilic addition/
elimination reaction took place that effected the required methyl-
for-bromine exchange and thus resulted in the formation of the
target βꢀ-methoxylated enone 17a. This was obtained in 89%
yield as a pale-yellow oil.
Interestingly, essentially the same reaction sequence as
just described can be used to prepare the regioisomeric

1176
A. D. Findlay et al.
Table 1. Comparison of the 1H and 13C NMR spectroscopic datasets
derived from the isomeric enones 17a and 17b
In the final step of the reaction sequence, β-bromoenone 16b
was subjected to the same type of methyl-for-halogen exchange
reaction as used for the conversion of 16a into 17a, and in this
way compound 17b was obtained as a light-yellow oil in 80%
yield.
A
B
δH
δC
17a
17b
17a
17b
1
A comparison of the H and 13C NMR spectroscopic data
7.32 (2H, d, J 8.7)
6.89 (2H, d, J 8.7)
5.79 (1H, s)
4.76 (2H, ABq, J 11.1)
4.44 (1H, d, J 8.4)
4.26 (1H, d, J 3.0)
3.81 (3H, s)
7.29 (2H, d, J 8.4)
6.88 (2H, d, J 8.4)
5.80 (1H, d, J 1.2)
4.68 (2H, ABq, J 12.0)
4.41 (1H, d, J 8.4)
3.87 (1H, d, J 3.3)
3.81 (3H, s)
196.6 196.7
159.5 159.2
156.7 156.7
130.1 130.3
130.1 129.4
126.2 126.1
113.8 113.7
obtained for regioisomers 17a and 17b is provided in Table 1.
This clearly indicates that the compounds are distinct but,
nevertheless, closely related in a structural sense. Furthermore,
the infrared and mass spectra obtained for each of these com-
pounds were very similar and fully consistent with the illustrated
structures. As such, and given the X-ray analysis carried out
on compound 16b, the structure assigned to target enone 17a
appears quite secure. Accordingly, investigations into establish-
ing a total synthesis of ent-virdin by the pathway defined in Fig. 2
have begun. The results of such efforts will be reported in due
course.
3.54 (3H, s)
3.53 (1H, dd, J 9.0 and 3.3) 3.58 (3H, s)
1.93 (3H, s)
0.92 (9H, s)
0.14 (3H, s)
0.12 (3H, s)
3.75 (1H, dd, J 8.4 and 3.3)
83.0
75.2
74.1
73.9
59.5
55.3
25.8
21.6
18.5
79.4
79.2
74.3
73.1
60.6
55.2
25.8
21.8
18.5
2.00 (3H, d, J 1.2)
0.92 (9H, s)
0.14 (3H, s)
0.08 (3H, s)
Experimental
General Experimental Procedures
−4.7 −4.7
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded at 18◦C in base-filtered CDCl3 on aVarian
Mercury or Inova 300 spectrometer operating at 300 MHz for
proton and 75 MHz for carbon nuclei. 1H NMR data are recorded
as follows: chemical shift (δ) (relative integral, multiplicity,
coupling constant(s) J (Hz)) where multiplicity is defined as:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
or combinations of the above. The residual CHCl3 peak (δ 7.26)
−5.3 −5.2
ASpectrum recorded in CDCl3 at 300 MHz.
BSpectrum recorded in CDCl3 at 75 MHz.
Companies and were used as supplied. Drying agents and other
inorganic salts were purchased from AJAX, BDH, or Unilab
Chemical Companies. Tetrahydrofuran (THF) and diethyl ether
were distilled from sodium benzophenone ketyl. Methanol was
distilled from its magnesium alkoxide salt. CH2Cl2 was dis-
tilled from calcium hydride. Triethylamine was distilled from
and stored over potassium hydroxide pellets.
1
was used as a reference for H NMR spectra, and the central
peak (δ 77.0) of the CDCl3 ‘triplet’ was used as a reference
for proton-decoupled 13C NMR spectra. Infrared spectra (νmax
)
were recorded on a Perkin–Elmer 1800 Series FTIR Spectro-
meter. Samples were analyzed as thin films on NaCl plates. A
VG FisonsAutoSpec three-sector (E/B/E) double-focusing mass
spectrometer was used to obtain both low- and high-resolution
electron impact (EI) mass spectra. Low- and high-resolution
electrospray (ESI) mass spectra were obtained on aVG Quattro II
triple quadrupole MS instrument operating in positive ionization
mode.
Specific Chemical Conversions
Compound 11
A solution of (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol
(10)[12] (1.00 g, 5.26 mmol) in CH2Cl2 maintained under a
nitrogen atmosphere at −35◦C was treated with p-MBDMA
(0.99 mL, 1.07 mmol) and (+)-camphorsulfonic acid (61 mg,
0.26 mmol). The resulting solution was stirred at this temper-
ature for 0.33 h and then quenched with NaHCO3 (20 mL of a
saturated aqueous solution). The phases were separated and the
aqueous one was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic phases were then washed with NaOH (1 × 50 mL
of 2 M aqueous solution) before being dried (Na2SO4), fil-
tered, and concentrated under reduced pressure to give acetal
11[14a] (∼1.30 g, 80%) as a clear, colourless oil, RF 0.5
(in 3/7, v/v, ethyl acetate/hexanes), [α]D +193.8 (c 1.53,
CHCl3). (Found: [M + Na]+, 330.9919. C14H1379BrO3 requires
[M + Na]+: 330.9946.) δH (300 MHz, CDCl3) 7.41 (2H, d, J
8.1), 6.88 (2H, d, J 8.1), 6.41 (1H, d, J 6.0), 6.03 (1H, dd, J
9.6 and 3.3), 5.93 (1H, dd, J 9.6 and 6.0), 5.72 (1H, s), 4.77
(2H, s), 3.80 (3H, s). δC (75 MHz, CDCl3) 160.7, 128.5, 128.1,
125.9, 124.2, 123.4, 123.1, 113.7, 99.4, 76.0, 73.4, 55.3. νmax
(NaCl)/cm−1 1612, 1517, 1439, 1310, 1251, 1057, 1027, 1000.
m/z (ESI) 333 and 331 [M + Na]+ (45 and 40%), 257 (37), 239
(34), 213 (58), 199 (98), 185 (100), 171 (50).
Optical rotations were measured at 20–25◦C with a Perkin–
Elmer 241 polarimeter at the sodium-D line (589 nm) and the
concentrations (c) (g per 100 mL) indicated using spectroscopic
grade solvents.The measurements were carried out in a cell with
a path length (l) of 1 dm. Specific rotations, [α]D, were calcu-
lated using the equation [α]D = 100 · α/(c · l) and are given in
10−1 deg cm2 g−1. Melting points were measured on an Opti-
melt automated melting point system or a Reichert hot-stage
microscope apparatus and are uncorrected.
AnalyticalTLCwasperformedonaluminium-backed0.2 mm
thick silica gel 60 F254 plates as supplied by Merck.
Eluted plates were visualized using a 254 nm UV lamp
and/or by treatment with a suitable dip followed by heating.
These dips included phosphomolybdic acid/ceric sulfate/sulfuric
acid (conc.)/water (37.5 g/7.5 g/37.5 g/720 mL) or potassium
permanganate/potassium carbonate/5% w/v sodium hydroxide
aqueous solution/water (3 g/20 g/5 mL/300 mL). The retention
factor (RF) was quoted to the nearest 0.1. Flash column
chromatography[21] was performed using silica gel 60 (0.040–
0.0063 mm) as the stationary phase and the analytical reagent
(AR) or HPLC grade solvents indicated.
The sample of acetal 11 obtained as described immediately
above was used without purification in the next step of the
reaction sequence.
Starting materials and reagents were generally available from
the Sigma–Aldrich, Merck, TCI, Strem, or Lancaster Chemical

Enantiocontrolled Synthesis of a Highly Functionalized Cyclohexenone
1177
Compound 12a
1249, 1106, 1063, 1034, 823. m/z (ESI) 349 and 347 [M + Na]+
(6 and 6%), 215 (100), 121 (50).
A magnetically stirred solution of acetal 11 (500 mg,
1.62 mmol)inTBME(17 mL)maintainedunderanitrogenatmo-
sphere at −78◦C was treated with DIBAL-H (3.25 mL of a 1 M
solution in hexanes, 3.25 mmol) in TBME (8 mL). The ensuing
mixture was stirred at −78◦C for 2 h and then treated with a fur-
ther aliquot of DIBAL-H (3.25 mL of a 1 M solution in hexanes)
in TBME (8 mL). The resulting mixture was stirred at −78◦C
for 2 h and then yet another aliquot of DIBAL-H (3.25 mL
of 1 M solution in hexanes) in TBME (8 mL) was added. The
ensuing solution was stirred at −78◦C for a further 2 h before
being quenched by the careful addition (CAUTION!) of sodium
potassium tartrate (50 mL of a saturated aqueous solution). The
resulting mixture was stirred vigorously at 18◦C for 1 h and then
the phases were separated.The aqueous phase was extracted with
diethyl ether (3 × 30 mL) and the combined organic phases were
dried (MgSO4), filtered, and concentrated under reduced pres-
sure. Subjection of the resulting light-yellow oil to flash column
chromatography (15/85, v/v, ethyl acetate/hexanes) afforded two
fractions, A and B.
Concentration of fraction A (RF 0.24 in 3/7, v/v, ethyl
acetate/hexanes) yielded ether 12a (284 mg, 57%) as a clear,
colourless oil, [α]D −61.6 (c 1.67, CHCl3). (Found: [M + Na]+,
333.0101. C14H1579BrO3 requires [M + Na]+: 333.0102.) δH
(300 MHz, CDCl3) 7.31 (2H, d, J 8.7), 6.89 (2H, d, J 8.7), 6.45
(1H, d, J 5.7), 5.90 (1H, dm, J 9.6), 5.77 (1H, ddd, J 9.6, 5.7,
and 2.1), 4.73 (2H, ABq, J 11.1), 4.59–4.51 (1H, complex m),
4.10 (1H, d, J 6.9), 3.81 (3H, s), 2.59 (1H, d, J 9.3). δC (75 MHz,
CDCl3) 159.5, 131.4, 129.9, 129.5, 128.5, 122.6, 122.2, 113.9,
78.4, 73.1, 69.6, 55.2. νmax (NaCl)/cm−1 3410, 1611, 1513,
1248, 1173, 1098, 1034, 823. m/z (ESI) 335 and 333 [M + Na]+
(51 and 53%), 121 (100).
Compound 14a
A magnetically stirred solution of diene 13a (930 mg,
2.87 mmol) in acetone (1.8 mL) maintained under a nitro-
gen atmosphere at 0◦C was treated with a solution of
N-methylmorpholine N-oxide (504 mg, 4.31 mol) in water
(2.0 mL). OsO4 (0.58 mL of a 0.2 M solution in t-BuOH,
0.11 mmol) was then added dropwise to the reaction mixture.
The resulting solution was allowed to warm to 18◦C and stirred
at this temperature for 16 h before being quenched with Na2S2O3
(4 mL of a saturated aqueous solution). The separated aqueous
phase was extracted with CH2Cl2 (5 × 4 mL) and the combined
organic phases were washed with brine (1 × 20 mL) before being
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure to give a light-yellow oil. Subjection of this material to flash
column chromatography (1/1, v/v, ethyl acetate/hexanes elution)
and concentration of the appropriate fractions (RF 0.13) then
afforded diol 14a (709 mg, 69%) as a clear, colourless oil, [α]D
−136.4(c2.71, CHCl3). (Found:M+•, 358.0419. C15H1979BrO5
requires M+•: 358.0416.) δH (300 MHz, CDCl3) 7.35 (2H, d, J
8.7), 6.88 (2H, d, J 8.7), 6.23 (1H, d, J 5.1), 4.78 (2H, ABq, J
11.1), 4.33 (1H, d, J 3.9), 4.30–4.27 (1H, complex m), 4.10–4.05
(1H, complex m), 3.80 (3H, s), 3.63 (1H, dd, J 10.2 and 3.9), 3.45
(3H, s), 3.04–3.00 (2H, m). δC (75 MHz, CDCl3) 159.4, 131.1,
129.9(1), 129.8(7), 125.2, 113.7, 79.3, 77.0, 74.5, 66.9, 66.5,
58.3, 55.2. νmax (NaCl)/cm−1 3418, 2933, 1612, 1514, 1463,
1302, 1249, 1115, 1094, 818. m/z (EI, 70 eV) 360 and 358 M+•
(5 and 5%), 206 and 204 (19 and 21), 137 (80), 121 (100).
Compound 15a
Concentration of fraction B (RF 0.26 in 3/7, v/v, ethyl
acetate/hexanes) yielded ether 12b[19] (76 mg, 24%) as a clear,
colourless oil.The 1H NMR spectroscopic data derived from this
material matched those reported for an authentic sample.[19]
A magnetically stirred solution of diol 14a (160 mg,
0.45 mmol) in CH2Cl2 (6 mL) maintained under a nitrogen
atmosphere at 0◦C was treated with p-TsOH·H2O (127 mg,
0.67 mmol). The ensuing mixture was then treated, in four
equal portions over 0.5 h, with 4-acetamido-TEMPO (143 mg,
0.67 mmol). The resulting solution was allowed to warm to
18◦C and stirred at this temperature for 2 h before being re-
cooled to 0◦C and then treated with more p-TsOH·H2O (127 mg,
0.67 mmol). The ensuing mixture was then treated, yet again and
now in four equal portions over 0.5 h, with 4-acetamido-TEMPO
(143 mg, 0.67 mmol). The resulting solution was again allowed
to warm to 18◦C, stirred at this temperature for 1 h, and then
quenched with NaHCO3 (5 mL of a saturated aqueous solution).
The phases were separated and the aqueous one was extracted
with CH2Cl2 (3 × 5 mL). The combined organic phases were
then dried (Na2SO4), filtered, and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material
to flash column chromatography (3/7, v/v, ethyl acetate/hexane)
and concentration of the appropriate fractions (RF 0.07) afforded
αꢀ-hydroxyenone 15a (141 mg, 88%) as a clear, colourless oil,
[α]D −100.3 (c 2.03, CHCl3). (Found: [M + Na]+, 379.0162.
C15H1779BrO5 requires [M + Na]+: 379.0157.) δH (300 MHz,
CDCl3) 7.37 (2H, d, J 8.7), 6.90 (2H, d, J 8.7), 6.55 (1H, d, J
0.6, H2), 4.88 (2H, ABq, J 10.8), 4.64 (1H, dd, J 10.5 and 1.8),
4.56 (1H, dd, J 3.6 and 0.6), 3.81 (3H, s), 3.57 (3H, s), 3.54 (1H,
dd, J 10.5 and 3.6), 3.32–3.31 (1H, complex m). δC (75 MHz,
CDCl3) 195.2, 159.6, 146.5, 131.4, 130.2, 129.3, 113.8, 82.6,
78.2, 75.1, 73.0, 59.1, 55.2. νmax (NaCl)/cm−1 3440, 2933, 1689,
1611, 1514, 1248, 1117, 1062, 1031, 822. m/z (ESI) 381 and 379
[M + Na]+ (65 and 63%), 121 (100).
Compound 13a
A magnetically stirred solution of alcohol 12a (570 mg,
1.84 mmol) in CH2Cl2 (35 mL) maintained at 0◦C under a
nitrogen atmosphere was treated with 1,8-bis(dimethyamino)
naphthalene (Proton Sponge, 1.18 g, 5.52 mmol) followed by
trimethyloxonium tetrafluoroborate (406 mg, 2.76 mmol). The
resulting solution was stirred at ∼18◦C for 1 h and then
quenched by the addition of NaHCO3 (40 mL of a saturated
aqueous solution). The phases were separated and the aque-
ous one was extracted with CH2Cl2 (3 × 20 mL). The combined
organic phases were then washed with citric acid (80 mL of a
1/9, w/v, aqueous solution) before being dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The resulting
light-yellow oil was subjected to flash column chromatogra-
phy (1/10/89, v/v/v, triethylamine/ethyl acetate/hexane elution)
and thus yielded, after concentration of the appropriate frac-
tions (RF 0.45 in 3/7, v/v, ethyl acetate/hexane), bis-ether 13a
(588 mg, 99%) as a clear, colourless oil, [α]D −85.7 (c 1.50,
CHCl3). (Found: [M + Na]+, 347.0259. C15H1779BrO3 requires
[M + Na]+: 347.0259.) δH (300 MHz, CDCl3) 7.33 (2H, d, J
8.7), 6.87 (2H, d, J 8.7), 6.50 (1H, d, J 5.7), 5.99 (1H, dm, J
9.6), 5.82 (1H, ddd, J 9.6, 5.7, and 2.4), 4.63 (2H, s), 4.26–
4.19 (2H, complex m), 3.80 (3H, s), 3.44 (3H, s). δC (75 MHz,
CHCl3) 159.2, 130.2, 129.9, 129.3, 129.1, 122.7, 122.6, 113.6,
79.1, 75.2, 71.0, 57.3, 55.2. νmax (NaCl)/cm−1 2932, 1612, 1513,

1178
A. D. Findlay et al.
Compound 16a
phase was extracted with CH2Cl2 (3 × 30 mL) and the com-
bined organic phases were then dried (MgSO4), filtered, and
concentrated under reduced pressure to afford a pale-yellow oil.
Subjection of this material to flash chromatography (15/85, v/v,
ethyl acetate/hexane elution) afforded two fractions, A and B.
Concentration of fraction A (RF 0.24 in 3/7, v/v, ethyl
acetate/hexane) afforded the ether 12a (117 mg, 10%) as a clear,
colourless oil. This material was identical, in all respects, with
an authentic sample obtained as described above.
Concentration of fraction B (RF 0.26 in 3/7, v/v, ethyl
acetate/hexane) afforded ether 12b (818 mg, 72%) as a clear,
colourless oil. This material was identical, in all respects, with
an authentic sample obtained as described above.
A magnetically stirred solution of compound 15a (132 mg,
0.37 mmol) in CH2Cl2 (6 mL) maintained under a nitrogen
atmosphere at −78◦C was treated with 2,6-lutidine (129 µL,
1.11 mmol). The ensuing mixture was stirred at −78◦C for
5 min and then treated with TBDMSOTf (128 µL, 0.56 mmol).
After stirring the reaction mixture at −78◦C for 10 min it was
allowed to warm to 0◦C and stirred at this temperature for 1 h
then quenched with NH4Cl (2 mL of a saturated aqueous solu-
tion). The separated aqueous phase was extracted with CH2Cl2
(3 × 2 mL) and the combined organic phases were then dried
(MgSO4), filtered, and concentrated under reduced pressure to
givealight-yellowoil. Subjectionofthismaterialtoflashcolumn
chromatography (hexane → 1/9, v/v, ethyl acetate/hexane gradi-
ent elution) and concentration of the relevant fractions (RF 0.26
in 1/9, v/v, ethyl acetate/hexane) then gave the title tris-ether
16a (158 mg, 91%) as a clear, pale-yellow oil, [α]D −97.5 (c
3.02, CHCl3). (Found: [M + Na]+, 493.1021. C21H3179BrO5Si
requires [M + Na]+: 493.1022.) δH (300 MHz, CDCl3) 7.37
(2H, d, J 8.7), 6.90 (2H, d, J 8.7), 6.41 (1H, s), 4.84 (2H, ABq, J
10.8), 4.52 (1H, d, J 3.3), 4.46 (1H, d, J 9.0), 3.81 (3H, s), 3.54
(1H, dd, J 8.7 and 3.3), 3.52 (3H, s), 0.92 (9H, s), 0.13 (3H, s),
0.10 (3H, s). δC (75 MHz, CDCl3) 194.1, 159.5, 145.5, 132.1,
130.1, 129.4, 113.7, 82.7, 77.9, 74.7, 74.0, 59.5, 55.2, 25.6, 18.4,
−4.9, −5.3. νmax (NaCl)/cm−1 2952, 2930, 2856, 1698, 1612,
1514, 1463, 1250, 1150. m/z (ESI) 495 and 493 [M + Na]+ (25
and 23%), 121 (100).
Compound 13b
A magnetically stirred solution of alcohol 12b (150 mg,
0.48 mmol) in CH2Cl2 (10 mL) maintained at 0◦C under
a nitrogen atmosphere was treated with 1,8-bis(dimethyl-
amino)naphthalene (Proton Sponge, 311 g, 1.45 mmol) followed
by trimethyloxonium tetrafluoroborate (107 mg, 0.73 mmol).
The resulting solution was stirred at 18◦C for 2 h before
being quenched with NaHCO3 (10 mL of a saturated aque-
ous solution). The separated aqueous phase was extracted with
CH2Cl2 (3 × 10 mL) and the combined organic phases were
then washed with citric acid (50 mL of a 10% w/v aqueous
solution) before being dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The resulting light-yellow oil
was subjected to flash column chromatography (1/10/89, v/v/v,
Et3N/ethyl acetate/hexane elution) to yield, after concentra-
tion of the appropriate fractions (RF 0.2 in 15/85, v/v, ethyl
acetate/hexane), methyl ether 13b (139 mg, 89%) as a clear,
colourless oil, [α]D −95.1 (c 2.18, CHCl3). (Found: [M + Na]+,
347.0260. C15H1779BrO3 requires [M + Na]+: 347.0259.) δH
(300 MHz, CDCl3) 7.31 (2H, d, J 8.7), 6.90 (2H, d, J 8.7), 6.47
(1H, d, J 5.7), 5.99 (1H, ddt, J 9.6, 2.4, and 0.9), 5.78 (1H, ddd, J
9.6, 5.7, and 2.7), 4.63 (2H, ABq, J 11.7), 4.43–4.37 (1H, com-
plex m), 4.04 (1H, dd, J 6.9 and 0.9), 3.81 (3H, s), 3.51 (3H, s).
δC (75 MHz, CDCl3) 159.3, 129.9, 129.7, 129.4, 129.0, 122.4,
121.9, 113.8, 78.2, 76.1, 70.8, 57.8, 55.2. νmax (NaCl)/cm−1
2930, 1612, 1513, 1248, 1172, 1111, 1074, 1033, 822. m/z (ESI)
349 and 347 [M + Na]+ (9 and 9%), 229 (48), 215 (100).
Compound 17a
A magnetically stirred solution of thiophenyl copper[22]
(17 mg, 96 µmol) in THF (0.8 mL) maintained under a nitrogen
atmosphere at 18◦C was treated with MeLi (59 µL of a 1.6 M
solution in hexanes, 96 µmol).The resulting solution was stirred
at this temperature for 10 min by which time a clear, red solu-
tion had formed. This solution was cooled to −78◦C and then a
solution of bromide 16a (30 mg, 64 µmol) in THF (1 mL) was
added dropwise. The resulting mixture was allowed to warm to
0◦C and stirred at this temperature for 1 h before being treated
with methanol (1 mL) followed by NH4Cl (2 mL of a saturated
aqueous solution). The two phases so-formed were separated
and the aqueous one was extracted with diethyl ether (3 × 2 mL).
The combined organic phases were then dried (MgSO4), filtered,
and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash column chromatography
(1/9, v/v, ethyl acetate/hexane elution) and concentration of the
appropriate fractions (RF 0.07) afforded the β-methylenone 17a
(23 mg, 89%) as a clear, pale-yellow oil, [α]D −71.1 (c 1.10,
CHCl3). (Found: [M + Na]+, 429.2072. C22H34O5Si requires
[M + Na]+: 429.2073.) δH (300 MHz, CDCl3) see Table 1. δC
(75 MHz, CDCl3) see Table 1. νmax (NaCl)/cm−1 2930, 2856,
1690, 1612, 1514, 1250, 1154, 1109, 1065, 1039, 881, 837. m/z
(ESI) 445 [M + K]+ (56%), 429 [M + Na]+ (35), 121 (100).
Compound 14b
A magnetically stirred solution of diene 13b (418 mg,
1.29 mmol) in acetone (10.8 mL) maintained at 0◦C was treated
with a solution of N-methylmorpholine N-oxide (334 mg,
2.84 mmol) in H2O (1.2 mL) then dropwise, with OsO4 (0.33 mL
of 0.197 M solution in t-BuOH, 64.4 µmol). The ensuing mix-
ture was allowed to warm to 18◦C and stirred at this temperature
for 16 h before being treated with Na2S2O3 (20 mL of a sat-
urated aqueous solution). The separated aqueous phase was
extracted with CH2Cl2 (5 × 10 mL) and the combined organic
phases were then washed with brine (1 × 70 mL) before being
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The ensuing light-yellow oil was subjected to flash column
chromatography (1/1, v/v, ethyl acetate/hexane elution) and con-
centration of the appropriate fractions (RF 0.2) afforded diol 14b
(238 mg, 52%) as a clear, colourless oil, [α]D −110.5 (c 2.25,
CHCl3). (Found: [M + Na]+, 381.0310. C15H1979BrO5 requires
[M + Na]+: 381.0314.) δH (300 MHz, CDCl3) 7.29 (2H, d, J
9.0), 6.90 (2H, d, J 9.0), 6.22 (1H, d, J 5.4), 4.62 (2H, ABq, J
11.1), 4.30 (1H, dd, J 5.4 and 4.5), 4.02 (1H, dd, J 9.9 and 4.2),
4.01 (1H, d, J 3.9), 3.87 (1H, dd, J 10.2 and 3.6), 3.81 (3H, s),
Compound 12b
A magnetically stirred solution of acetal 11 (1.12 g,
3.64 mmol) in CH2Cl2 (25 mL) maintained at −78◦C under a
nitrogen atmosphere was treated with DIBAL-H (14.5 mL of
a 1 M solution in hexanes, 14.5 mmol). The resulting solution
was stirred at −78◦C for 1 h and then quenched (CAUTION!)
with sodium potassium tartrate (30 mL of a saturated aque-
ous solution). The resulting mixture was stirred vigorously at
18◦C for 1 h and then the phases were separated. The aqueous

Enantiocontrolled Synthesis of a Highly Functionalized Cyclohexenone
1179
3.64 (3H, s), 2.86 (2H, br s). δC (75 MHz, CDCl3) 159.6, 130.9,
129.7, 129.4, 125.2, 114.0, 80.6, 76.8, 72.6, 67.0, 66.6, 61.2,
55.3. νmax (NaCl)/cm−1 3412, 2930, 2834, 1612, 1514, 1249,
1107, 1037, 822. m/z (ESI) 383 and 381 [M + Na]+ (55 and
54%), 121 (100).
2930, 2856, 1697, 1613, 1514, 1249, 1147, 1121, 827, 780. m/z
(ESI) 495 and 493 [M + Na]+ (21 and 20%), 121 (100).
A sample of this compound could be crystallized from
hexane/CHCl3 to give material (mp 71–72◦C) suitable for
single-crystal X-ray analysis.
Compound 17b
Compound 15b
A magnetically stirred solution of thiophenyl copper[22]
(25 mg, 0.15 mmol) in THF (1.2 mL) maintained at 18◦C under
a nitrogen atmosphere was treated with methyllithium (92 µL
of a 1.6 M solution in diethyl ether, 0.15 mmol). The resulting
solution was stirred at 18◦C for 10 min at which point a clear,
red solution had formed. The reaction mixture was cooled to
−78◦C and then a solution of bromide 16b (46 mg, 98 µmol)
in THF (1.8 mL) was added dropwise. The resulting solution
was allowed to warm to 0◦C, stirred at this temperature for
1 h, and then treated with methanol (1 mL) followed by NH4Cl
(2 mL of a saturated aqueous solution). The separated aqueous
phase was extracted with diethyl ether (3 × 2 mL) and the com-
bined organic phases were then dried (MgSO4), filtered, and
concentrated under reduced pressure. The ensuing yellow oil
was subjected to flash column chromatography (1/9, v/v, ethyl
acetate/hexane elution) and concentration of the relevant frac-
tions (RF 0.09 in 1/9, v/v, ethyl acetate/hexane) gave enone 17b
(32 mg, 80%) as a clear, pale-yellow oil, [α]D −20.9 (c 1.60,
CHCl3). (Found: [M + Na]+, 429.2072. C22H34O5Si requires
[M + Na]+: 429.2073.) δH (300 MHz, CDCl3) see Table 1. δC
(75 MHz, CDCl3) see Table 1. νmax (NaCl)/cm−1 2952, 2929,
2886, 2856, 1688, 1514, 1249, 1152, 1092, 837. m/z (ESI) 429
[M + Na]+ (38%), 121 (100).
A magnetically stirred a solution of diol 14b (69 mg,
0.19 mmol) in CH2Cl2 (3 mL) maintained at 0◦C under a
nitrogen atmosphere was treated, in portions over 0.5 h, with
p-TsOH·H2O (55 mg, 0.29 mmol) followed by 4-acetamido-
TEMPO (62 mg, 0.29 mmol).The resulting solution was allowed
to warm to 18◦C and then stirred at this temperature for 2 h. The
reaction mixture was then re-cooled to 0◦C and further aliquots
of p-TsOH·H2O (55 mg, 0.29 mmol) and 4-acetamido-TEMPO
(62 mg, 0.29 mmol)wereaddedinportionsover0.5 h.Theresult-
ing solution was, once again, allowed to warm to 18◦C. After
1 h at this temperature, the reaction mixture was treated with
NaHCO3 (5 mL of a saturated aqueous solution) and the sep-
arated aqueous phase extracted with CH2Cl2 (3 × 3 mL). The
combined organic phases were then dried (Na2SO4), filtered,
and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash column chromatography
(3/7, v/v, ethyl acetate/hexane elution) and concentration of the
appropriate fractions (RF 0.16 in 1/4, v/v, ethyl acetate/hexane)
afforded hydroxy enone 15b (41 mg, 61%) as a clear, colourless
oil, [α]D −42.7 (c 2.05, CHCl3). (Found: [M + Na]+, 379.0151.
C15H1779BrO5 requires [M + Na]+: 379.0157.) δH (300 MHz,
CDCl3) 7.32 (2H, d, J 8.7), 6.90 (2H, d, J 8.7), 6.52 (1H, d, J
0.6), 4.78 (2H, ABq, J 11.7), 4.61 (1H, dd, J 10.5 and 1.5), 4.13
(1H, dd, J 3.9 and 0.6), 3.81 (3H, s), 3.73 (3H, s), 3.72 (1H, dd,
J 10.5 and 3.6), 3.33 (1H, d, J 1.5). δC (75 MHz, CDCl3) 195.4,
159.4, 146.3, 131.2, 129.6(5), 129.5(7), 113.9, 82.5, 79.2, 73.3,
73.1, 62.0, 55.2. νmax (NaCl)/cm−1 3460, 2931, 2834, 1689,
1611, 1514, 1248, 1119, 827. m/z (ESI) 381 and 379 [M + Na]+
(37 and 38%), 121 (100).
X-Ray Crystallographic Study
Crystal Data for Compound 16b
C21H31O5Si, M 471.46, T200(1) K, orthorhombic, space
group P212121, Z 4, a 7.3920(1), b 10.6998(2), c 29.7883(5) Å,
V 2356.04(7) Å3, Dx 1.329 g cm−3, 5393 unique data (2θmax
55◦), 4044 with I > 2.0σ(I); R 0.040, Rw 0.095, S 0.88, Flack
parameter = 0.010.
Compound 16b
A magnetically stirred solution of alcohol 15b (41 mg,
0.12 mmol) in CH2Cl2 (3 mL) maintained at −78◦C under
a nitrogen atmosphere was treated with 2,6-lutidine (40 µL,
0.35 mmol). The ensuing mixture was stirred at −78◦C for
5 min and thenTBDMSOTf (40 µL, 0.17 mmol) was added. The
reaction mixture was then stirred at −78◦C for 10 min before
being allowed to warm to 0◦C and then stirred at this temper-
ature for 1 h before being quenched by the addition of NH4Cl
(4 mL of a saturated aqueous solution). The separated aqueous
phase was extracted with CH2Cl2 (3 × 3 mL) and the combined
organic phases were then dried (MgSO4) before being filtered
and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash column chromatography
(hexane → 5/95, v/v, ethyl acetate/hexane gradient elution) and
concentration of the relevant fractions (RF 0.3 in 1/9, v/v, ethyl
acetate/hexane) then gave ether 16b (46 mg, 82%) as a pale-
yellow oil, [α]D −50.2 (c 1.84, CHCl3). (Found: [M + Na]+,
493.1021. C21H3179BrO5Si requires [M + Na]+: 493.1022.) δH
(300 MHz, CDCl3) 7.27 (2H, d, J 8.7), 6.88 (2H, d, J 8.7), 6.40
(1H, s), 4.68 (2H, ABq, J 11.7), 4.42 (1H, d, J 9.3), 4.08 (1H,
d, J 3.6), 3.81 (3H, s), 3.78 (1H, dd, J 9.3 and 3.6), 3.67 (3H,
s), 0.92 (9H, s), 0.13 (3H, s), 0.07 (3H, s). δC (75 MHz, CDCl3)
194.4, 159.4, 145.1, 132.2, 129.8, 129.5, 113.8, 81.9, 79.0, 74.3,
73.4, 61.3, 55.2, 25.7, 18.5, −4.8, −5.2. νmax (NaCl)/cm−1 2952,
Structure Determination
Images were measured on a Nonius Kappa CCD diffracto-
meter (MoKα, graphite monochromator, λ 0.71073 Å) and data
extracted using the DENZO package.[23] Structure solution was
by direct methods (SIR92)[24] and the refinement was carried
out using the CRYSTALS program package.[25] Atomic coordi-
nates, bond lengths and angles, and displacement parameters
have been deposited at the Cambridge Crystallographic Data
Centre (CCDC 715994). 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 contactingThe Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
Acknowledgements
The authors thank the Australian Research Council and the Institute of
Advanced Studies for generous financial support.
References
[1] For useful reviews on members of the class see: (a) J. R. Hanson, Nat.
Prod. Rep. 1995, 12, 381. doi:10.1039/NP9951200381
(b) P. Wipf, R. J. Halter, Org. Biomol. Chem. 2005, 3, 2053.
doi:10.1039/B504418A

1180
A. D. Findlay et al.
[2] (a) P. W. Brian, J. G. McGowan, Nature 1945, 156, 144.
aromatics, as well as the synthetic applications of these metabolites,
see: (a) T. Hudlicky, D. Gonzalez, D. T. Gibson, Aldrichim. Acta 1999,
32, 35.
doi:10.1038/156144A0
(b) E. B. Vischer, S. R. Howland, H. Raudnitz, Nature 1950, 165, 528.
doi:10.1038/165528A0
(b) R. A. Johnson, Org. React. 2004, 63, 117.
(c) J. F. Grove, P. McCloskey, J. S. Moffatt, Chem. Commun. 1965,
343. doi:10.1039/C19650000343
(d) J. F. Grove, J. S. Moffatt, E. B. Vischer, J. Chem. Soc. 1965, 3803.
doi:10.1039/JR9650003803
(c) Refs [9a] and [9b].
[13] C. C. R. Allen, D. R. Boyd, H. Dalton, N. D. Sharma, I. Brannigan,
N. A. Kerley, G. N. Sheldrake, S. C. Taylor, J. Chem. Soc., Chem.
Commun. 1995, 117. doi:10.1039/C39950000117
(e) J. F. Grove, P. McCloskey, J. S. Moffatt, J. Chem. Soc. C 1966, 743.
[3] (a) M. M. Blight, J. J. W. Coppen, J. F. Grove, Chem. Commun. 1968,
1117. doi:10.1039/C19680001117
[14] (a) M. G. Banwell, O. J. Kokas, A. C. Willis, Org. Lett. 2007, 9, 3503.
doi:10.1021/OL071344Y
(b) M. Matveenko, O. J. Kokas, M. G. Banwell,A. C. Willis, Org. Lett.
2007, 9, 3683. doi:10.1021/OL701552R
(b) J. F. Grove, J. Chem. Soc. C 1969, 549.
(c) W. S. Golder, T. R. Watson, J. Chem. Soc., Perkin Trans. 1 1980,
422. doi:10.1039/P19800000422
(c) M. Matveenko, M. G. Banwell, A. C. Willis, Org. Lett. 2008, 10,
4693. doi:10.1021/OL801815K
[4] S. Neidle, D. Rogers, M. B. Hursthouse, J. Chem. Soc., Perkin Trans.
2 1972, 760. doi:10.1039/P29720000760
(d) O. J. Kokas, M. G. Banwell, A. C. Willis, Tetrahedron 2008, 64,
6444. doi:10.1016/J.TET.2008.04.070
[5] J. MacMillan, A. E. Vanstone, S. K. Yeboah, Chem. Commun. 1968,
613. doi:10.1039/C19680000613
[6] Synthetic approaches to the viridin framework: (a) R. Carlini,
K. Higgs, C. Older, S. Randhawa, R. Rodrigo, J. Org. Chem. 1997,
62, 2330. doi:10.1021/JO970394L
[15] D. A. Evans, A. M. Ratz, B. E. Huff, G. S. Sheppard, Tetrahedron Lett.
1994, 35, 7171. doi:10.1016/0040-4039(94)85352-5
[16] (a) V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976,
17, 1973.
(b) V. VanRheenen, D. Y. Cha, W. M. Hartley, Org. Synth. 1978, 58,
43. doi:10.1016/S0040-4039(00)78093-2
[17] M. G. Banwell, V. S. Bridges, J. R. Dupuche, S. L. Richards, J. M.
Walter, J. Org. Chem. 1994, 59, 6338. doi:10.1021/JO00100A040
[18] E. Piers, I. Nagakura, J. Org. Chem. 1975, 40, 2694. doi:10.1021/
JO00906A033
(b) F. E. S. Souza, R. Rodrigo, Chem. Commun. 1999, 1947.
doi:10.1039/A905731E
(c) E. H. Sessions, P. A. Jacobi, Org. Lett. 2006, 8, 4125.
doi:10.1021/OL061697H
(d) K. M. Muller, B. A. Keay, Synlett 2008, 1236.
[7] (a) Total synthesis of ( )-viridin: E. A. Anderson, E. J. Alexanian,
E. J. Sorensen, Angew. Chem. Int. Ed. 2004, 43, 1998. doi:10.1002/
ANIE.200353129
[19] M. Matveenko, A. C. Willis, M. G. Banwell, Tetrahedron Lett. 2008,
49, 7018. doi:10.1016/J.TETLET.2008.09.130
[20] For related solvent effects observed during the reductive cleavage
of PMP-acetals see: I. Paterson, K. Ashton, R. Britton, G. Cecere,
G. Chouraqui, G. J. Florence, H. Knust, J. Stafford, Chem. Asian J.
2008, 3, 367. doi:10.1002/ASIA.200700357
[21] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.
doi:10.1021/JO00408A041
[22] G. H. Posner, D. J. Brunelle, L. Sinoway, Synthesis 1974, 662.
doi:10.1055/S-1974-23397
[23] DENZO-SMN: Z. Otwinowski, W. Minor, Processing of X-ray
Diffraction Data Collected in Oscillation Mode, in Methods in Enzy-
mology, Volume 276: Macromolecular Crystallography, Part A (Eds
C. W. Carter Jr, R. M. Sweet) 1997, pp. 307–326 (Academic Press:
New York, NY).
(b) A total synthesis of ( )-wortmannin has been reported by
Shibasaki and coworkers: T. Mizutani, S. Honzawa, S.-Y. Tosaki,
M. Shibasaki, Angew. Chem. Int. Ed. 2002, 41, 4680. doi:10.1002/
ANIE.200290014
[8] See, for example, J. Blois, H. Yuan, A. Smith, M. E. Pacold,
R. Weissleder, L. C. Cantley, L. Josephson, J. Med. Chem. 2008, 51,
4699 and references cited therein. doi:10.1021/JM800374F
[9] (a) M. G. Banwell, A. J. Edwards, G. J. Harfoot, K. A. Jolliffe, M. D.
McLeod, K. J. McRae, S. G. Stewart, M. Vögtle, Pure Appl. Chem.
2003, 75, 223. doi:10.1351/PAC200375020223
(b) K. A. B. Austin, M. Matveenko, T. A. Reekie, M. G. Banwell,
Chem. Aust. 2008, 75(11), 3.
[10] (a) M. E. Garst, T. A. Spencer, J. Am. Chem. Soc. 1973, 95, 250.
doi:10.1021/JA00782A051
[24] SIR92: A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi,
M. C. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr. 1994, 27,
435. doi:10.1107/S002188989400021X
[25] P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout,
D. J. Watkin, J. Appl. Crystallogr. 2003, 36, 1487. doi:10.1107/
S0021889803021800
(b) For more recent applications of this protocol see: M. Kurosu,
L. R. Marcin,Y. Kishi,Tetrahedron Lett. 1998, 39, 8929 and references
cited therein. doi:10.1016/S0040-4039(98)02017-6
[11] T. Krumm, K. Bandemer, W. Boland, FEBS Lett. 1995, 377, 523.
doi:10.1016/0014-5793(95)01398-9
[12] Compounds 6 and 10 can be obtained from Questor, Queen’s Uni-
versity of Belfast, Northern Ireland (see: http://questor.qub.ac.uk/
newsite/contact.htm). For reviews on methods for generating cis-1,2-
dihydrocatechols by microbial dihydroxylation of the corresponding