Chemoenzymatic and enantioselective assembly of the (1α,3aβ, 6α,7aβ)- octahydro-1,6-methano-1 H-indene framework associated with 2-isocyanoallopupukeanane: Validation of a new synthetic strategy and the identification of enantiomeric switching regimes

Article abstract of DOI:10.1016/j.tet.2010.04.056

The octahydro-1,6-methano-IH-indene framework associated with the marine sesquiterpenoid 2-iso- cyanoallopupukeanane (1) has been prepared in enantiomerically pure form from the cis-1,2-dihy- drocatechol 8 using DielsAlder cycloaddition, oxa-di-π-methane rearrangement and intramolecular enolate alkylation steps as the key bond-forming events. Three distinct strategies for employing such sequences in the selective synthesis of either enantiomeric form of the target framework have been identified.

Full text of DOI:10.1016/j.tet.2010.04.056

Tetrahedron 66 (2010) 5250e5261
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoenzymatic and enantioselective assembly of the (1
a,3ab,6a,7ab)-
octahydro-1,6-methano-1H-indene framework associated with
2-isocyanoallopupukeanane: validation of a new synthetic strategy
and the identification of enantiomeric switching regimes
,
b
a
Christine E. Dietinger a, Martin G. Banwell a , Mary J. Garson , Anthony C. Willis
*
a Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
b School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The octahydro-1,6-methano-1H-indene framework associated with the marine sesquiterpenoid 2-iso-
cyanoallopupukeanane (1) has been prepared in enantiomerically pure form from the cis-1,2-dihy-
drocatechol 8 using DielseAlder cycloaddition, oxa-di-p-methane rearrangement and intramolecular
enolate alkylation steps as the key bond-forming events. Three distinct strategies for employing such
sequences in the selective synthesis of either enantiomeric form of the target framework have been
identified.
Received 1 February 2010
Received in revised form 23 March 2010
Accepted 12 April 2010
Available online 24 April 2010
Keywords:
2-Isocyanoallopupukeanane
Isonitrile
Ó 2010 Elsevier Ltd. All rights reserved.
Octahydro-1,6-methano-1H-indene
Oxa-di-p-methane rearrangement
Sesquiterpenoid
1. Introduction
As part of a program directed towards developing a comprehen-
sive understanding of the biogenesis of compound 1 we sought to
In 1991 Fusetani et al. reported1 on the elucidation, using 2D NMR
spectroscopic techniques, of the structure of 2-isocyanoallopupuke-
anane (1), a sesquiterpenoid isonitrile isolated from two specimens of
a Phyllidia pustulosa species of nudibranch collected off Hachijo-jima
Island, Japan. Such isocyano-containing species, which include the
framework-isomeric natural products 2-isocyanopupukeanane (2),2
9-isocyanopupukeanane (3)2 and 9-isocyanoneopupukeanane (4),3
are found in the secretions of a variety of marine molluscs, where
they are presumed to play a defensive role, and are known to be
sequestered from the sponge diet of these creatures.2c The origins of
the isocyano-function have been the subject of various studies4,5
including a number conducted by one of us (M.J.G.).5
establish methods for synthesising, in either enantiomeric form,6 the
associated octahydro-1,6-methano-1H-indene framework incor-
porating relevant functionality, especially those that would allow for
ready installation of isocyano and related groups at the 2-position. In
contrast to the situation with compounds 2 and 3,7 there have been
few studies concerned with the total synthesis of compound 1 or its
enantiomer.8,9 Indeed, the single reported total synthesis of the title
natural product was described by Ho et al. in 19998 and only pro-
vided the racemic modification of the target. More recently (2006),
Srikrishna and Satyanarayana have communicated9 a biogenetically
patterned and enantiospecific synthesis of ‘allopupukeanones’ from
6-methylcarvone that involves, as the key step, the acid-induced
WagnereMeerwein rearrangement of a pupukeanyl cation to the
corresponding allopupukeanane species. However, the extension of
such chemistry to the preparation of natural product 1 has not been
reported thus far.
The approach to the tricyclic framework of ent-2-iso-
cyanoallopupukeanane (ent-1) that we have pursued is outlined in
Figure 1, and this incorporates several key transformations used
during the course of our development of total syntheses of various
triquinane-type sesquiterpenes including hirsutene, hirsutic acid,
complicaticacidandphellodonicacid.10 A pivotalaspectof thepresent
work was the recognition that the framework of target ent-1 (and 1) is
* 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.2010.04.056

C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
5251
Figure 1. Retrosynthetic analysis of ent-2-isocyanoallopupukeanane (ent-1).
a 1,5-ethano-bridged diquinane and that this could, therefore, be as-
sembled from a precursor of the general form 5 through its subjection
to reductive cleavage of the carbonyl-conjugated cyclopropane moi-
ety and in situ intramolecular alkylation of the ensuing enolate by the
C5-appended and endo-orientated side-chain bearing a leaving group
at itsterminus. Conventionalfunctional groupinterconversions (FGIs)
of the OP and carbonyl groups within the anticipated product of this
sequence should then deliver ent-2-isocyanoallopupukeanane (ent-1)
and related compounds. It was expected that compound 5 could, in
acetonide derivative, 9, of cis-1,2-dihydrocatechol 8 in a Dielse
Alder cycloaddition reaction with -chloroacrylonitrile. Hydrolysis
of the ensuing mixture of epimeric
-chloronitriles12 to give the
a
a
previously reported ketone 1012 was achieved most effectively us-
ing a modification of conditions originally reported by Evans et al.15
As a prelude to introducing the vinyl group required in a photo-
chemical substrate of the general form 6, the enolate anion derived
by deprotonation of ketone 10 was treated, in diethyl ether, with
2 mol equiv of Mander’s reagent16 and thus affording the
turn, be obtained via a photochemically promoted oxa-di-
p
-methane
b
-ketoester 11 in 67% yield. Reduction of the latter with sodium
rearrangement11 of the disubstituted bicyclo[2.2.2]octenone
6
borohydride in ethanol then gave -hydroxyester 12 and its
b
followed by or, if necessary, preceded by manipulation of the associ-
ated vinyl group so as to establish the relevant functionality on the
side-chain of compound 5. Access to compound 6 was expected to be
gained via conventional manipulations of ketone 7, versions of which
we have obtained previously through DielseAlder cycloaddition
stereoisomers C9-epi-12 and C8,C9-di-epi-12 in 82% combined
yield.17 The structure of compound 12 was confirmed by single-
crystal X-ray analysis (see Experimental section).
Compound C9-epi-12, the predominant product of the reduction
process, could be converted into isomer 12 (67% yield at 73% con-
version) upon treatment with the weakly nucleophilic base DBU.
Subjection of a mixture of compounds 12 and C8,C9-di-epi-12 to
mesylation under the CrosslandeServis conditions18 then gave the
corresponding mixture of mesylate 13 and isomer C8,C9-di-epi-13.
Treatment of the latter mixture with DBU in hot (72 ꢀC) benzene
overnight resulted in elimination of the elements of methanesulfonic
acid and formation of the unsaturated ester 14 (92%). Reaction of
compound 14 with sodium borohydride in methanol/THF then gave
a ca. 1:1 mixture of ester 15 and its epimer C9-epi-15 (81% combined
yield) that could be separated from one another byconventional flash
chromatographic techniques. Interestingly, treatment of compound
C9-epi-15 with sodium methoxide in methanol at 0 to 70 ꢀC for 24 h
afforded a ca. 3:1 mixture of the starting material and epimer 15 (89%
combined yield) and thus demonstrating that additional quantities of
the desired isomer (15) could be generated from the unwanted one.
Treatment of ester 15 with DIBAL-H in dichloromethane/hexane at
ꢁ78 ꢀC for 1.25 h afforded a chromatographically separable mixture
of alcohol 16 (57%) and aldehyde 17 (30%). The former product could
be oxidised to the latter in 51% yield using the ParikheDoering pro-
tocol.19 Additional quantities of aldehyde 17 could also be obtained by
reducing ester C9-epi-15 to aldehyde C9-epi-17 and then epimerising
the latter with DBU (47% yield of compound 17 over the two steps).
Wittig-type methylenation of aldehyde 17 then gave the required
olefin 18 in 60% yield. Cleavage of the acetonide unit within the latter
compound was achieved by exposing the substrate to activated
DOWEX-50 resin in refluxing aqueous methanol for 6 days. By this
reactionsbetweena-chloroacrylonitrileandhydroxy-protectedforms
of the cis-1,2-dihydrocatechol 8.12 Starting material 8 is readily
obtained in multi-gram quantities and enantiomerically pure form
(>99.8% ee) through the whole-cell biotransformation of toluene
using a genetically engineered micro-organism Escherichia coli JM109
(pDTG601) that over-expresses the responsible enzyme, viz. toluene-
dioxygenase (TDO).13 In an overall sense, then, there are three critical
chemical sequences associated with the implementation of the
proposed synthetic plan, namely the DielseAlder cycloaddition
process leading to compounds of the general form 7 and the manip-
ulation of such adducts to give bicyclo[2.2.2]octenone 6, the
photochemical rearrangement of the latter to give, after appropriate
FGIs, the cyclopropa-fused diquinane 5 and, finally, a reductive al-
kylation process leading to the complete tricyclic framework associ-
ated with target ent-1. Each of these pivotal steps is discussed
separately in the following sections as is the capacity to adapt the
reported chemistry to the synthesis of either enantiomeric form of
2-isocyanoallopupukeanane, viz. 1 and/or ent-1.
2. Results and discussion
2.1. Synthesis of the substrate for the oxa-di-
p-methane
rearrangement reaction
The first critical chemical sequence associated with the present
work started (Scheme 1) with the engagement of the well known14

5252
C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
Scheme 1.
means the diol 19 was obtained in 66% yield. So, despite the harsh
conditions required to effect cleavage of the acetonide group, there
appeared to be no complications arising from isomerisation of the
terminal olefin into a more stable internal position. Selective oxida-
tion of the hydroxyl group remote from the bridgehead methyl group
within diol 19 could be achieved using the sterically demanding
oxammonium salt derived from reaction of 4-AcNH-TEMPO with p-
TsOH$H2O20 and the ensuing acyloin 20 (81%) was immediately
subjected to O-benzoylationusing benzoyl chloride inthe presence of
4-(N,N-dimethylamino)pyridine (DMAP) and triethylamine. By such
means the keto-ester 21 was obtained in quantitative yield.
was subjected to irradiation with a medium pressure mercury-va-
pour lamp at 15 ꢀC for 4.5 h (Scheme 2). By such means a ca. 1:1
mixture of the C4-epimeric forms of compound 22 was obtained,
albeit in a disappointing 32% combined yield. This low yield could
be attributed to interference from the vinyl group associated with
substrate 21, especially the potential for this moiety to participate
in a competing oxa-di-p-methane rearrangement process. The
formation of the C4-epimeric forms of product 22 from a single
epimeric form of precursor 21 presumably arises from a secondary
photochemical process involving photo-enolisation and/or Nor-
rish-type 1 reactions10 of the primary photo-product. The driving
force for the epimerisation of the primary photo-product is the
migration of the O-benzoyl unit from the exo-face to the endo-face
of the cyclopropa-fused diquinane framework and thereby re-
lieving steric interactions with the adjacent methyl group.
While in the original plan (Fig. 1) deletion of the O-benzoyl
group within keto-ester 21 would now be required in order to
produce the photo-substrate 6, our previous studies10 had shown
that systems related to the former compound readily engage in
oxa-di-
p
-methane rearrangement reactions. Accordingly, and
The chemical manipulation of photo-product 22 so as to generate
a substrate for examination of the proposed intramolecular enolate
alkylation step (Fig. 1) involved initial reductive removal of the O-
benzoyl residue. This was best accomplished by treating a meth-
anolic solution of compound 22 with 2.2 mol equiv of samarium(II)
diiodide at ꢁ78 ꢀC for 5 min.21 The ensuing unsaturated ketone 23
(54%) was subjected to olefin dihydroxylation using the UpJohn
conditions22 and thereby affording an inseparable and 1:1 mixture
of the diastereoisomeric forms of the product diol 24 in 48% com-
bined yield. Attempts to improve upon this outcome, in terms of
both yield and diastereoselectivity, by using Sharpless asymmetric
given the capacity to delete the OBz group at a later stage in the
synthesis, compound 21 was selected as the substrate to be used in
studies of the photochemical rearrangement process. Details are
presented in the following section.
2.2. The oxa-di-p-methane rearrangement reaction and
chemical manipulation of the photo-product
Following procedures developed earlier,10 a solution of com-
pound 21 in acetone containing acetophenone (triplet sensitiser)

C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
5253
lack of any products of intramolecular enolate alkylation processes
may be attributed to the limited nucleophilicity and/or the ready
protonation of the intermediate samarium enolate.25,26
Scheme 3.
Sufficient quantities of compound 28 were obtained by the
means just described to allow for an investigation of the intra-
molecular enolate alkylation reaction under more conventional
conditions. Thus, treatment of a THF solution of ketone 28 main-
tained at ꢁ78 ꢀC with 1.2 mol equiv of lithium hexamethyldisila-
zide (LiHMDS) (Scheme 4) and then allowing the reaction mixture
to warm to 18 ꢀC provided, after work up and chromatographic
Scheme 2.
dihydroxylation protocols23 either gave no reaction at all (with AD-
mix-
b
) or resulted in a 1:1:1 mixture of the starting material and the
). The selective tosylation of the pri-
product diols (with AD-mix-
a
mary hydroxygroup within compound 24 was readilyaccomplished
using p-toluenesulfonyl chloride in the presence of dibutyltin ox-
ide24 and thereby affording the desired epimeric mono-tosylates 25
in 77% combined yield. O-Benzoylation of the secondary hydroxyl
groups within the epimeric forms of compound 25 was effected
under standard conditions (BzCl, DMAP, Et3N) and the co-formed
bis-esters 26 and 27 were readily separated from one another by
conventional chromatographic techniques and thereby obtained in
yields of 40% and 55%, respectively. The illustrated stereochemistries
assigned to products 26 and 27 follow from a single-crystal X-ray
analysis of a derivative of the former compound (vide infra).
Scheme 4.
purification, compound 32 in 53% yield. All the spectroscopic data
obtained on this material were in full accord with the assigned
structure but final confirmation of this was secured by a single-
crystal X-ray analysis. The derived ORTEP is shown in Figure 2 while
other details of this analysis are presented in the Experimental
section. The formation of this product must arise through selec-
tive formation of precursor enolate 30, which then engages in
intramolecular alkylation with the tosyloxy-bearing side-chain to
give ketone 32 incorporating the tricyclic framework of 2-
isocyanoallopupukeanane but carrying the methyl group in the C6a
rather than the desired C6 position. Interestingly, no evidence could
be obtained for the formation of the isomeric ketone 33 that would
arise from intramolecular alkylation of intermediate 31.
2.3. Completion of the synthesis through intramolecular
enolate alkylation
With compounds 26 and 27 in hand studies of the validity of the
proposed reductive-cleavage/intramolecular enolate alkylation
chemistry (see conversion 5/1, Fig. 1) could begin. The initial ex-
periments simply involved treating each of substrates 26 and 27
with 1.2 mol equiv of samarium(II) diiodide in THF/methanol at ꢁ78
to 18 ꢀC for periods of up to 8 h (Scheme 3).25 However, after
quenching the reaction mixtures and then subjecting them to work
up, onlythe products of cyclopropane ring-cleavage, viz. compounds
28 and 29, were obtained in yields of 52% and 21%, respectively. The

5254
C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
using methodology reported by Boyd et al.28 Accordingly, the op-
tical antipodes of all of compounds 9e29 and 32 are automatically
available using the chemistries reported herein. Another possible
mode of entry into the other enantiomeric series would involve
reversing the facial selectively of the initial DielseAlder cycload-
dition reaction involving cis-1,2-dihydrocatechol
derivatives since an -face addition process affords the pseudo-
enantiomeric form of the compound (e.g., ketone 10) arising from
the corresponding
-face addition reaction. In recent work10a,b,29
8 and/or its
a
b
we have shown that such facial selectivities can be controlled, to
some extent at least, by using either compound 8 or a protected
form thereof (e.g., acetonide 9) as the 4p-addend in the cycload-
dition process. A third possible mode of enantiomeric ‘switching’
arises from the pseudo-symmetrical nature of ketonic systems such
as compound 28. In particular, if the non-methylated variant of this
diquinane could be obtained from the known, benzene-derived
cis-1,2-dihydrocatechol13 then this could be desymmetrised using
the relevant KogaeSimpkins type-base30 to generate either enan-
tiomeric form of the corresponding enolate and thence, through
intramolecular alkylation, either enantiomeric form of the title
framework.31 The required methyl group could then be introduced
through
a conventional dehydrogenation/conjugate addition
reaction sequence. Efforts to examine all of these possibilities are
now underway in our laboratories. Results will be reported in
due course.
3. Experimental section
3.1. General experimental procedures
Proton (1H) and carbon (13C) NMR spectra were recorded on
a Varian Gemini machine operating at 300 or 75 MHz, respectively.
Unless otherwise specified, spectra were acquired at 20 ꢀC in deu-
terochloroform(CDCl3) thathad beenstoredoveranhydrous sodium
Figure 2. Molecular structure of compound 32 (C18H20O3). Anisotropic displacement
ellipsoids show 30% probability levels. Hydrogen atoms are drawn as circles with
small radii.
carbonate. Chemical shifts are recorded as
d values in parts per
Presumably, the selective formation of enolate 30 over isomer
31 under the conditions of thermodynamic control27 defined above
is a reflection of the reduction in torsional strain (between the
angular methyl and the syn-1,2-related methylene proton adjacent
to the carbonyl group) associated with the conversion 28/30. This
reduction is greater than that which would be encountered in the
equivalent process leading to 31 (where the corresponding re-
duction in torsional strain would ‘only’ be that arising from loss
of the interaction between the angular hydrogen and the syn-
1,2-related methylene proton adjacent to the carbonyl group). In
principle, carrying out enolate formation under conditions of
kinetic control (viz. adding the substrate ketone 28 to a solution of
the base)27 might be expected to lead to enolate 31 and thence the
tricyclic product 33, which bears a pseudo-enantiomeric relation-
ship to isomer 32. Unfortunately, a lack of sufficient quantities of
ketone 28 has prevented us from conducting the relevant experi-
ments. Current efforts are directed towards achieving a much more
efficient route to compound 28 and the results of these will be
reported in due course.
million (ppm). Infrared spectra (nmax) were normally recorded on
a PerkineElmer 1800 Series FTIR Spectrometer and samples were
analysed 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 Micromass-Waters LC-ZMD single quadrupole liquid
chromatograph-mass spectrometer while low- and high-resolution
EImass spectrawere recordedon a Fisons VGAUTOSPEC instrument.
Melting points were measured on a Stanford Research Systems
Optimelt-Automated Melting Point System and are uncorrected.
Optical rotations were measured at the sodium-D line (
l¼589 nm)
between 17 and 20 ꢀC and at the concentrations (c, in g/100 mL)
indicated using spectroscopic grade chloroform (CHCl3) as solvent.
Analytical thin layer chromatography (TLC) was performed on alu-
minium-backed 0.2 mm thick silica gel 60 F254 plates as supplied by
Merck. Eluted plates were visualised using a 254 nm UV lamp and/or
by treatment with a suitable dip followed by heating. These dips
included a mixture of vanillin/sulfuric acid/ethanol (1 g:1 g:18 mL)
or phosphomolybdic 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
defined by Still et al.32 with silica gel 60 (0.040e0.0063 mm) as the
stationary phase and using the AR- or HPLC-grade solvents in-
dicated. Starting materials and reagents were generally available
from the SigmaeAldrich, Merck, TCI, Strem or Lancaster Chemical
Companies 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 Companies.
THF, dichloromethane, acetonitrile and benzene were dried using
a Glass Contour solvent purification system that is based upon
a technology originally described by Grubbs et al.33 Spectroscopic
2.4. Potentially enantiodivergent routes to the octahydro-1,6-
methano-1H-indene framework associated with 2-
isocyanoallopupukeanane
The lack of certainty regarding the absolute configuration of the
naturally occurring form of 2-isocyanoallopupukeanane6 has
prompted us to consider ways in which either enantiomeric form of
this compound could be synthesised using the now validated
strategy shown in Figure 1. Three distinct ways of achieving this
seem possible. First of all, the enantiomeric form of the starting
material, viz. compound ent-8, is available from p-iodotoluene

C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
5255
grade solvents were used for all analyses. Where necessary, re-
actions were performed under a nitrogen or argon atmosphere.
spectrum identical with that derived from a pure sample (see be-
low); 13C NMR (75 MHz, CDCl3)
(compound C8,C9-di-epi-12)
d
173.7 (C), 134.9 (CH), 129.7 (CH), 108.5 (C), 78.6 (CH), 77.7 (CH), 75.0
3.2. Specific chemical transformations
(CH), 52.3 (CH3), 49.9 (CH), 43.9 (C), 37.5 (CH), 25.4 (CH3), 24.9
ꢃ
þ
(CH3), 17.7 (CH3); MS (EI, 70 eV) m/z 268 (Mþ , 2%), 253 [(MꢁCH3 ) ,
54], 133 (100), 109 (73), 108 (91), 105 (90), 100 (86), 43 (85).
Concentration of fraction B [Rf¼0.4(1) in 1:7:12 v/v/v MeOH/
ethyl acetate/hexane] gave compound C9-epi-12 (56 mg, 58%) as
ꢃ
3.2.1. Compound 11. LiHMDS (28.8 mL of a 1 M solution in THF,
28.8 mmol, 2 mol equiv) was diluted with diethyl ether (132 mL)
then cooled to ꢁ78 ꢀC.
A
solution of ketone 1012 (3.00 g,
14.40 mmol) in diethyl ether (12 mL) was then added to the re-
action mixture via syringe pump at the rate of 15 mL/h. After ad-
dition was complete, the resulting mixture was stirred at ꢁ78 ꢀC for
2.5 h then methyl cyanoformate (Mander’s reagent) (2.45 g or
2.30 mL, 28.8 mmol, 2 mol equiv) was added via syringe pump at
0.45 mL/h. The ensuing mixture was stirred at ꢁ78 ꢀC for 0.5 h after
which it was poured into dichloromethane/water (300 mL of a 1:1
v/v mixture). The separated aqueous phase was extracted with
dichloromethane (3ꢂ100 mL) and the combined organic layers
were washed with brine (1ꢂ150 mL) then dried (MgSO4), filtered
and concentrated under reduced pressure. The orange oil thus
obtained was subjected to column chromatography (silica, 1:4 v/v
ethyl acetate/hexane elution) and concentration of the appropriate
a white, crystalline solid, mp¼84e86 ꢀC, [
a
]
þ26.5 (c 0.9, CHCl3).
D
þ
þ
ꢃ
ꢃ
Found: (MꢁCH3 ) , 253.1076. C14H20O5 requires (MꢁCH3 ) ,
253.1076. 1H NMR (300 MHz, CDCl3)
d 6.35e6.29 (m, 1H), 5.74 (dd,
J¼8.2 and 1.2 Hz, 1H), 4.17 (dd, J¼7.2 and 3.6 Hz, 1H), 3.83 (dd, J¼7.2
and 1.2 Hz, 1H), 3.72 (d, J¼8.6 Hz, 1H), 3.67 (s, 3H), 3.11e3.06
(complex m, 1H), 2.75 (d, J¼8.6 Hz, 1H), 2.10 (br s, 1H), 1.37 (s, 3H),
1.31 (s, 3H), 1.26 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 172.0 (C), 131.9
(CH),131.5 (CH),109.6 (C), 80.3 (CH), 78.3 (CH), 71.8 (CH), 51.9 (CH3),
47.8 (CH), 44.9 (C), 36.2 (CH), 25.3 (CH3), 24.9 (CH3), 18.2 (CH3); IR
nmax (KBr) 3481, 2977, 2934, 2876,1737,1454,1437,1371,1346,1260,
1203, 1171, 1080, 1056, 1031, 883, 836, 731 cmꢁ1; MS (EI, 70 eV) m/z
ꢃ
þ
268 (Mþ , <1%), 253 [(MꢁCH3 ) , 26], 133 (63), 109 (61), 108 (100),
ꢃ
105 (47), 80 (43), 43 (40).
fractions (Rf¼0.2) gave
b
-ketoester 11 (2.56 g, 67%) as a white,
Method B (epimerisation of compound C9-epi-12): DBU (58
m
L,
mol) was added to a solution of compound C9-epi-12 (59 mg,
mol) in benzene (1.1 mL) and the reaction mixture heated at
crystalline solid. This material was used in the subsequent steps of
the synthesis (see below). For the purposes of analysis a sample of
this material was recrystallised (ethyl acetate/hexane) to give col-
220
220
m
m
72 ꢀC for 21 h then cooled to 18 ꢀC and diluted with dichloromethane
(10 mL). The solution thus obtained was washed with HCl (2ꢂ10 mL
of a 2 M aqueous solution), sodium bicarbonate (1ꢂ10 mL of a satu-
rated aqueous solution) and brine (1ꢂ10 mL) before being dried,
filteredandconcentratedunderreducedpressure.Theresultinglight-
ourless crystals, mp¼115e116 ꢀC, [
a]
þ210.0 (c 1, CHCl3). Found:
D
ꢃ
ꢃ
M
þ , 266.1163; C, 63.43; H, 6.91. C14H18O5 requires Mþ , 266.1154; C,
63.15; H, 6.81%. 1H NMR (300 MHz, CDCl3)
d
6.44 (br dd, J¼8.1 and
6.4 Hz, 1H), 5.71 (br dt, J¼8.1 and 1.5 Hz, 1H), 4.49 (br dd, J¼7.1 and
3.4 Hz, 1H), 4.08 (dd, J¼7.1 and 1.5 Hz, 1H), 3.71 (s, 3H), 3.46e3.41
(complex m, 1H), 2.92 (d, J¼1.6 Hz, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.30
yellow solid (52 mg), which was comprised of a 1:3.4 mixture of b-
hydroxyesters C9-epi-12 and 12 (as determined by 1H NMR analysis),
was subjected to column chromatography (silica,1:7:12 v/v/v MeOH/
ethyl acetate/hexane elution) to afford two fractions, A and B.
Concentration of fraction A [Rf¼0.4(4) in 1:7:12 v/v/v MeOH/ethyl
acetate/hexane] yielded compound 12 (29 mg, 67% at 73% conver-
(s, 3H); 13C NMR (150 MHz, CDCl3)
d 202.0 (C), 167.8 (C), 133.0 (CH),
129.2 (CH), 110.9 (C), 79.4 (CH), 78.1 (CH), 54.6 (C), 52.8 (CH3), 50.4
(CH), 38.3 (CH), 25.3 (CH3), 25.0 (CH3), 14.6 (CH3); IR nmax (KBr)
2979, 2949, 2937, 2891, 1747, 1725, 1374, 1262, 1243, 1207, 1163,
ꢃ
1088, 1063, 103þ4, 973, 714 cmꢁ1; MS (EI, 70 eV) m/z 266 (Mþ , 48%),
sion) as a white, crystalline solid, mp¼132.2e132.4 ꢀC, [
a]
D þ47.9 (c
ꢃ
251 [(MꢁCH3 ) , 45], 235 (24), 176 (100), 148 (93), 121 (71), 108
1, CHCl3). Found: Mþ , 268.1312; C, 62.69; H, 7.54. C14H20O5 requires
ꢃ
ꢃ
(69), 100 (89), 91 (63), 85 (65), 43 (68).
M
þ , 268.1311; C, 62.67; H, 7.51%. 1H NMR (300 MHz, CDCl3)
d
6.28
(ddd, J¼8.1, 6.7 and 0.8 Hz, 1H), 5.77 (dd, J¼8.1 and 1.2 Hz, 1H), 4.23
(ddd, J¼7.3, 3.4 and 1.2 Hz, 1H), 3.91 (dd, J¼3.3 and 1.2 Hz, 1H), 3.87
(dd, J¼7.4 and 1.2 Hz, 1H), 3.74 (s, 3H), 3.20e3.15 (complex m, 1H),
2.33 (t, J¼3.4 Hz,1H),1.59 (s,1H),1.37 (s, 3H),1.31 (s, 3H),1.25 (s, 3H);
3.2.2. Compound 12. Method A: A solution of
380
mol) in ethanol (17.4 mL) was cooled to 0 ꢀC then treated, in one
portion, with sodium borohydride (14.4 mg, 380 mol, 1 mol equiv).
b-ketoester 11 (101 mg,
m
m
The ensuing mixture was stirred at 0 ꢀC for 0.5 h then allowed to
warm to 18 ꢀC. After 1 h at this temperature the reaction mixture was
treated with ammonium chloride (5 mL of a saturated aqueous
solution) and, after a further 5 min, with distilled water (50 mL) then
concentrated under reduced pressure to ca.1/3 of its original volume.
The residue so obtained was diluted with dichloromethane (10 mL).
The separated aqueous phase was extracted with dichloromethane
(3ꢂ10 mL) and the combined organic phases were then washed with
brine (1ꢂ10 mL) before being dried (magnesium sulfate), filtered and
concentrated under reduced pressure. The resulting yellow oil was
subjectedto column chromatography(silica,1:7:12 v/v/vMeOH/ethyl
acetate/hexane elution) to afford two fractions, A and B.
13C NMR (75 MHz, CDCl3)
d 173.3 (C),133.4 (CH),131.2 (CH),109.5 (C),
80.6 (CH), 75.7 (CH), 73.0 (CH), 52.4 (CH), 52.3 (CH3), 44.9 (C), 36.4
(CH), 25.4 (CH3), 24.9 (CH3), 17.8 (CH3); IR nmax (KBr) 3461, 2976,
2927, 2876, 1731, 1374, 1266, 1248, 1206, 1163, 1078, 1066, 1029, 882,
ꢃ
þ
730 cmꢁ1; MS (EI, 70 eV) m/z 268 (Mþ , 8%), 253 [(MꢁCH3 ) , 49],
ꢃ
133 (100), 109 (64), 108 (63), 105 (69), 100 (67), 43 (71).
Concentration of fraction B [Rf¼0.4(1) in 1:7:12 v/v/v MeOH/
ethyl acetate/hexane] afforded
b-hydroxyester C9-epi-12 (16 mg,
27% recovery) as a white, crystalline solid that was identical, in all
respects, with an authentic sample.
3.2.3. Compound 14. Step i: Triethylamine (2.27 g, 22.44 mmol,
1.5 mol equiv) was added to a magnetically stirred solution of a ca.
4:1 mixture34 of alcohols 12 and C8,C9-di-epi-12 (4.01 g,
14.96 mmol) in dichloromethane (75 mL) and the resulting mixture
cooled to 0 ꢀC then treated, dropwise over 5 min, with meth-
anesulfonyl chloride (1.89 g, 16.46 mmol, 1.1 mol equiv). The ensu-
ing mixture was stirred at 0 ꢀC for 1 h then at 18 ꢀC for 4 h after
which it was diluted with dichloromethane (25 mL). The resulting
solution was washed with ice-cold water (1ꢂ100 mL), hydrochloric
acid (1ꢂ100 mL of a 2 M aqueous solution), sodium hydrogen car-
bonate (1ꢂ100 mL of a saturated aqueous solution) and brine
(1ꢂ100 mL) before being dried (magnesium sulfate), filtered and
concentrated under reduced pressure to give an off-white solid
Concentration of fraction A [Rf¼0.4(4) in 1:7:12 v/v/v MeOH/
ethyl acetate/hexane] yielded an inseparable 1:1.7 mixture of
compounds 12 and C8,C9-di-epi-12 (25 mg, 24%) as a clear, colour-
ꢃ
ꢃ
less oil. Found: Mþ , 268.1306. C14H20O5 requires Mþ , 268.1311. 1H
NMR (300 MHz, CDCl3)
that derived from a pure sample (see below); 1H NMR (300 MHz,
CDCl3)
d (compound 12) spectrum identical with
d
(compound C8,C9-di-epi-12) 6.03 (dd, J¼8.1 and 6.0 Hz,
1H), 5.78e5.70 (complex m, 1H), 4.40 (ddd, J¼7.3, 3.2 and 0.8 Hz,
1H), 4.35 (dd, J¼7.3 and 0.8 Hz,1H), 3.79 (br d, J¼4.4 Hz,1H), 3.69 (s,
3H), 3.22e3.14 (complex m, 1H), 2.28 (dd, J¼4.4 and 1.8 Hz, 1H),
1.36 (s, 3H), 1.32 (s, 3H), 1.28 (s, 3H) (signal due to OH proton ob-
scured or overlapping); 13C NMR (75 MHz, CDCl3)
d (compound 12)

5256
C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
(4.89 g). This material, which was comprised (as determined by 1H
NMR analysis) of a ca. 4:1 mixture of the mesylates of alcohols 12
(viz. 13) and C8,C9-di-epi-12, was used directly in the step ii of the
reaction sequence.
39.6 (CH), 38.1 (C), 37.5 (CH), 32.3 (CH2), 25.5 (CH3), 25.0 (CH3), 21.5
(CH3); IR nmax (KBr) 2971, 2956, 2931, 2873, 1738, 1373, 1285, 1254,
ꢃ
1203, 1167, 106þ3, 885, 714 cmꢁ1; MS (þEI, 70 eV) m/z 252 (Mþ , 7%),
ꢃ
237 [(MꢁCH3 ) , 61], 221 [(MꢁCH3Oꢃ) , 27], 194 (84), 162 (84), 135
Step ii: DBU (2.40 mL, 16.07 mmol, 2.6 mol equiv) was added to
a solution of the above-mentioned mixture of mesylates (2.14 g,
6.18 mmol) in benzene (30 mL). The resulting mixture was heated to
72 ꢀC for 15 h then cooled to 18 ꢀC and diluted with dichloro-
methane (20 mL). The ensuing solution was washed with hydro-
chloric acid (1ꢂ50 mL of a 2 M aqueous solution), sodium hydrogen
carbonate (1ꢂ50 mL of a saturated aqueous solution) and brine
(1ꢂ50 mL) then dried (magnesium sulfate), filtered and concen-
trated under reduced pressure. The yellow oil (1.62 g) thus obtained
was subjected to column chromatography (silica, 1:7:12 v/v/v
MeOH/ethyl acetate/hexane elution) and concentration of the ap-
propriate fractions (Rf¼0.8) then gave compound 14 (1.42 g, 92%) as
(100), 134 (83), 117 (70), 105 (70), 100 (81), 93 (70).
Method B (epimerisation of compound C9-epi-15): A solution of
ester C9-epi-15 (368 mg, 1.46 mmol) in MeOH (27 mL) was cooled
to 0 ꢀC then sodium methoxide [generated from NaH (105 mg,
4.38 mmol, 3 mol equiv) and MeOH (18 mL)] was added. After
5 min, the cooling bath was removed and the reaction mixture
heated to 70 ꢀC for 24 h then allowed to cool to 18 ꢀC and quenched
with ammonium chloride (20 mL of a saturated aqueous solution).
The separated aqueous phase was extracted with dichloromethane
(3ꢂ20 mL) then the combined organic phases were washed with
brine (1ꢂ10 mL) before being dried (magnesium sulfate), filtered
and concentrated under reduced pressure to yield a clear, colour-
less oil. Subjection of this material to column chromatography
(silica, 1:7:12 v/v/v MeOH/ethyl acetate/hexane elution) afforded
two fractions, A and B.
þ
ꢃ
a light-yellow oil, [
a
]
þ43.7 (c 1, CHCl3). Found: (MꢁCH3 ) ,
ꢃ
D
235.0968. C14H18O4 requires (MꢁCH3 ) , 235.0970. 1H NMR
þ
(300 MHz, CDCl3)
d 6.92 (s, 1H), 6.34e6.28 (complex m, 1H),
5.99e5.95 (complex m, 1H), 4.30e4.25 (complex m, 2H), 3.93e3.89
Concentration of fraction A [Rf¼0.8(4) in 1:7:12 v/v/v MeOH/
ethyl acetate/hexane] gave ester 15 (62 mg, 36% at 47% conversion)
as a clear, colourless oil that was identical, in all respects, with an
authentic sample.
Concentration of fraction B [Rf¼0.7(9) in 1:7:12 v/v/v MeOH/
ethyl acetate/hexane] afforded ester C9-epi-15 (196 mg, 53% re-
covery) as a clear, colourless oil that was identical, in all respects,
with an authentic sample.
(complex m,1H), 3.71 (s, 3H),1.57 (s, 3H),1.30 (s, 3H),1.22 (s, 3H); 13C
NMR (75 MHz, CDCl3)
d 164.8 (C), 150.1 (CH), 138.1 (C), 136.2 (CH),
132.1 (CH), 113.2 (C), 82.9 (CH), 79.9 (CH), 51.7 (CH), 47.7 (C), 41.7
(CH3), 25.8 (CH3), 25.5 (CH3), 19.0 (CH3); IR nmax (KBr) 2977, 2949,
2934, 2905,1718,1456,1437,1380,1371,1263,1242,1211,1162,105þ8,
1037, 881, 755, 744, 717 cmꢁ1; MS (EI, 70 eV) m/z 235 [(MꢁCH3 ) ,
ꢃ
33%], 163 (90), 119 (75), 100 (96), 91 (64), 85 (100), 43 (85).
3.2.4. Compound 15. Method A: A solution of
a
,b
-unsaturated ester
3.2.5. Compounds 16 and 17. Method A (reduction of ester 15): A
14 (897 mg, 3.59 mmol) in THF/MeOH (124 mL of a 7:1 v/v mixture)
was cooled to 0 ꢀC and sodium borohydride (489 mg, 12.93 mmol,
3.6 mol equiv) was then added in one portion. The ensuing mixture
was stirred at 0 ꢀC to 18 ꢀC for 4.5 h then re-cooled to 0 ꢀC and
quenched with ammonium chloride (100 mL of a saturated aque-
ous solution). The resulting mixture was extracted with dichloro-
methane (3ꢂ50 mL) and the combined organic extracts were
washed with brine (1ꢂ100 mL) before being dried (magnesium
sulfate), filtered and concentrated under reduced pressure. The
ensuing light-yellow oil was subjected to column chromatography
(silica, 1:7:12 v/v/v MeOH/ethyl acetate/hexane elution) to afford
two fractions, A and B.
magnetically stirred solution of ester 15 (50 mg, 198 mmol) in
dichloromethane (5.20 mL) was cooled to ꢁ78 ꢀC then DIBAL
(0.34 mL of a 1 M solution in hexane, 340 mmol, 1.7 mol equiv) was
added dropwise over 10 min. The resulting mixture was stirred at
ꢁ78 ꢀC for 1.25 h then quenched with potassium sodium tartrate
(2 mL of a saturated aqueous solution), warmed to 18 ꢀC and stirred at
this temperature for 15 h. The separated aqueous layer was extracted
with dichloromethane (3ꢂ2 mL) and the combined organic phases
were then dried (magnesium sulfate), filtered and concentrated un-
der reduced pressure to yield a clear, colourless oil (46 mg). Sub-
jectionof thismaterialtocolumnchromatography(silica,1:4v/vethyl
acetate/hexane elution) afforded two fractions, A and B.
Concentration of fraction A [Rf¼0.8(4) in 1:7:12 v/v/v MeOH/ethyl
Concentration of fraction A (Rf¼0.4 in 1:4 v/v ethyl acetate/hex-
acetate/hexane]gavecompound15 (333 mg, 37%)asaclear, colourless
ane) gave aldehyde 17 (13 mg, 30%) as a white, crystalline solid,
ꢃ
ꢃ
ꢃ
oil,[a
]D ꢁ1.6 (c1, CHCl3). Found:Mþ , 252.1357. C14H20O4 requiresMþ
,
mp¼59e62 ꢀC,[
a
]D ꢁ31.0(c1, CHCl3). Found:Mþ , 222.1253;C,70.05;
ꢃ
252.1362.1H NMR (300 MHz, CDCl3)
d
6.11 (ddd, J¼8.1, 6.3 and 0.9 Hz,
H, 8.00. C13H18O3 requires Mþ , 222.1256; C, 70.25; H, 8.16%. 1H NMR
1H), 5.83 (dd, J¼8.1 and 0.9 Hz, 1H), 4.22 (ddd, J¼7.2, 3.3 and 0.9 Hz,
1H), 3.88 (dd, J¼7.2 and 1.2 Hz, 1H), 3.69 (s, 3H), 3.16e3.10 (complex
m, 1H), 2.47 (ddd, J¼11.4, 5.4 and 3.0 Hz, 1H), 1.65 (dd, J¼13.5 and
5.4 Hz, 1H), 1.31 (dd, J¼13.5 and 11.4 Hz, 1H), 1.29 (s, 3H), 1.25 (s, 3H),
(500 MHz, CDCl3)
d
9.77 (s,1H), 6.16 (dd, J¼8.1 and 6.8 Hz,1H), 5.88 (d,
J¼8.1 Hz,1H), 4.05 (ddd, J¼7.2, 3.2 and 1.0 Hz,1H), 3.78 (dd, J¼7.2 and
1.0 Hz, 1H), 3.29e3.27 (complex m, 1H), 2.47 (ddd, J¼11.2, 5.4 and
2.9 Hz, 1H), 1.70 (dd, J¼13.6 and 5.4 Hz, 1H), 1.29 (s, 3H), 1.27 (s, 3H),
1.21 (s, 3H), 1.20 (dd, J¼13.6 and 11.2 Hz, 1H); 13C NMR (125 MHz,
1.23 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 174.8 (C), 136.7 (CH), 130.0
(CH),107.9 (C), 82.6 (CH), 76.1 (CH), 52.0(CH3), 40.8(CH), 38.5(C), 37.3
(CH), 31.4 (CH2), 25.4 (CH3), 24.9 (CH3), 21.5 (CH3); IR nmax (KBr) 2976,
2955, 2936, 2900, 2873,1733,1458,1435,1374,1343,1297,1265,1239,
CDCl3) d 202.4 (CH), 137.5 (CH), 129.5 (CH), 108.1 (C), 82.5 (CH), 75.9
(CH), 49.5 (CH), 38.8 (C), 35.4 (CH), 28.1 (CH2), 25.4 (CH3), 24.9 (CH3),
21.6 (CH3); IR nmax (KBr) 2975, 2955, 2934, 2872, 1722, 1458, 1373,
1205, 1165, 1070, 1055, 1021, 997, 885, 724 cmꢁ1; MSþ(EI, 70 eV) m/z
1264,1254,1208,1165,1135,1071,1058, 971, 884, 824, 729, 699 cmꢁ1
;
ꢃ
ꢃ
þ
þ
ꢃ
252 (Mþ ,13%), 237 [(MꢁCH3 ) , 44], 221 [(MꢁCH3Oꢃ) ,16],194 (66),
MS (EI, 70 eV) m/z 223 [(MþH)þ, 15%], 222 (Mþ , 5), 207 [(MꢁCH3 ) ,
46], 164 (63), 135 (98), 117 (65), 93 (67), 92 (100), 91 (63), 43 (75).
Concentration of fraction B (Rf¼0.1 in 1:4 v/v ethyl acetate/
ꢃ
135 (100), 134 (60), 117 (55), 105 (55), 91 (64).
Concentration offraction B [Rf¼0.7(9) in 1:7:12 v/v/v MeOH/ethyl
acetate/hexane] yielded compound C9-epi-15 (398 mg, 44%) as
hexane) afforded alcohol 16 (25 mg, 57%) asþa clear, colourless oil,
ꢃ
D ꢁ26.2 (c 1, CHCl3). Found: Mþ , 252.1363.
[a
]
ꢁ17.3 (c 0.9, CHCl3). Found: (MꢁCH3 ) , 209.1179. C13H20O3
ꢃ
a clear, colourless oil, [
a]
D
ꢃ
C14H20O4 requires Mþ , 252.1362. 1H NMR (300 MHz, CDCl3)
d
5.96
requires (MꢁCH3 ) , 209.1178. H NMR (300 MHz, CDCl3)
d 6.16 (dd,
þ
1
ꢃ
(dd, J¼8.1 and 6.3 Hz, 1H), 5.88 (dd, J¼8.1 and 0.6 Hz,1H), 4.24 (ddd,
J¼7.2, 3.3 and 0.9 Hz,1H), 3.84 (dd, J¼7.2 and 1.2 Hz,1H), 3.65 (s, 3H),
3.23e3.18 (complex m, 1H), 2.50 (ddd, J¼10.2, 5.1 and 2.4 Hz, 1H),
1.59 (dd, J¼13.5 and 5.1 Hz, 1H), 1.39 (dd, J¼13.5 and 10.2 Hz, 1H),
J¼8.2 and 6.9 Hz, 1H), 5.80 (d, J¼8.2 Hz, 1H), 4.39 (dd, J¼7.3 and
3.2 Hz, 1H), 3.79 (d, J¼7.3 Hz, 1H), 3.64e3.47 (complex m, 2H),
2.96e2.92 (complex m, 1H), 1.85e1.74 (complex m, 2H), 1.35 (dd,
J¼13.3 and 11.1 Hz, 1H), 1.31 (s, 3H), 1.26 (s, 3H), 1.22 (s, 3H), 0.69
1.30 (s, 3H),1.26 (s, 3H),1.26 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
174.6
(dd, J¼13.3 and 5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 135.6 (CH),
(C),136.9 (CH),127.8 (CH),108.6 (C), 82.7 (CH), 78.8 (CH), 52.0 (CH3),
131.9 (CH), 107.7 (C), 83.1 (CH), 75.6 (CH), 65.0 (CH2), 38.6 (CH), 38.4

C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
5257
(C), 35.9 (CH), 33.1 (CH2), 25.5 (CH3), 24.9 (CH3), 21.7 (CH3); IR nmax
(KBr) 3417, 3044, 2970, 2933, 2869, 1457, 1374, 1269, 1246, 1207,
1165, 1075, 1058, 10þ28, 885, 730, 705, 691, 513 cmꢁ1; MS (EI, 70 eV)
cooled to 0 ꢀC and treated, dropwise over 0.5 h, with NaHMDS
(4.58 mL of a 1 M solution in THF, 4.58 mmol, 2.4 mol equiv). The
resulting mixture was stirred at 0 ꢀC for 2.5 h and the bright-yellow
reaction mixture so-formed was treated, dropwise over 0.5 h, with
a solution of aldehyde 17 (424 mg, 1.91 mmol) in THF (8.50 mL).
Stirring was continued at 0 ꢀC for 2 h then the reaction mixture was
quenched with ammonium chloride (10 mL of a saturated aqueous
solution) and diluted with dichloromethane (10 mL). The separated
aqueous phase was extracted with dichloromethane (3ꢂ20 mL)
then the combined organic phases were washed with brine
(1ꢂ10 mL) before being dried (magnesium sulfate), filtered and
concentrated under reduced pressure. The orange oil thus obtained
was subjected to column chromatography (silica, 1:9 v/v ethyl ac-
etate/hexane elution) and concentration of the appropriate frac-
tions (Rf¼0.5) then gave olefin 18 (253 mg, 60%) as a clear,
ꢃ
m/z 209 [(MꢁCH3 ) , 25%], 166 (60), 135 (100), 93 (63).
Method B (oxidation of alcohol 16): A magnetically stirred solu-
tion of alcohol 16 (980 mg, 4.37 mmol) in dichloromethane/DMSO
(62 mL of a 1:1 v/v mixture) was cooled to 0 ꢀC then treated with
triethylamine (3 mL, 21.85 mmol, 5 mol equiv) and sulfur triox-
ide$pyridine complex (2.09 g, 13.11 mmol, 3 mol equiv). The ensu-
ing mixture was stirred at 0 ꢀC for 1 h, diluted with diethyl ether
(50 mL) then washed with hydrochloric acid (1ꢂ10 mL of a 1 M
aqueous solution), sodium hydrogen carbonate (1ꢂ10 mL of a sat-
urated aqueous solution) and brine (1ꢂ10 mL) before being dried
(magnesium sulfate), filtered and concentrated under reduced
pressure. The resulting light-orange oil (922 mg) was subjected to
column chromatography (silica, 1:5:14 v/v/v MeOH/ethyl acetate/
hexane elution) and gave, after concentration of the appropriate
fractions, aldehyde 17 (497 mg, 51%) as a white, crystalline solid
that was identical, in all respects, with an authentic sample.
Method C (reduction of ester C9-epi-15 and epimerisation of the
resulting aldehyde C9-epi-17). Step i: A magnetically stirred solution
of ester C9-epi-15 (100 mg, 0.40 mmol) in dichloromethane (10 mL)
was cooled to ꢁ78 ꢀC then DIBAL (0.48 mL of a 1 M solution in
hexane, 0.48 mmol,1.2 mol equiv) was added dropwise over 10 min
and the ensuing mixture then stirred at ꢁ78 ꢀC for 2 min before
being quenched with potassium sodium tartrate (5 mL of a satu-
rated solution), warmed to 18 ꢀC and stirred at this temperature for
5 h. The separated aqueous phase was extracted with dichloro-
methane (3ꢂ10 mL) then the combined organic phases were
washed with brine (1ꢂ5 mL) then dried (magnesium sulfate), fil-
tered and concentrated under reduced pressure to give a clear,
colourless oil. Subjection of this material to column chromatogra-
phy (silica, 1:4/1:1 v/v ethyl acetate/hexane gradient elution)
afforded two fractions, A and B.
colourless oil, [
a]
D ꢁ45.3 (c 0.55, CHCl3). Found: (MꢁHꢃ)þ, 219.1382.
C14H20O2 requires (MꢁHꢃ)þ, 219.1385. 1H NMR (300 MHz, CDCl3)
d
6.17 (ddd, J¼7.8, 6.3 and 1.0 Hz, 1H), 5.83 (ddd, J¼17.2, 10.3 and
6.9 Hz, 1H), 5.79 (dd, J¼7.8 and 1.0 Hz, 1H), 5.11e5.01 (complex m,
2H), 4.36 (ddd, J¼7.4, 3.3 and 1.0 Hz, 1H), 3.81 (dd, J¼7.4 and 1.0 Hz,
1H), 2.80e2.74 (complex m, 1H), 2.29e2.18 (complex m, 1H), 1.39
(dd, J¼13.4 and 11.0 Hz, 1H), 1.32 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H),
1.01 (dd, J¼13.4 and 5.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 141.0
(CH), 135.4 (CH), 131.9 (CH), 114.6 (CH2), 107.6 (C), 83.3 (CH), 75.9
(CH), 40.8 (CH), 39.4 (CH), 38.7 (C), 34.6 (CH2), 25.5 (CH3), 24.9
(CH3), 21.8 (CH3); IR nmax (KBr) 3045, 2976, 2952, 2937, 2903, 2869,
1638, 1457, 1378, 1371, 1262, 1233, 1207, 1165, 1069, 1056, 995, 912,
ꢃ
885, 861, 80þ9, 729, 707 cmꢁ1; MS (EI, 70 eV) m/z 220 (Mþ , 18%),
þ
219 [(MꢁHꢃ) , 38], 205 [(MꢁCH3 ) ,11], 163 (68),105 (64), 57 (100),
ꢃ
43 (46).
3.2.7. Compound 19. DOWEX-50 was activated by washing it twice
with MeOH, twice with hydrochloric acid (2 M aqueous solution)
and, finally, twice with water. The activated resin (269 mg) thus
obtained was added to a magnetically stirred solution of acetonide
18 (269 mg, 1.22 mmol) in MeOH/water (6 mL of a 5:1 v/v mixture)
and the resulting suspension heated in an oil bath maintained at
110 ꢀC. After 6 days the reaction mixture was cooled, filtered and
the DOWEX washed three times with MeOH. The combined fil-
trates were concentrated under reduced pressure. The resin was
also washed twice with dichloromethane and the filtrate added to
the concentrated residue, which was then washed with sodium
chloride (1ꢂ10 mL of a 1.5 M aqueous solution). The separated
aqueous phase was extracted with dichloromethane (3ꢂ10 mL)
then the combined organic phases were dried (magnesium sulfate),
filtered and concentrated under reduced pressure. The orange oil
(201 mg) thus obtained was subjected to column chromatography
(silica, 1:4/1:1 v/v ethyl acetate/hexane gradient elution) and
concentration of the appropriate fractions (Rf¼0.5 in 1:1 v/v ethyl
Concentration of fraction A (Rf¼0.4 in 1:4 v/v ethyl acetate/hex-
ane) gave aldehyde 17 (4 mg, 5%) as a white, crystalline solid. This
material was identical, in all respects, with an authentic sample.
Concentration of fraction B (Rf¼0.3 in 1:4 v/v ethyl acetate/
hexane) afforded compound C9-epi-17 (58 mg, 65%) as þa clear, col-
ꢃ
ourless oil, [
a
]
D þ15.3 (c 1.15, CHCl3). Found: (MꢁCH3 ) , 207.1026.
þ
1
ꢃ
C13H18O3 requires (MꢁCH3 ) , 207.1021. H NMR (300 MHz, CDCl3)
d
9.49 (d, J¼1.1 Hz, 1H), 5.95e5.86 (complex m, 2H), 4.32 (ddd,
J¼7.2, 3.3 and 1.0 Hz, 1H), 3.89 (dd, J¼7.2 and 1.0 Hz, 1H), 3.25e3.20
(complex m,1H), 2.44 (dddd, J¼9.9, 4.7, 2.2 and 1.0 Hz,1H),1.64 (dd,
J¼13.6 and 4.7 Hz, 1H), 1.31 (dd, J¼13.6 and 9.9 Hz, 1H), 1.30 (s, 3H),
1.28 (s, 3H), 1.27 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 201.9 (CH),
137.9 (CH), 127.1 (CH), 108.7 (C), 83.1 (CH), 79.0 (CH), 48.0 (CH), 38.4
(C), 35.9 (CH), 29.6 (CH2), 25.4 (CH3), 25.0 (CH3), 21.5 (CH3); IR nmax
(KBr) 2975, 2954, 2932, 2873, 1726, 1458, 1374, 1277, 1251, 1209,
1166, 1121, 1068, 1023, 884, 728 cmꢁ1; MS (EI, 70 eV) m/z 223
acetate/hexane) then gave diol 19 (146 mg, 66%) as a clear, col-
ꢃ
ꢃ
þ
[(MþH)þ, 20%], 222 (Mþ , 1), 207 [(MꢁCH3 ) , 16], 135 (79), 117 (52),
ourless oil, [a]
D
ꢃ
ꢁ76.1 (c 1, CHCl3). Found: Mþ , 180.1144. C11H16O2
ꢃ
100 (51), 93 (49), 91 (63), 85 (46), 43 (100).
requires Mþ , 180.1150. 1H NMR (300 MHz, CDCl3)
d
6.32 (ddd, J¼8.1,
Step ii: DBU (26
mL, 171
mmol, 1 mol equiv) was added to a mag-
7.0 and 0.8 Hz, 1H), 5.90 (dd, J¼8.1 and 0.8 Hz, 1H), 5.82 (ddd,
J¼17.0, 10.3 and 6.7 Hz, 1H), 5.10e5.01 (complex m, 2H), 4.05 (ddd,
J¼7.6, 2.5 and 0.8 Hz, 1H), 3.44 (dd, J¼7.6 and 0.8 Hz, 1H), 2.80 (br s,
2H), 2.67e2.62 (complex m, 1H), 2.20e2.09 (complex m, 1H), 1.38
(dd, J¼13.5 and 11.2 Hz, 1H),1.23 (s, 3H), 1.06 (dd, J¼13.5 and 6.2 Hz,
netically stirred solution of aldehyde C9-epi-17 (38 mg, 171
mmol) in
benzene (1 mL) and the resulting mixture heated at 70 ꢀC for 16 h,
then cooled to 18 ꢀC and diluted with dichloromethane (4 mL) before
being washed successively with hydrochloric acid (1ꢂ2 mL of a 2 M
aqueous solution), sodium hydrogen carbonate (1ꢂ2 mL of a satu-
rated aqueous solution) and brine (1ꢂ2 mL) then dried (magnesium
sulfate), filtered and concentrated under reduced pressure. 1H NMR
analysis of the resulting yellow oil (33 mg) established that this was
comprised of a ca. 1:4.8 mixture of aldehydes C9-epi-17 and 17.
1H); 13C NMR (75 MHz, CDCl3)
d 140.8 (CH), 136.6 (CH), 133.4 (CH),
114.9 (CH2), 75.6 (CH), 67.9 (CH), 43.8 (CH), 40.2 (C), 40.0 (CH), 35.3
(CH2), 21.6 (CH3); IR nmax (KBr) 3374, 2928, 2869, 1637, 1457, 1403,
1372, 1065, 1031, 994, 959, 910, 726, 703, 601 cmꢁ1; MS (EI, 70 eV)
ꢃ
m/z 180 (Mþ , 5%), 120 (97), 105 (100), 92 (72), 91 (53).
3.2.6. Compound 18. MePPh3Br was dried at 100 ꢀC for 15 h then
cooled and stored under nitrogen. Some of the dried material
(2.05 g, 5.73 mmol, 3.0 mol equiv) was stirred in THF (19.1 mL) then
3.2.8. Compound 20. A magnetically stirred solution of diol 19
(146 mg, 0.81 mmol) in dichloromethane (19.50 mL) was cooled to
0 ꢀC then p-TsOH$H2O (339 mg, 1.78 mmol, 2.2 mol equiv) was

5258
C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
added followed by 4-AcNH-TEMPO (380 mg, 1.78 mmol,
2.2 mol equiv) and the mixture thus obtained was warmed to 18 ꢀC.
After 17 h at the latter temperature, the reaction mixture was
quenched with sodium hydrogen carbonate (10 mL of a saturated
aqueous solution) and extracted with dichloromethane (3ꢂ20 mL).
The combined organic extracts were washed with brine (1ꢂ10 mL)
before being dried (magnesium sulfate), filtered and concentrated
under reduced pressure. The resulting orange semi-solid (533 mg)
was subjected to column chromatography (silica, 1:4 v/v ethyl ac-
etate/hexane elution) and concentration of the appropriate frac-
colourless oil. Resubjection of the material to flash chromatography
(silica, 1:9 v/v ethyl acetate/hexane elution) and concentration of
the appropriate fractions (Rf¼0.2) then gave the C4-
a
-form of
diquinane 22 (29 mg, 15%) as a clear, colourless oil, [
a]
þ139.1 (c
D
ꢃ
ꢃ
0.9, CHCl3). Found: Mþ , 282.1260. C18H18O3 requires Mþ , 282.1256.
1H NMR (300 MHz, CDCl3)
d 8.06e8.02 (complex m, 2H), 7.60e7.54
(complex m, 1H), 7.47e7.40 (complex m, 2H), 5.82 (ddd, J¼17.3, 10.4
and 5.6 Hz, 1H), 5.19e5.02 (complex m, 2H), 5.08 (br s, 1H),
3.46e3.35 (complex m, 1H), 2.61 (ddd, J¼6.0, 5.1 and 1.0 Hz, 1H),
2.43 (dd, J¼13.5 and 11.0 Hz, 1H), 2.35e2.30 (m, 1H), 2.24e2.22 (m,
1H), 1.89 (dt, J¼13.5 and 1.4 Hz, 1H), 1.28 (s, 3H); 13C NMR (75 MHz,
tions (Rf¼0.3) then gave acyloin 20 (118 mg, 81%) as a clear,
ꢃ
colourless oil, [
a]
þ346.5 (c 0.65, CHCl3). Found: Mþ , 178.0986.
CDCl3) d 210.9 (C), 165.6 (C),139.5 (CH), 133.2 (CH), 129.9 (CH), 129.5
D
ꢃ
C11H14O2 requires Mþ , 178.0994. 1H NMR (300 MHz, CDCl3)
d
6.19
(C),128.4 (CH),115.8 (CH2), 83.5 (CH), 49.9 (C), 49.8 (CH2), 43.0 (CH),
42.0 (CH), 39.8 (CH), 38.4 (CH), 19.3 (CH3); IR nmax (KBr) 2970, 2935,
2874, 1722, 1451, 1266 (br), 1177, 1107, 1094, 1069, 1026, 990, 957,
(dd, J¼7.7 and 6.6 Hz, 1H), 6.11 (d, J¼7.7 Hz, 1H), 5.68 (ddd, J¼17.0,
10.3 and 7.3 Hz, 1H), 5.10e4.98 (complex m, 2H), 3.37 (s, 1H), 3.20
(dd, J¼6.6 and 2.2 Hz, 1H), 2.73 (br s, 1H), 2.61e2.50 (complex m,
1H), 1.80 (dd, J¼13.4 and 11.7 Hz, 1H), 1.43 (dd, J¼13.4 and 4.7 Hz,
ꢃ
915, 852, 709, 668 cmꢁ1; MS (EI, 70 eV) m/z 282 (Mþ , 2%), 160 (25),
132 (45), 106 (55), 105 (71), 91 (37), 77 (100).
1H), 1.31 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
211.6 (C), 140.7 (CH),
Concentration of fraction B (Rf¼0.5) gave the C4-
b
-form of
D þ60.2 (c 0.6,
ꢃ
140.5 (CH), 126.9 (CH), 115.1 (CH2), 75.1 (CH), 52.7 (CH), 42.2 (C),
diquinane 22 (30 mg, 17%) as a clear, colourless oil, [
a
]
ꢃ
39.0 (CH), 37.9 (CH2), 20.0 (CH3); IR nmax (KBr) 3448, 2970, 2954,
CHCl3). Found: Mþ , 282.1256. C18H18O3 requires Mþ , 282.1256. 1H
2931, 2869, 1725, 1639, 1457, 1115, 1068, 990, 915, 776, 709 cmꢁ1
;
NMR (300 MHz, CDCl3) d 8.07e8.03 (complex m, 2H), 7.61e7.55
ꢃ
MS (EI, 70 eV) m/z 178 (Mþ , 8%),106 (72),105 (100), 91 (71), 79 (70),
(complex m,1H), 7.48e7.42 (complex m, 2H), 5.80 (ddd, J¼17.0, 10.3
and 7.0 Hz, 1H), 5.44 (t, J¼1.5 Hz, 1H), 5.11 (dt, J¼17.0 and 1.5 Hz,
1H), 5.01 (dt, 10.3 and 1.5 Hz, 1H), 3.45e3.35 (complex m, 1H), 2.37
(dd, J¼5.9 and 4.8 Hz, 1H), 2.28 (dt, J¼9.8 and 5.9 Hz, 1H), 2.12 (ddd,
J¼14.0,11.0 and 1.5 Hz,1H), 2.05e1.98 (complex m, 2H),1.45 (s, 3H);
43 (73), 39 (64), 32 (67).
3.2.9. Compound 21. A magnetically stirred solution of acyloin 20
(118 mg, 0.66 mmol) in dichloromethane (21 mL) was cooled to 0 ꢀC
then treated with triethylamine (0.46 mL, 3.30 mmol, 5 mol equiv),
DMAP (9 mg, 0.07 mmol, 10 mol %) and benzoyl chloride (0.15 mL,
1.32 mmol, 2 mol equiv). The ensuing mixture was allowed to warm
to 18 ꢀC and after 16 h it was quenched with sodium hydrogen car-
bonate (10 mL of a saturated aqueous solution). The separated
aqueous phase was extracted with dichloromethane (3ꢂ20 mL)
then the combined organic extracts were washed with brine
(1ꢂ10 mL) before being dried (magnesium sulfate), filtered and
concentrated under reduced pressure. The yellow semi-solid
(301 mg) thus obtained was subjected to column chromatography
(silica,1:4 v/vethyl acetate/hexane elution) and concentration of the
appropriate fractions (Rf¼0.6) gave keto-ester 21 (199 mg,
13C NMR (75 MHz, CDCl3)
d 207.1 (C), 165.4 (C), 139.2 (CH), 133.3
(CH), 129.9 (CH), 129.3 (C), 128.4 (CH), 115.3 (CH2), 82.1 (CH), 49.3
(C), 44.2 (CH), 43.5 (CH2), 36.4 (CH), 35.8 (CH), 32.6 (CH), 24.3
(CH3); IR nmax (KBr) 2959, 1739, 1724, 1452, 1331, 1269, 1248, 1177,
1113, 1097, 1071, 1026, 1000, 916, 850, 709 cmꢁ1; MS (EI, 70 eV) m/z
ꢃ
282 (Mþ , 11%), 160 (37), 132 (49), 106 (52), 105 (100), 77 (69).
3.2.11. Compound 23. A magnetically stirred solution of the C4-a-
and b-epimeric forms of compound 22 (296 mg, 1.05 mmol) in THF
(10.5 mL) containing MeOH (5.3 mL) was cooled to ꢁ78 ꢀC then
samarium(II) diiodide (23.1 mL of
a 0.1 M solution in THF,
2.31 mmol, 2.2 mol equiv) was added dropwise over 0.5 h. Stirring
was continued at ꢁ78 ꢀC for 5 min then the reaction mixture was
quenched with potassium carbonate (20 mL of a saturated aqueous
solution) before being allowed to slowly warm to 18 ꢀC. The sepa-
rated aqueous phase was extracted with diethyl ether (3ꢂ50 mL)
and the combined organic phases were washed with brine
(1ꢂ20 mL) then dried (magnesium sulfate), filtered and concen-
trated under reduced pressure. The yellow oil (289 mg) thus
obtained was subjected to column chromatography (silica, 1:39 v/v
ethyl acetate/dichloromethane elution) and concentration of the
0.71 mmol, quant.) as a clear, colourless oil, [
a
]
D þ255.9 (c 1, CHCl3).
ꢃ
ꢃ
Found: Mþ , 282.1255. C18H18O3 requires Mþ , 282.1256. 1H NMR
(300 MHz, CDCl3) d 8.02e7.98 (complex m, 2H), 7.59e7.52 (complex
m, 1H), 7.46e7.39 (complex m, 2H), 6.32 (dd, J¼7.8 and 6.7 Hz, 1H),
6.20 (d, J¼7.8 Hz, 1H), 5.76 (ddd, J¼17.2, 10.3 and 7.4 Hz, 1H),
5.16e5.05 (complex m, 2H), 5.08 (s, 1H), 3.26 (ddd, J¼6.7, 2.9 and
1.1 Hz,1H), 2.67e2.56 (complex m,1H),1.89 (dd, J¼13.6 and 11.5 Hz,
1H), 1.62 (dd, J¼13.6 and 4.9 Hz, 1H), 1.22 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 205.3 (C), 166.1 (C),140.0 (CH),139.8 (CH),133.2 (CH),129.9
(CH), 129.4 (C), 128.3 (CH), 127.6 (CH), 115.6 (CH2), 74.5 (CH), 53.5
(CH), 41.3 (C), 39.5 (CH), 37.5 (CH2), 20.1 (CH3); IR nmax (KBr) 2965,
2925, 2869, 2853,1741,1724,1451,1328,1266,1254,1177, 1111,1070,
appropriate fractions (Rf¼0.5) gave diquinane 23 (93 mg, 54%) as
ꢃ
a clear, colourless oil, [
a
]D þ74.0 (c 0.6, CHCl3). Found: Mþ ,162.1044.
ꢃ
C11H14O requires Mþ , 162.1045. 1H NMR (300 MHz, CDCl3)
d 5.82
ꢃ
1029, 921, 708 cmꢁ1; MS (EI, 70 eV) m/z 282 (Mþ , 21%),160 (37),132
(ddd, J¼17.2, 10.3 and 5.8 Hz, 1H), 5.08 (dt, J¼17.2 and 1.7 Hz, 1H),
4.97 (dt, J 10.3 and 1.7 Hz,1H), 3.37e3.26 (complex m,1H), 2.45 (ddd,
J¼6.3, 4.9 and 0.8 Hz, 1H), 2.33e2.22 (complex m, 2H), 2.20e2.04
(complex m, 2H),1.96 (m,1H),1.63 (d, J¼12.6 Hz,1H),1.36 (s, 3H); 13C
(62), 120 (41), 106 (76), 105 (100), 91 (30), 77 (89), 51 (43).
3.2.10. Compound 22. A magnetically stirred and deoxygenated
solution of keto-ester 21 (186 mg, 0.66 mmol) and acetophenone
(0.23 mL, 1.98 mmol, 3 mol equiv) in acetone (300 mL) was placed
in a quartex immersion well photoreactor (Ace Glass Inc., 500 mL)
equipped with a Pyrex filter. The mixture was subjected to irradi-
ation, at 18 ꢀC, with a Hanovia 450 W medium pressure mercury-
vapour lamp. After 4.67 h the reaction mixture was removed from
the photoreactor and concentrated under reduced pressure to give
a yellow oil (459 mg) that was subjected to column chromatogra-
phy (silica, 1:4 v/v ethyl acetate/hexane elution) and thereby
affording two fractions, A and B.
NMR (125 MHz, CDCl3)
d 215.5 (C), 139.9 (CH), 115.0 (CH2), 55.0
(CH2), 52.4 (CH2), 46.3 (C), 43.4 (CH), 42.3 (CH), 39.6 (CH), 36.8 (CH),
25.7 (CH3); IR nmax (KBr) 2954, 2928, 2870, 1724, 1454, 1407, 1331,
1313, 1250, 1197, 1096, 989, 965, 914, 885, 871 cmꢁ1; MS (EI, 70 eV)
ꢃ
m/z 162 (Mþ , 11%), 120 (50), 105 (100), 77 (45).
3.2.12. Compound 24. A magnetically stirred solution of diquinane
23 (52 mg, 321
was cooled to 0 ꢀC then N-methylmorpholine N-oxide (45 mg,
385 mol, 1.2 mol equiv) and osmium tetroxide (1.22 mL of a 0.1 M
solution in tert-butanol, 122 mol, 0.38 mol equiv) were added. The
ensuing mixture was allowed to warm to 18 ꢀC and after 4.5 h at
mmol) in acetone/water (2 mL of a 1:1 v/v mixture)
m
Concentration of fraction A (Rf¼0.5) yielded a mixture of ace-
m
tophenone and the C4-a-form of diquinane 22 (49 mg) as a clear,

C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
5259
this temperature it was quenched with sodium hydrogensulfite
(4 mL of a saturated aqueous solution) then stirred at 18 ꢀC for
another hour. The resulting mixture was diluted with diethyl ether
(4 mL) and just enough water to dissolve any solids. Solid sodium
chloride was then added to saturate the aqueous phase which, after
separation, was extracted with diethyl ether (3ꢂ10 mL) then
dichloromethane (3ꢂ10 mL). The combined organic extracts were
dried (magnesium sulfate), filtered and concentrated under re-
duced pressure. Subjection of the resulting clear, colourless oil to
column chromatography (silica, ethyl acetate/1:9 v/v MeOH/ethyl
acetate gradient elution) and concentration of the appropriate
fractions (Rf¼0.4 in 1:9 v/v methanol/ethyl acetate) then gave a 1:1
mixture of the epimeric forms of diol 24 (30 mg, 48%) as a clear,
1H), 2.55e2.48 (complex m, 2H), 2.45 (s, 3H), 2.40 (dd, J 17.8 and
2.2 Hz, 1H), 2.18e2.02 (complex m, 3H), 1.99 (dd, J¼9.5 and 5.2 Hz,
1H), 1.37 (s, 3H), 1.33 (d, J¼13.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
215.3 (C), 145.1 (C), 132.7 (C), 129.9 (CH), 127.9 (CH), 73.1 (CH2),
71.3 (CH), 56.4 (CH2), 48.6 (CH2), 46.6 (C), 43.6 (CH), 42.1 (CH), 39.0
(CH), 35.7 (CH), 25.8 (CH3), 21.7 (CH3); IR nmax (KBr) 3420, 2956,
2918, 2870, 2850, 1712, 1598, 1453, 1358, 1312, 1189, 1176, 1097, 972,
957, 946, 918, 880, 853, 815, 667, 555 cmꢁ1; MS (EI, 70 eV) m/z 350
ꢃ
(Mþ , 5%), 165 (47), 136 (100), 93 (68), 91 (95), 43 (67), 32 (48).
3.2.14. Compounds 26 and 27. Method A: A magnetically stirred
solution of a ca. 1:1.5 mixture of the C10S- and C10R-epimeric forms
of mono-tosylate 25 (29 mg, 83
(2.9 mL) was cooled to 0 ꢀC then triethylamine (58
5 mol equiv) was added followed by DMAP (834
10 mol %) and benzoyl chloride (20.7 L, 166
mmol) in dichloromethane
ꢃ
ꢃ
colourless oil. Found:
M
þ , 196.1098. C11H16O3 requires Mþ
,
m
L, 414
m
m
mol,
mol,
196.1099. 1H NMR (300 MHz, CDCl3)
d
3.84 (dd, J¼11.3 and 2.2 Hz,
mg, 8.28
0.5H), 3.66e3.58 (complex m, 0.5H), 3.50 (br s, 2H), 3.45 (dd, J¼11.3
and 7.4 Hz, 0.5H), 3.40e3.30 (complex m, 1.5H), 2.71e2.55 (com-
plex m, 1H), 2.54e2.48 (complex m, 1H), 2.43e2.30 (complex m,
1H), 2.27e1.80 (complex m, 5H), 1.37 (s, 1.5H), 1.36 (s, 1.5H); 13C
m
mmol, 2 mol equiv).
The resulting mixture was allowed to warm to 18 ꢀC then stirred at
this temperature for 14 h before being quenched with sodium
hydrogen carbonate (1 mL of a saturated aqueous solution). The
separated aqueous phase was extracted with dichloromethane
(5ꢂ2 mL) then the combined organic phases were dried (magne-
sium sulfate), filtered and concentrated under reduced pressure.
The clear, colourless oil (51 mg) thus obtained was subjected to
column chromatography (silica, 1:3:6 v/v/v MeOH/ethyl acetate/
hexane elution) to afford two fractions, A and B.
NMR (75 MHz, CDCl3) d 217.6 (C), 217.4 (C), 74.2 (CH), 74.1 (CH), 66.2
(CH2), 65.4 (CH2), 56.4 (CH2), 56.0 (CH2), 48.8 (CH2), 48.6 (CH2), 46.6
(C), 46.2 (C), 43.8 (2ꢂCH), 42.9 (CH), 42.8 (CH), 39.3 (CH), 39.1 (CH),
37.1 (CH), 35.4 (CH), 25.9 (CH3), 25.8 (CH3); IR nmax (KBr) 3405, 2951,
2928, 2871, 1709, 1454, 1408, 1379, 1360, 1335, 1312, 1254, 1200,
1161, 1101, 1076, 1041, 964, 920, 879, 813, 735 cmꢁ1; MS (EI, 70 eV)
ꢃ
m/z 196 (Mþ , 2%), 178 [(MꢁH2Oꢃ)þ, 14], 165 (75), 136 (96), 95 (94),
Concentration of fraction A (Rf¼0.5) gave compound 27 (15 mg,
ꢃ
94 (88), 93 (100), 91 (77), 43 (75).
40%) as a clear, colourless oil, [
a]
D þ14.2 (c 0.38, CHCl3). Found: Mþ
,
ꢃ
454.1447. C25H26O6S requires Mþ , 454.1450. 1H NMR (500 MHz,
3.2.13. Compound 25. Dibutyltin(IV) oxide (8 mg, 32
%) then triethylamine (21 L, 153 mol, 1 mol equiv) were added to
a magnetically stirred solution of a 1:1 mixture of the epimeric
forms of diol 24 (30 mg, 153 mol) in dichloromethane (0.45 mL).
Stirring was continued at 18 ꢀC for 10 min then a solution of p-
toluenesulfonyl chloride (29 mg, 152 mol, 1 mol equiv) in
m
mol, 20 mol
CDCl3)
d
7.92 (dd, J¼8.3 and 1.2 Hz, 2H), 7.73 (d, J¼8.3 Hz, 2H),
m
m
7.59e7.55 (complex m, 1H), 7.42 (dd, J¼8.3 Hz, 2H), 7.20 (d, J¼8.3 Hz,
2H), 4.98 (m, J¼11.1 Hz, 1H), 4.44 (dd, J¼11.2 and 2.6 Hz,1H), 4.24 (dd,
J¼11.2 and 2.2 Hz, 1H), 3.24 (m, 1H), 2.54 (dd, J¼5.9 and 5.3 Hz, 1H),
2.40 (dd, J¼18.1 and 1.0 Hz, 1H), 2.34 (s, 3H), 2.30 (d, J¼18.1 Hz, 1H),
2.20 (ddd, J¼13.2, 10.7 and 2.0 Hz, 1H), 2.11e2.06 (complex m, 1H),
1.95 (dd, J¼9.8 and 5.3 Hz,1H),1.55 (d, J¼13.2 Hz,1H),1.36 (s, 3H); 13C
m
m
dichloromethane (ca. 0.25 mL) was added dropwise over 10 min.
After 5 h at 18 ꢀC, the reaction mixture was diluted with dichloro-
methane (0.4 mL) then filtered through a plug of CeliteÔ and the
filtrate concentrated under reduced pressure to give a light-yellow
oil (67 mg). This was subjected to column chromatography (silica,
1:3:6 v/v/v MeOH/ethyl acetate/hexane elution) and thus affording
three fractions, A, B and C.
NMR (125 MHz, CDCl3)
d 214.8 (C), 165.5 (C), 144.9 (C), 133.3 (CH),
132.3 (C),129.9 (CH),129.8 (CH),129.5 (C),128.3 (CH),127.9 (CH), 73.0
(CH), 69.7 (CH2), 55.3 (CH2), 48.7 (CH2), 46.5 (C), 42.3 (CH), 41.1 (CH),
39.0 (CH), 34.0 (CH), 25.8 (CH3), 21.6 (CH3); IR nmax (KBr) 2956, 2927,
1720, 1599, 1452, 1364, 1270, 1190, 1177, 1109, 1097, 1070, 1026, 962,
946, 922, 881, 814, 793, 714, 667, 554 cmꢁ1; MS (EI, 70 eV) m/z 454
ꢃ
Concentration of fraction A (Rf¼0.4) yielded the C10S-epimeric
(Mþ , 4%),149 (18),118 (55),105(100), 91 (27), 77 (34), 57 (32), 43(35).
form of mono-tosylate 25 (9 mg, 17%) as a clear, colourless oil, [
a
]
Concentration of fraction B (Rf¼0.4) afforded compound 26
D
ꢃ
þ26.4 (c 0.64, CHCl3). Found: Mþ , 350.1182. C18H22O5S requires
(21 mg, 55%) as a white, crystalline solid, mp¼134e139 ꢀC. Found:
ꢃ
ꢃ
ꢃ
M
þ , 350.1188. 1H NMR (500 MHz, CDCl3)
d
7.80 (d, J¼8.0 Hz, 2H),
Mþ 454.1448. C25H26O6S requires Mþ 454.1450. 1H NMR
, ,
7.36 (d, J¼8.0 Hz, 2H), 4.17 (dd, J¼10.4 and 4.6 Hz, 1H), 4.13 (dd,
J¼10.4 and 2.7 Hz, 1H), 3.56e3.50 (complex m, 1H), 2.77e2.71
(complex m, 1H), 2.49 (dd, J¼5.9 and 5.3 Hz, 1H), 2.45 (s, 3H), 2.37
(ddd, J¼17.8, 2.3 and 1.2 Hz, 1H), 2.26e2.12 (complex m, 2H),
1.94e1.88 (complex m, 1H), 1.85 (dd, J¼9.8 and 5.3 Hz, 1H), 1.81 (d,
(300 MHz, CDCl3) d 7.97e7.93 (complex m, 2H), 7.70e7.66 (complex
m, 2H), 7.60e7.54 (complex m, 1H), 7.45e7.40 (complex m, 2H),
7.15e7.12 (complex m, 2H), 4.87 (dt, J¼11.2 and 2.9 Hz,1H), 4.31 (dd,
J¼11.4 and 2.9 Hz, 1H), 4.17 (dd, J¼11.4 and 2.9 Hz, 1H), 3.34 (m, 1H),
2.51 (t, J¼5.4 Hz, 1H), 2.44e2.30 (complex m, partially concealed,
1H), 2.34e2.24 (complex m, partially concealed, 1H), 2.30 (s, 3H),
2.15e2.07 (complex m, partially concealed, 1H), 2.07 (d, J¼17.0 Hz,
1H), 1.87 (dd, J¼10.2 and 5.4 Hz, 1H), 1.44 (d, J¼13.2 Hz, 1H), 1.39 (s,
J¼13.4 Hz, 1H), 1.38 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 215.3 (C),
145.1 (C), 132.4 (C), 130.0 (CH), 128.0 (CH), 72.7 (CH2), 71.4 (CH),
56.0 (CH2), 48.6 (CH2), 46.3 (C), 43.8 (CH), 42.3 (CH), 38.9 (CH), 34.6
(CH), 25.9 (CH3), 21.7 (CH3); IR nmax (KBr) 3418, 2954, 2926, 2870,
1715, 1598, 1453, 1406, 1357, 1309, 1189, 1176, 1098, 1019, 972, 957,
3H); 13C NMR (75 MHz, CDCl3)
d 213.7 (C), 165.1 (C), 145.0 (C), 133.2
(CH), 132.1 (C), 129.9 (CH), 129.8 (CH), 129.5 (C), 128.2 (CH), 127.8
(CH), 73.2 (CH), 69.4 (CH2), 56.2 (CH2), 47.8 (CH2), 46.5 (C), 42.1 (CH),
40.9 (CH), 38.9 (CH), 35.6 (CH), 25.8 (CH3), 21.6 (CH3); IR nmax (KBr)
2956,1723, 1599,1451,1361, 1312, 1266,1189, 1176, 1109, 1096, 1069,
1025, 957, 946, 921, 884, 839, 814, 713, 667, 554 cmꢁ1; MS (EI, 70 eV)
ꢃ
917, 878, 855, 814, 667, 555 cmꢁ1; MS (EI, 70 eV) m/z 350 (Mþ , 1%),
165 (31), 155 (33), 136 (100), 105 (45), 93 (51), 91 (80).
Concentration of fraction B (Rf¼0.35) afforded a ca. 1:1.5 mixture
of the C10S- and C10R-epimeric forms of mono-tosylate 25 (29 mg,
54%) as a clear, colourless oil.
ꢃ
m/z 454 (Mþ , 3%), 283 (16), 118 (72), 105 (100), 91 (36), 77 (41).
Concentration of fraction C (Rf¼0.3) gave C10R-epimeric form of
Method B: A magnetically stirred solution of the C10R-epimeric
mono-tosylate 25 (3 mg, 6%) as a clear, colourless oil, [
a
]
þ25.7 (c
form of mono-tosylate 25 (7 mg, 20 mmol) in dichloromethane
D
ꢃ
ꢃ
0.35, CHCl3). Found: Mþ
,
350.1188. C18H22O5S requires Mþ
,
(0.7 mL) was treated in the same way as described immediately
above. The clear, colourless oil (5 mg) thus obtained was subjected
to column chromatography (silica, 1:3:6 v/v/v MeOH/ethyl ace-
tate/hexane elution) and concentration of the appropriate
350.1188. 1H NMR (500 MHz, CDCl3)
J¼8.0 Hz, 2H), 4.06 (dd, J¼10.5 and 2.7 Hz, 1H), 3.90 (dd, J¼10.5 and
6.3 Hz, 1H), 3.58e3.52 (complex m, 1H), 2.73e2.66 (complex m,
d
7.78 (d, J¼8.0 Hz, 2H), 7.35 (d,

5260
C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
fractions (Rf¼0.5) then gave compound 27 (3 mg, 35%) as a white,
crystalline solid. This material was identical, in all respects, with
an authentic sample.
479.1504. 1H NMR (500 MHz, CDCl3):
d 7.93e7.89 (complex m, 2H),
7.73e7.69 (complex m, 2H), 7.61e7.56 (complex m, 1H), 7.46e7.42
(complex m, 2H), 7.20e7.16 (complex m, 2H), 5.12 (ddd, J¼7.8, 4.5 and
3.4 Hz,1H),4.21(dd,J¼11.1and3.4 Hz,1H), 4.17(dd, J¼11.1and4.5 Hz,
1H), 2.62e2.72(complexm,1H), 2.53(ddd, J¼19.0,9.3and1.5 Hz,1H),
2.34 (s, 3H), 2.34e2.14 (complex m, 4H), 2.05 (ddd, J¼19.0, 4.6 and
1.5 Hz, 1H), 1.84 (dd, J¼13.2 and 7.8 Hz, 1H), 1.58 (dd, J¼13.2 and
10.7 Hz, 1H), 1.22e1.14 (complex m, 1H), 1.18 (s, 3H); 13C NMR
3.2.15. Compound 28. A solution of diquinane 26 (21 mg, 46 mmol)
in THF/MeOH (0.9 mL of a 2:1 v/v mixture) was cooled to ꢁ78 ꢀC
and samarium(II) diiodide (0.55 mL of a 0.1 M solution in THF,
55 mmol, 1.2 mol equiv) was added dropwise over 5 min. The
resulting mixture was stirred at ꢁ78 ꢀC until the initial blue colour
associated with the reaction mixture had turned yellow (ca.
25 min) then more samarium(II) diiodide (0.55 mL of a 0.1 M so-
(125 MHz, CDCl3) d 219.0 (C),165.6 (C),145.0 (C),133.4 (CH),132.4 (C),
129.8 (CH),129.7 (CH),129.4 (C),128.4 (CH),127.9 (CH), 74.2 (CH), 69.5
(CH2), 52.4 (CH2), 46.7 (CH), 46.2 (C), 44.4 (CH2), 42.4 (CH2), 39.7 (CH),
36.3 (CH2), 27.7 (CH3), 21.6 (CH3); IR nmax (KBr) 2953,1738,1722,1451,
1364, 1269, 1190, 1177, 1109, 1097, 1070, 1026, 976, 942, 815, 714, 667,
554 cmꢁ1; MS (ESI, þve) m/z 495 [(MþK)þ, 7%], 479 [(MþNa)þ, 100],
455 (38), 285 (93), 206 (35), 163 (50), 135 (35), 105 (69).
lution in THF, 55 mmol, 1.2 mol equiv) was added dropwise over
15 min and the reaction mixture warmed to 0 ꢀC at which point
sufficient additional samarium(II) diiodide was added to re-estab-
lish a deep-blue colour. The reaction mixture was then warmed to
18 ꢀC and stirred at this temperature until the blue colour had
faded. This procedure was repeated twice more at 18 ꢀC until the
starting material had been consumed as determined by TLC anal-
ysis. The reaction mixture was then quenched with potassium
carbonate (1 mL of a saturated aqueous solution) and the separated
aqueous phase extracted with diethyl ether (3ꢂ5 mL) and then
with dichloromethane (3ꢂ5 mL). The combined organic phases
were dried (magnesium sulfate), filtered and concentrated under
reduced pressure. The yellow oil thus obtained was subjected to
column chromatography (silica, 1:3:6 v/v/v MeOH/ethyl acetate/
hexane elution) and concentration of the appropriate fractions
(Rf¼0.6) then gave diquinane 28 (11 mg, 52%) as a clear, colourless
3.2.17. Compound 32. A magnetically stirred solution of diquinane
28 (10 mg, 22
LiHMDS (26
m
mol) in THF (0.2 mL) was cooled to ꢁ78 ꢀC then
m
L of a 1 M solution in THF, 26 mmol, 1.2 mol equiv)
added dropwise over 5 min. After 0.5 h the reaction mixture was
warmed to 0 ꢀC and then, after 1 h, to 18 ꢀC. After 5 h at this tem-
perature the reaction mixture was quenched with water (0.2 mL)
and the separated aqueous phase washed with dichloromethane
(5ꢂ1 mL). The combined organic layers were then dried (magne-
sium sulfate), filtered and concentrated under reduced pressure.
The resulting light-yellow oil was subjected to column chroma-
tography (silica, 1:3:6 v/v/v MeOH/ethyl acetate/hexane elution)
and thereby affording two fractions, A and B.
ꢃ
ꢃ
oil. Found: Mþ , 456.1606. C25H28O6S requires Mþ , 456.1607. 1H
NMR (300 MHz, CDCl3) 7.94e7.88 (complex m, 2H), 7.74e7.68
d
Concentration of fraction A (Rf¼0.7) gave compound 32 (3 mg,
(complex m, 2H), 7.62e7.55 (complex m, 1H), 7.47e7.40 (complex
m, 2H), 7.21e7.15 (complex m, 2H), 5.16e5.06 (m, 1H), 4.22 (dd,
J¼11.1 and 3.4 Hz, 1H), 4.15 (dd, J¼11.1 and 4.6 Hz, 1H), 2.74e2.57
(complex m, 1H), 2.52 (ddd, J¼18.8, 8.8 and 1.2 Hz, 1H), 2.34 (s, 3H),
2.36e2.08 (complex m, 4H), 2.07 (dd, J¼18.8 and 4.8 Hz, 1H), 1.79
(dd, J¼12.9 and 8.0 Hz, 1H), 1.41 (dd, J¼12.9 and 11.1 Hz, 1H),
1.41e1.30 (complex m, 1H), 1.18 (s, 3H); 13C NMR (75 MHz, CDCl3)
53% at 91% conversion) as a white, crystalline solid, mp¼128e133 ꢀC.
ꢃ
ꢃ
Found: Mþ , 284.1412. C18H20O3 requires Mþ , 284.1412. 1H NMR
(300 MHz, CDCl3) d 8.04e7.99 (complex m, 2H), 7.58e7.52 (complex
m, 1H), 7.47e7.40 (complex m, 2H), 4.73 (t, J¼8.1 Hz, 1H), 2.56 (dd,
J¼18.3 and 7.8 Hz, 1H), 2.46e2.17 (complex m, 4H), 2.10 (d, J¼9.1 Hz,
1H), 1.96 (d, J¼12.3 Hz, 1H), 1.76 (dt, J¼13.7 and 9.1 Hz, 2H), 1.45 (dd,
J¼12.3, 4.5 and 1.1 Hz, 1H), 1.26 (s, 3H), 1.19e1.11 (complex m, 1H);
d
219.0 (C), 165.6 (C), 145.0 (C), 133.3 (CH), 132.3 (C), 129.8 (CH),
13C NMR (75 MHz, CDCl3)
d 222.6 (C), 165.8 (C), 132.9 (CH), 130.5 (C),
129.7 (CH), 129.4 (C), 128.4 (CH), 127.8 (CH), 74.3 (CH), 69.5 (CH2),
52.4 (CH2), 46.7 (CH), 46.3 (C), 44.2 (CH2), 42.5 (CH2), 39.7 (CH),
36.3 (CH2), 27.7 (CH3), 21.6 (CH3); IR nmax (KBr) 3020, 2954, 2918,
2848, 1736, 1727, 1452, 1364, 1269, 1216, 1190, 1177, 1110, 1097, 814,
129.5 (CH), 128.3 (CH), 75.8 (CH), 50.9 (CH), 47.0 (C), 44.3 (CH2), 43.1
(CH), 41.3 (CH), 38.4 (CH2), 36.0 (CH2), 25.8 (CH2), 25.0 (CH3); IR nmax
(KBr) 2930, 1732, 1717, 1451, 1336, 1313, 1275, 1258, 1179, 1143, 1112,
ꢃ
1068, 1024, 1003, 981, 710 cmꢁ1; MS (EI, 70 eV) m/z 284 [Mþ , 3%],
ꢃ
756, 713, 667, 554 cmꢁ1; MS (EI, 70 eV) m/z 456 (Mþ , <1%), 285
163 (45), 162 (89), 134 (52), 106 (44), 105 (100), 93 (89), 92 (63), 77
(83). A sample of this material was recrystallised (ethyl acetate/
hexane) to provide a crystal suitable for X-ray analysis. Details of this
analysis are presented below and in Figure 2.
Concentration of fraction B (Rf¼0.6) gave starting material 28
(1 mg, 9% recovery) as a clear, colourless oil that was identical, in all
respects, with an authentic sample.
(11), 179 (21), 162 (25), 105 (100), 91 (34), 77 (32).
3.2.16. Compound 29. A solution of diquinane27 (15 mg, 33 mmol) in
THF/MeOH (0.6 mL of a 2:1 v/v mixture) was cooled to ꢁ78 ꢀC then
samarium(II) diiodide (0.4 mL of a 0.1 M solution in THF, 40 mmol,
1.2 mol equiv) was added dropwise over 15 min. The resulting mix-
ture was stirred at ꢁ78 ꢀC for 20 min then warmed to 0 ꢀC, stirred at
this temperature for 3 h then at 18 ꢀC for 1 h. After this time, the re-
action mixture was re-cooled to ꢁ78 ꢀC and additional samarium(II)
3.3. Single-crystal X-ray analysis of compounds 12 and 32
diiodide (0.4 mL of a 0.1 M solution in THF, 40
mmol, 1.2 mol equiv)
3.3.1. Data for compound 12. C14H20O5, M¼268.31, T¼200 K,
monoclinic, space group P21, Z¼4, a¼14.7414(4), b¼6.6985(2),
was added dropwise over 2 min. The reaction mixture was stirred at
ꢁ78 ꢀC for 1 minand then allowed towarm to 18 ꢀC. After0.5 h at this
temperature samarium(II) diiodide (0.4 mL of a 0.1 M solution inTHF,
3
ꢀ
ꢀ
c¼15.2998(5) A,
b
¼111.7498(19); V¼1403.23(8) A , Dx¼1.270
g cmꢁ3
,
2697 unique data (2qmax¼50ꢀ), R¼0.0307 [for 2192
40
m
mol, 1.2 mol equiv) was again added and after 0.5 h at 18 ꢀC the
reflections with I>1.5
s
(I)]; Rw¼0.0376 (all data), S¼1.1764.
reaction mixture was quenched with potassium carbonate (1 mL of
a saturated aqueous solution). The separated aqueous phase was
extracted with diethyl ether (3ꢂ5 mL) then saturated with sodium
chloride and extracted with dichloromethane (3ꢂ5 mL). The com-
bined organic phases were dried (magnesium sulfate), filtered and
concentrated under reduced pressure. The resulting yellow oil was
subjected to column chromatography (silica,1:3:6 v/v/v MeOH/ethyl
acetate/hexane elution) and concentration of the appropriate frac-
tions (Rf¼0.5) then gave diquinane 29 (3 mg, 21%) as a clear, colourless
oil. Found: (MþNa)þ, 479.1500. C25H28O6S requires (MþNa)þ,
3.3.2. Data for compound 32. C18H20O3, M¼284.36, T¼200 K,
monoclinic, space group P21, Z¼2, a¼6.8933(3), b¼7.4523(2),
3
ꢀ
ꢁ3
,
ꢀ
c¼14.8977(6) A,
b
¼100.166(2); V¼753.29(5) A , Dx¼1.254 g cm
1439 unique data (2qmax¼50ꢀ), R¼0.035 [for 1084 reflections with
I>2.0
s
(I)]; Rw¼0.081 (all data), S¼0.82.
3.3.3. Structure determination. Images were measured on a Nonius
Kappa CCD diffractometer (Mo graphite monochromator,
Ka,
35
ꢀ
l
¼0.71073 A) and data extracted using the DENZO package.

C.E. Dietinger et al. / Tetrahedron 66 (2010) 5250e5261
5261
Structure solution was by direct methods (SIR92).36 The structures of
compounds 12 and 32 were refined using the CRYSTALS program
package.37 Crystallographic data (excluding structure factors) have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC nos. 763134 and 760492 for compounds 12 and 32, re-
spectively). 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 Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.
12. See, for example: (a) Banwell, M. G.; Darmos, P.; Hockless, D. C. R. Aust. J. Chem.
2004, 57, 41; (b) Banwell, M. G.; McLeod, M. D.; Riches, A. G. Aust. J. Chem. 2004,
57, 53.
13. Compound 8 can be obtained from Questor, Queen’s University of Belfast,
Northern Ireland. Questor Centre Contact Page: http://questor.qub.ac.uk/
newsite/contact.htm (accessed 11.01.10). For reviews on methods for generating
cis-1,2-dihydrocatechols by microbial dihydroxylation of the corresponding
aromatics, as well as the synthetic applications 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.
14. Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc. 1988, 110, 4735.
15. Evans, D. A.; Scott, W. L.; Truesdale, L. K. Tetrahedron Lett. 1972, 13, 121.
16. (a) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1992, 70, 256; (b) Bis-
sember, A. C. Synlett 2009, 681.
17. The initial assignment of stereochemistry in these systems was based upon the
magnitude of the vicinal couplings between H8 and H9 and the observation (or
otherwise) of NOEs between H8 and/or H9 and those resonances due to the
oxymethine protons associated with the acetonide residue.
Acknowledgements
We thank the Institute of Advanced Studies and the Australian
Research Council for financial support.
References and notes
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34. This ca. 4:1 mixture of alcohols 12 and C8,C9-di-epi-12 was generated by
combining material obtained from the reduction of ketone 11 and the epi-
merisation of compound C9-epi-12.
8. (a) Ho, T.-L.; Kung, L.-R. Org. Lett. 1999, 1, 1051; (b) Ho, T.-L.; Kung, L.-R.; Chein,
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