Making mixtures to solve structures: structural elucidation via combinatorial synthesis

Article abstract of DOI:10.1021/cc900134t

A domino Horner-Wadsworth-Emmons olefination strategy has been used to prepare homologous series of (polyen)ones, and through combinatorial elaboration, corresponding families of highly branched hydrocarbons. Gas chromatography-mass spectrometry of the mixtures has enabled the rapid and unambiguous identification of several highly branched alkanes of geochemical importance. This is the first example of the use of combinatorial synthesis for the elucidation of structural connectivity.

Full text of DOI:10.1021/cc900134t

J. Comb. Chem. 2010, 12, 141–150
141
Making Mixtures to Solve Structures: Structural Elucidation via
Combinatorial Synthesis
Nigel A. Lengkeek,† Paul F. Greenwood,‡ Blake Nguyen,† George A. Koutsantonis,†
and Matthew J. Piggott*,†
Chemistry, School of Biomedical, Biomolecular and Chemical Sciences, and John De Laeter Mass
Spectrometry and WA Biogeochemistry Centres, School of Plant Biology, The UniVersity of Western
Australia, Perth, Western Australia 6009, Australia
ReceiVed August 26, 2009
A domino Horner-Wadsworth-Emmons olefination strategy has been used to prepare homologous series
of (polyen)ones, and through combinatorial elaboration, corresponding families of highly branched
hydrocarbons. Gas chromatography-mass spectrometry of the mixtures has enabled the rapid and
unambiguous identification of several highly branched alkanes of geochemical importance. This is the first
example of the use of combinatorial synthesis for the elucidation of structural connectivity.
Introduction
sedimentary occurrence of these compounds has been closely
correlated with several distinctive lithological features,24,25,27,30
raising the possibility of a novel biological source.
Although several structural features have been inferred
from their GC-MS characteristics, and four candidate series
(1-4) were proposed (Figure 1),26 unequivocal structural
assignment requires correlation with authentic compounds.32–34
Accordingly, we developed a synthetic route to the four
candidate HBA series previously proposed, along with three
other closely related families (5-7) (Figure 1).
Synthetic Strategy. The total or partial synthesis of
polypropylene oligomers35,36 and natural products37–42 con-
taining C3 repeat units like those in the target molecules has
been reported previously. While natural products might be
suitable precursors to series 3, 5, and 6, they are not readily
amenable to the synthesis of the other target compounds;
accordingly we opted for total synthesis.
Unambiguous synthesis has always provided the ultimate
proof of molecular structure, most notably of natural
products. The traditional one starting material, one (major)
product approach to synthesis has confirmed the structure
of myriad natural products, which have been the main
inspiration and proving ground driving the development of
novel, sophisticated synthetic organic chemistry over the last
century.1–6 In many other cases, synthesis has refuted the
putative structure of a natural product,7–9 even where an
X-ray crystal structure had been determined.10
Structural elucidation of the components of compound
libraries is generally considered to be a problem associated
with combinatorial diversity-oriented synthesis.11,12 How-
ever, Curran has elegantly and extensively demonstrated the
power of a combinatorial split and mix approach using
fluorous tagging for the elucidation of stereochemical con-
figuration of various natural products.13–23 Herein, we report
the rapid, combinatorial synthesis of seven homologous series
of highly branched alkanes (HBAs), which were used to
unambiguously identify several hydrocarbons detected in
environmental samples. To the best of our knowledge, this
is the first time combinatorial synthesis has been used as a
tool for elucidating structural connectivity.
Initially we were attracted by two similar, linear ap-
proaches in which the core C3 units were derived from a
The hydrocarbons of interest are unusual (C3)n (n ) 4-10)
series of HBAs, which have been detected in the extracts of
several ancient sediments,24–30 and in the surface and
groundwater of a South Australian winery.26,31 An anthro-
pogenic origin was supported by their GC-MS correlation
with components of extracts of a commercially available
polypropylene (PP);15 however, fluctuation in the abundance
of the HBAs through several sedimentary profiles was not
consistent with a common plastic source. Furthermore, the
* To whom correspondence should be addressed. E-mail: piggott@
cyllene.uwa.edu.au. Phone: +61 8 6488 3170. Fax: +61 8 6488 1005.
† School of Biomedical, Biomolecular and Chemical Sciences.
‡ School of Plant Biology.
Figure 1. Target HBA series, n ) 1-3.
10.1021/cc900134t  2010 American Chemical Society
Published on Web 12/14/2009

142 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Lengkeek et al.
Scheme 1. Proposed Synthetic Route to HBAs (n ) 1-3) Employing Iterative Wittig Olefination
Scheme 2. Proposed Synthetic Route to HBAs (n ) 1-3) Employing Iterative HWE Olefination
Scheme 3. Reaction of Butyraldehyde with the Phosphorane 9
single precursor, namely, the phosphorane 9 (Scheme 1) or
phosphonate 12 (Scheme 2), making use of iterative Wittig
or Horner-Wadsworth-Emmons (HWE) reactions, respec-
tively. In each case, the homologous series are differentiated
by the choice of starting aldehyde 8 (Scheme 1) or ketone
11 (Scheme 2), and Grignard reagent 10, which define the
terminal alkyl substituents.
We envisaged that complications associated with the
production of mixtures of E/Z isomers would be overcome
by immediate reduction of the olefins. Mixtures of regioi-
someric alkenes formed after dehydration of the penultimate
alcohols would be treated similarly. Obviously, we expected
these approaches to provide mixtures of all the possible
diastereomers; indeed they were required for comparison with
the naturally occurring hydrocarbons. We anticipated that
the diastereomers might be separable using gas chromatog-
raphy, a prediction that was ultimately substantiated.
Although the approaches in Scheme 1 and 2 appear
straightforward, it rapidly became apparent that traditional
synthesis of all target compounds would be prohibitively
laborious. Each series required approximately 15 linear steps
to make the n ) 1-3 homologues, amounting to well over
100 synthetic operations in total. Consequently, we opted
for a much more efficient combinatorial strategy that would
provide structurally well-defined mixtures, which could be
resolved and analyzed by GC-MS.
Scheme 4. Synthesis of 19a
a Reagents and conditions: (a) Mg, THF, 0 °C; (b) (i) CuBr-LiCl, -78
°C, (ii) methyl methacrylate, 26% over 3 steps; (c) Dowex 1X2 (BH4- form),
Ni(OAc)2, MeOH, methyl methacrylate, X ) Br, 42%, X ) I, 84%; (d)
LiAlH4, THF, ∆, 3 d, 92%; (e) PCC, DCM, 0 °C, 2 h, 89%.
Results and Discussion
Wittig Approach. Initial investigations focused on a
Wittig reaction of butyraldehyde (13) (Scheme 3), which
could ultimately give rise to the series 2 and 6 hydrocarbons.
No reaction between 13 and the phosphorane 9 was observed
in DCM at room temperature, and at higher temperatures in
a variety of different solvents the major product was 15,
resulting from aldol condensation of the butyraldehyde (13).
Only the use of H2O/THF (1/9) as solvent avoided significant
aldol coupling, but the conversion to the desired olefin (14)
was low. This was improved with a large excess of the
phosphorane 9, but its expense made such methodology
uneconomical.
hydrocarbons, by an alternative route, and test the Wittig
methodology on this substrate. An initial attempt at the
synthesis of 21 began with the conjugate addition of the
cuprate derived from 2-hexylmagnesium bromide (17) with
methyl methacrylate (Scheme 4). Preparation of the Grignard
was complicated by formation of the homocoupled product
18 unless highly activated magnesium was used at 0 °C or
lower. The organocuprate, formed by treatment of 17 with
CuBr-LiCl, underwent Michael addition with methyl meth-
acrylate, but the desired product 19 was contaminated by
the diester 20, arising from a second Michael addition of
the intermediate enolate to another molecule of methyl
methacrylate.
To circumvent the problems associated with volatile
starting materials, we chose to prepare 2,4-dimethyloctanal
(21), a more advanced precursor to the series 2 and 6
A more efficient and simple synthesis of 19 was achieved
using Ni2B-BER-catalyzed (BER ) borohydride exchange

Combinatorial Structural Elucidation
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 143
Scheme 6. Preparation of the Key Phosphonate, 12a
Scheme 5. Reactions of 19 with Different Stabilized
Phosphoranesa
a Reagents and conditions: (a) KI, Me2CO/MeCN, 0 °C, 12 h, 62% (12
only).
Scheme 7. Synthesis of a C12 HBAa
a Esters 25 and 26 gave rise (separately) to just two peaks with equivalent
mass spectra in the GC-MS, indicating only a single alkene configuration,
presumably E, but a mixture of diastereomers because of the two
stereocenters.
a Reagents and conditions: (a) 12, NaH, PhMe, 100 °C, 3 d, 82%; (b)
Pd/C, H2, MeOH, 12 h, 82%; (c) (i) i-PrMgBr, Et2O, 0 °C, (ii) H3O+,
57%; (d) BF3.Et2O, Et2O, 0 °C (e) Pd/C, H2, DCM/MeOH, 12 h, 71%
(2 steps).
-
resin, BH4 form Dowex 1X2 100-200 mesh) radical
addition of 2-halohexanes 16 to methyl methacrylate (Scheme
4).43 The reaction was particularly effective in the case of
the iodide, giving 19 in 84% yield after distillation. Reduction
of 19 to the corresponding alcohol,44 followed by PCC
oxidation, afforded the required aldehyde 21, which was
annoyingly prone to spontaneous oxidation.
phosphonate 12 of good purity, which in turn was critical
to the success of its HWE reactions.
To validate the HWE approach, the C12 HBA 33 (Figure
1, Series 2, n ) 1) was chosen as a target (Scheme 7).
The HWE reaction of 2-hexanone (29) with phosphonate
12 gave a 17:3 mixture of the known50 E and Z-enones
30, although reaction times were lengthy (1-3 days).
Catalytic hydrogenation of the mixture gave the known51
saturated ketone 31, which upon treatment with excess
isopropylmagnesium bromide afforded tertiary alcohol 32,
as a mixture of diastereomers, as shown by GC-MS.
Dehydration of 32 with boron trifluoride diethyl etherate52
gave a mixture of isomeric alkenes (again shown by GC-
MS), which simplified to the diastereomeric mixture of
alkanes 33 upon catalytic hydrogenation.
Attempts to improve the yield of the HWE reaction by
increasing the excess of phosphonate 12 resulted in near
complete consumption of ketone but produced a large
number of other products. Analysis of the GC-MS of these
mixtures revealed the other products to be (polyen)ones
arising from domino HWE reactions. To the best of our
knowledge, domino HWE (or Wittig) reactions have not been
used synthetically, presumably because mixtures of homo-
logues are formed. In our case the formation of a series of
homologous (polyen)ones was advantageous, and so we
sought to exploit this methodology for the combinatorial
synthesis of the target HBAs.
Surprisingly, the Wittig reaction of 21 with the phospho-
rane 9 gave only trace quantities of the desired enal 22 by
GC-MS, despite much experimentation and precedent with
similar reactants.45 It was unclear if the lack of reaction was
due to the aldehyde 21 or the phosphorane 9; thus, the
reactivity of the former was explored with two electronically
similar phosphoranes, 23 and 24 (Scheme 5). There was a
marked difference in the reactivity of the two phosphoranes
with 21; the olefination with 23 was complete within 1 h,
giving the R,ꢀ-unsaturated ester 25, whereas the reaction with
24 required nearly 24 h for consumption of the aldehyde.
The dramatic reduction in the reactivity of 24 would be
mirrored in 9, which presumably is also more susceptible to
auto-condensation, accounting for the poor conversion to 22.
These setbacks prompted us to progress to the second strategy
using the more reactive phosphonate 12.
HWE Approach. Although the phosphonate 12 required
for the HWE reactions is commercially available, it is quite
expensive, and as large amounts were required, we opted
for synthesis. The literature preparations of 1246–49 are either
low yielding or poorly described. The reaction of a trialkyl
phosphite with an R-haloketone can produce both Michaelis-
Arbuzov (ꢀ-ketophosphonate) and Perkow (enol phos-
phate) products, R-iodoketones giving the former, and
R-bromo and R-chloroketones giving predominately the
latter. Employing an in situ Finkelstein reaction46 of
chloroacetone (27), the Michaelis-Arbuzov reaction with
triethyl phosphite predominated, with separation of minor
amounts of the enol phosphate 28 achieved by treatment
with aqueous lithium carbonate,47 giving 12 in 70% yield
after distillation. Careful purification of the starting
materials, in particular freeing triethyl phosphite of
contaminating triethyl phosphate, was crucial in obtaining
Optimization of the Domino HWE Reaction. Progress
of the HWE reactions was monitored using GC-MS. The
choice of solvent and reaction temperature had a significant
effect on the product distribution; reactions performed under
reflux in tetrahydrofuran (THF) gave primarily the (mo-
noen)one 34 (n ) 1), irrespective of the excess of phospho-
nate used (up to 8 fold), or reaction time. Reactions in toluene
resulted in formation of the (monoen)one within the first 24 h,
followed by slow conversion to the (polyen)ones 34 (n > 1)
(Scheme 8), as expected given the reduced reactivity of the

144 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Scheme 8. Domino HWE Synthesis of (Polyen)ones 34
Lengkeek et al.
Scheme 9. Proposed Electrocyclization of E,Z,E-Triene 35,
Followed by Hydrogenation to Give Four Diastereomeric
Cyclohexanes 37
Figure 2. Section of the gas chromatogram from the crude mixture
of products derived from a domino HWE reaction that was left for
an extended period to maximize the formation of electrocyclization
byproducts, followed by catalytic hydrogenation. A ) four dia-
stereomeric C15 acyclic saturated ketones (m/z ) 226); B ) the
four diastereomeric cyclohexanes (m/z ) 224) (and their enanti-
omers). Unlabeled peaks are due to unidentified byproducts. It
should be noted that under the optimized domino HWE conditions,
all byproducts were much less prevalent.
Aside from these electrocyclization products, some other
minor peaks were observed by GC-MS, most of which could
not be identified. The few that were, comprised a family of
(C3)n hydrocarbons resistant to catalytic hydrogenation,
suggesting that they were aromatic. The mass spectrum of
the first peak in the series (n ) 4) was consistent with
mesitylene, with the higher order members presumably being
mesitylene derivatives bearing additional C3 units. Presum-
ably these are formed by homo-oligomerization of the
phosphonate. Again these were well separated by GC from
the desired HBAs of interest, and thus did not interfere with
subsequent analyses.
conjugated ketones. Reaction times of 1 week or more were
required to produce detectable amounts of the higher order
(polyen)ones 32 (n ) 2-4).
After prolonged reaction times, the number of peaks
observed in the gas chromatograms of the (polyen)ones 34
was greater than the total number of possible E/Z isomers
expected when n g 3. These minor byproducts were clearly
isomeric, given their equivalent m/z and similar mass spectra,
but their structure was not obvious until the mixtures of
(polyen)ones were subjected to exhaustive catalytic hydro-
genation, which revealed peaks in the GC-MS with [m/z-2]
relative to the desired saturated ketones, indicating mono-
cyclic structures. We propose that the byproducts arise from
electrocyclization, as exemplified in Scheme 9 for the triene
35.
As can be seen in Figure 2, only four of the possible eight
diastereomeric cyclohexanes are observed in the gas chro-
matogram of the hydrogenation product 37. It would seem
most likely that these arise via suprafacial electrocyclization
of the E,Z,E-triene 35 (the configuration of the central double
bond must be Z to allow electrocyclization to occur), to give
the cyclohexadiene 36 with a cis-relationship of the iso-butyl
and acetyl groups, hydrogenation of which results in four
diastereomeric cyclohexanes 37. Presumably, the other
diasteroisomeric E,Z,Z and Z,Z,E trienes and the correspond-
ing cyclohexadienes/cyclohexanes with a trans-relationship
of the iso-butyl and acetyl groups are formed in smaller
quantities.
Combinatorial Synthesis of the Target Hydrocar-
bons. Having established the synthesis of 33 (Scheme 7)
starting from a single ketone, the methodology was now
applied to the combinatorial synthesis of the target
hydrocarbon series, by elaboration of each mixture of
(polyen)ones 34 (Scheme 10). The starting ketones (11)
and Grignard reagents used for the synthesis of each target
series are listed in Table 1.
All reactions were monitored, and products characterized,
by GC-MS; given the complex mixtures of homologues and
diastereomers formed, spectroscopic characterization was of
very limited value. By way of example, gas chromatograms
of the series 2 intermediates and final products are shown in
Figure 3. The corresponding gas chromatograms for the other
series are included in the Supporting Information. In most
cases the gas chromatograms of the target HBAs 1-7
displayed peaks corresponding to the expected number of
diastereomers for each cluster (n ) 1, 2, etc.), which is
testament to the remarkable resolving power of analytical
gas chromatography. Some of the low molecular weight
homologues (usually n ) 1) were lost during the syntheses
because of their volatility. However, this was inconsequential
as only the higher homologues were required; the lower
homologues are not present in the environmental samples,
presumably because of evaporation.
The formation of the cyclohexadiene byproducts was
favored at higher temperatures, thus the optimal reaction
temperature, balancing (polyen)one formation with minimal
electrocyclization, was typically 90-100 °C. The cyclo-
hexadienes were difficult to preparatively separate from the
acyclic ketones and so were carried though the remaining
steps in the synthesis. However, they and their “progeny”
were in general easily separated from the desired products
with GC, and so did not interfere with the analysis of the
mixtures.

Combinatorial Structural Elucidation
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 145
Scheme 10. Combinatorial Synthesis of the Target HBAsa
a Reagents and conditions: (a) 12, NaH, PhMe, 100 °C, 3-7 d; (b) Pd/C, H2, MeOH, O/N; (c) (i) RMgBr, Et2O (ii) H3O+; (d) BF3.Et2O, Et2O, -10 °C,
2-4 h (e) Pd/C, H2, DCM/MeOH, O/N.
sis,23 although it is clear that some of the other diaster-
eomers are also present in smaller amounts. It has been
Table 1. Starting Ketones 11 and Grignard Reagents Used in
the Synthesis of the Target HBA Series (Figure 1)
target HBAs
ketone 11, R )
R′MgBr, R′ )
demonstrated with the use of pyrolysis GC-MS that the
fragments derived from isotactic PP elute before those of
syndiotactic or atactic PP.55,56 Accordingly, it is most
likely that the major correlating peaks from the PP extracts
and the series 4 and 6 hydrocarbons are the meson
diastereomers in both cases.
1
2
3
4
5
6
7
i-Pr
Bu
i-Bu
i-Bu
Pr
sec-Bu
i-Pr
Pr
3-methylpentyl
Bu
sec-Bu
i-Pr
Pr
i-Bu
A comprehensive comparison of the GC and MS data of
the series E and F (C3)n HBAs and the authentic materials
prepared in this study has been reported.53
Correlation with (C3)n HBAs from Polypropylene
and Environmental Extracts. The GC-MS data derived
from the synthetic HBAs were compared with those from a
polypropylene extract that had previously been shown to
contain the same (C3)n HBAs detected in environmental
samples. The C15 and C18 congeners of what have been
designated series E and F,27 correlate precisely with the first
eluting C15 and C18 diastereomers of HBA series 4 and 6,
respectively, both in retention time (Figure 4) and mass
spectra (detailed elsewhere53), allowing their structural
connectivity to be assigned unambiguously. In support of
these conclusions, series 4 and 6 compounds have been
identified as products of the hydro-oligomerization of pro-
pylene using a zirconium metallocene complex.54
Conclusions
We have developed an expedient and unambiguous
synthesis of seven homologous series of HBAs using
domino HWE reactions to prepare the initial mixtures of
(polyen)ones for subsequent combinatorial elaboration. In
conjunction with GC-MS, this strategy enabled the rapid
identification of the structures of some HBAs detected in
environmental samples, and has confirmed that they are
not biomarkers, but actually polypropylene oligomer
contaminants from plastic sampling containers. The com-
binatorial approach described herein may prove useful for
the preparation of other series of volatile oligomeric
In all cases, a single diastereomer predominates in the
PP extract, reflecting diastereoselective industrial synthe-
Figure 3. Gas chromatograms of Series 2 intermediates and targets.

146 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Lengkeek et al.
Figure 4. Partial m/z 85 chromatograms of a PP extract, series 4, and series 6, showing retention time correlations. The relative abundance
of each chromatogram has been separately normalized. E15/18 and F15/18 are the C15/18 members of (C3)n HBA series previously called E and
F.27
compounds, where the primary goal is rapid structural
elucidation of components of complex mixtures.
acquired as KBr discs. Routine GC-MS was carried out on
a Shimadzu QP2010 GC-MS using a Restek 5MS column
(30 m × 0.25 mm ID). UHP Helium was used as the carrier
gas at a flow rate of 0.94 mL/min at 44.7 KPa. Injections of
1:1 DCM/MeOH solutions of the mixtures were performed
using a split injection mode at an injection port temperature
of 250 °C. The oven was held at 40 °C for 10 min before
being heated to 250 at 12 °C/min. Full scan (m/z 25-350)
mass spectra were acquired with an electron energy of 70
eV and source temperature of 200 °C. Comparison GC-MS
data were acquired on an Agilent 6890/5975b GC-MS using
a Phenomenex ZB-5 column (30 m × 0.25 mm × 0.25 µm).
The GC was used in pulsed splitless mode, and the oven
was temperature programmed from an initial 40 °C held
isothermal for 2 min then increased at a rate of 4 °C/min
300 °C and held isothermal for 25 min. Helium carrier gas
was maintained at a constant flow of 1.1 mL/min. Full scan
(m/z 25-400) and selected ion (m/z 85, 141, 155, 169, 212,
254) mass spectral data were both acquired with an electron
energy of 70 eV, source temperature of 230 °C, and transfer
line temperature of 300 °C.
Experimental Section
Dry THF, toluene, and diethyl ether were distilled from
sodium benzophenone ketyl radical under argon. Boron
trifluoride etherate complex (BF3.Et2O), 1-bromobutane,
2-bromobutane, 2-bromopropane, ethyl bromoacetate, ethyl
2-bromopropionate, 2-hexanol, 2-hexanone, 2-pentanone,
3-methyl-2-butanone, 3-methyl-1-pentanol, 4-methyl-2-pen-
tanone, pyridinium chlorochromate (PCC), and triphenylphos-
phine were used as received. Methyl methacrylate and
triethylphosphite were distilled under reduced pressure just
prior to use. Chloroacetone was freshly distilled under
reduced pressure with the aid of an air-leak tube (fitted to
an argon filled balloon) and a 10 cm Vigreux column to avoid
carryover from bumping. 1-Bromo-3-methylpentane was
prepared from 3-methyl-1-pentanol as previously described.57
Grignard reagents were prepared by reaction of alkyl halides
with a 5-fold excess of mechanically activated58 magnesium
in anhydrous Et2O. Grignard reagents were standardized
immediately after preparation by titration against ∼1 M HCl,
and were typically between 0.5 and 2.0 M. Borohydride
2,4-Dimethyl-1-octanol (1:0.61 Ratio of Diastereo-
mers). Methyl 2,4-dimethyloctanoate (19) (10 g, 54 mmol)
was added to a suspension of LiAlH4 (15.54 g, 409 mmol)
in THF (350 mL) under argon, and the mixture was heated
under reflux for 2 d. The flask was cooled in an ice bath,
and MeOH was cautiously added until gas evolution ceased,
followed by H2O (10 mL). The mixture was diluted further
with H2O (100 mL), then acidified to pH 5 with 1 M HCl.
The resulting solution was extracted with DCM (3 × 100
mL). The organic extract was dried (MgSO4) and evaporated
giving the title alcohol as a colorless viscous oil (7.83 g,
92%). 1H NMR (600.1 MHz, C6D6): δ (ppm) 0.83-0.93 (m,
9H, all CH3), 0.97-1.37 (m, 8H, H3 and H5-H7), 1.40-1.49
(m, 1H, H4), 1.57-1.66 (m, 1H, H2), 3.18-3.35 (m, 2H,
-
(BH4 ) - form Dowex 1X2 (100 - 200 mesh) anion ex-
change resin (BER) was prepared by treatment of a stirring
slurry of the commercially available chloride (Cl-) - form
in water with excess NaBH4 for 30 min before being filtered,
washed with H2O and EtOH, and dried under vacuum. The
BH4- content was determined by measurement of the volume
of H2 produced on treatment with HCl. AR acetone, diethyl
ether, and MeCN were used as received. Solvents for general
use, DCM, and hexanes were distilled prior to use.
NMR spectra were acquired on either a Bruker AV500
(1H at 500.1 MHz and 13C at 125.4 HMz) or a Bruker AV600
(1H at 600.1 MHz and 13C at 150.9 HMz) spectrometer.
Infrared spectra were collected using a Perkin-Elmer Spec-
trum One Spectrometer at 2 cm-1 resolution; liquids were
acquired as thin films between NaCl plates and solids were
1
H1). The H NMR data were somewhat different to those
reported at 200 MHz;44 13C NMR (125.8 MHz, C6D6): δ
(ppm) 14.4 (CH3), 16.6, 17.6 (CH3), 19.7 (CH3), 20.6 (CH3),

Combinatorial Structural Elucidation
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 147
23.47 (CH2), 23.49 (CH2), 29.5 (CH2), 29.7 (CH2), 30.3 (CH),
30.4 (CH), 33.5 (CH), 33.6 (CH), 36.8 (CH2), 38.1 (CH2),
41.1 (CH2), 41.5 (CH2), 68.1 (CH2O), 68.9 (CH2O); GC-
MS: 15.45 min - m/z 43 (100%), 55, 56, 57, 69, 70, 71, 83,
84, 85, 98, 112, 127, 140, 157; 15.54 min - m/z 43 (100%),
55, 56, 57, 69, 70, 71, 83, 84, 85, 98, 112, 127, 140;
GC-CI+-HRMS: C10H21O requires 157.1592 found 156.9950;
IR (thin film): ν (cm-1) 3338 (OH).
113, 213, 125, 128, 129, 138, 141, 142, 143, 169, 181, 184,
197, 211, 226 (M•+, 0.59%); EI-HRMS: C14H26O2 requires
226.1933 found 226.1928; IR (thin film): ν (cm-1) 1721
(CdO), 1651 (CdC).
(E)-Ethyl 2,4,6-Trimethyldec-2-enoate (26) (1:0.76 Ra-
tio of Diastereomers). (2-Ethoxy-1-methyl-2-oxoethyl)t-
riphenyl phosphonium bromide (2.18 g, 4.92 mmol) was
dried under vacuum for 30 min. Dry THF (20 mL), Et3N (2
mL) and 21 (490 mg, 3.14 mmol) were added, and the
mixture was heated under reflux overnight. The mixture was
poured into H2O (250 mL) and extracted with Et2O (3 × 40
mL). The extract was dried (MgSO4) and evaporated. The
crude product was subjected to flash chromatography. Elution
with Et2O/hexane (2:98) gave 26 as a colorless oil (156 mg,
21%). 1H NMR (600.1 MHz, CDCl3): δ 0.78-0.90 (m, 6H),
0.96 (t, J ) 6.7 Hz, 3H), 0.99-1.63 (m, 12H, H5-H9 and
OEt(CH3)), 1.80-1.86 (m, 3H, C2(CH3)), 2.52-2.65 (m, 1H,
H4), 4.17 (q, J ) 7.1 Hz, OEt(CH2), 6.45-6.56 (m, 1H,
H3); 13C NMR (150.9 MHz, CDCl3): δ (ppm) 13.97 (CH3),
14.13 (CH3), 19.45, 19.65, 19.81, 20.93, 22.52 (CH2), 22.86
(CH2), 28.93 (CH2), 30.29, 30.56, 30.64, 30.75, 31.46 (CH2),
36.37 (CH2), 37.12 (CH2), 44.15 (CH2), 44.43 (CH2), 60.23
(CH2), 125.62 ()C), 126.00 ()C), 148.13 ()CH), 148.36
()CH), 168.24 (CdO), 168.39 (CdO); GC-MS: 19.82
min - m/z 43, 55, 57, 67, 69, 83, 87, 95, 102, 109, 113, 115
(100%), 126, 127, 139, 142, 155, 156, 179, 183, 195, 211,
225, 240 (M•+, 2.82%); 19.95 min - m/z 43, 55, 57, 67, 69,
83, 87, 95, 102, 109, 113, 115 (100%), 126, 127, 139, 142,
155, 156, 179, 183, 195, 211, 225, 240 (M•+, 3.68%); EI-
HRMS: C15H28O2 requires 240.2089 found 240.2096.
4-Methyloct-3-en-2-one (30)50 (17:3 Mixture of E/Z
Isomers). A suspension of NaH 60% dispersion in mineral
oil (2.71 g, 67.8 mmol) in anhydrous toluene (100 mL) was
vigorously stirred for 30 min to dissolve the mineral oil. The
stirring was stopped, and the toluene was removed using a
filter-tip cannula. The NaH was resuspended in toluene (100
mL), the suspension was cooled in an ice bath, and a solution
of diethyl 2-oxopropylphosphonate (12) (12.2 g, 62.8 mmol)
in toluene (50 mL) was added dropwise over 30 min,
resulting in effervescence because of production of H2. The
solution was allowed to stir for 1 h before the addition of
2-hexanone (6.22 g, 61.9 mmol) in one portion. The viscous
mixture was heated under reflux overnight, whereupon it
darkened considerably. Upon cooling to room temperature,
a viscous orange oil separated. The mixture was poured into
H2O (300 mL), and washed in with Et2O. 1 M HCl was
added until the water layer was neutral and the organic layer
was collected. The aqueous layer was extracted with Et2O
(2 × 100 mL), and the combined extract was dried (MgSO4)
and evaporated. The residue was fractionally distilled to give
30 as a colorless oil (7.14 g, 82%), bp ) 30-40 °C at 0.7
2,4-Dimethyloctanal (21) (1:0.73 Ratio of Diastereo-
mers). 2,4-Dimethyloctanol (1.00 g, 6.32 mmol) was dis-
solved in DCM (50 mL), and the solution was sparged with
argon for 5 min while being cooled in an ice-bath. PCC (4.07
g, 18.9 mmol) was added in portions over 10 min with
vigorous stirring. The mixture was stirred at room temper-
ature overnight, after which time Florosil (2 g) was added.
After stirring for 30 min the suspension was vacuum-filtered
through a column of Florosil (30 g). The column was washed
with DCM, and the filtrate was evaporated to give 21 as a
colorless oil (0.88 g, 89%). The compound was used
1
immediately because of its rapid aerial oxidation. H NMR
(600.1 MHz, CDCl3): δ (ppm) 0.84-0.89 (m, 6H), 1.06 (m,
3H), 1.08-1.32 (m, 6H), 1.43-1.72 (m, 2H), 2.35-2.46 (m,
1H, H2), 9.56 (d, J ) 2.5 Hz, 1H, CHO), 9.59 (d, J ) 2.1
Hz, 1H, CHO); 13C NMR (150.9 MHz, CDCl3): δ (ppm)
13.5 (CH3, C8), 14.2 (CH3), 14.3 (CH3), 19.4, 20.0, 23.04
(CH2, C7), 23.06 (CH2, C7), 29.1 (CH2, C6), 29.3 (CH2, C6),
30.3, 30.5, 36.6 (CH2, C5), 37.2 (CH2, C5), 37.8 (CH2, C3),
38.4 (CH2, C3), 44.3, (CH, C2), 44.4 (CH, C2), 196.2 (CH,
CHO); GC-MS: 14.13 min - m/z 43, 55, 56, 57 (100%), 58,
69, 71, 85, 98, 99, 113; 14.24 min - m/z 43, 55, 56, 57
(100%), 58, 69, 71, 85, 98, 99, 113; HREI-MS: C10H20O
requires 156.1514 found 156.1512; IR (thin film): ν (cm-1)
1727 (CdO). This compound has been reported but not
characterized.59
(E)-Ethyl 4,6-Dimethyldec-2-enoate (25) (1:0.73 Ratio
of Diastereomers). (2-Ethoxy-2-oxoethyl)triphenyl phos-
phonium bromide (2.05 g, 4.78 mmol) was dried under
vacuum for 30 min. Dry THF (20 mL), Et3N (2 mL) and 21
(487 mg, 3.12 mmol) were added, and the mixture was
heated under reflux overnight. The mixture was poured into
H2O (250 mL) and extracted with Et2O (3 × 40 mL). The
extract was dried (MgSO4) and evaporated. The crude
product was subjected to flash chromatography. Elution with
Et2O/hexane (2:98) gave 25 as a pale yellow oil (81 mg,
1
12%). H NMR (600.1 MHz, CDCl3): δ (ppm) 0.81-0.85
(m, 3H, C6(CH3)), 0.85-0.90 (m, 3H, H10), 0.99-1.04 (m,
3H, C4(CH3)), 1.05-1.48 (m, 12H, H5-H9 and OEt(CH3)),
4.18 (q, J ) 7.2 Hz, 2H, OCH2), 5.74- 5.79 (m, 1H, H2),
6.77-6.89 (m, 1H, H3); 13C NMR (150.9 MHz, CDCl3): δ
(ppm) 14.3 (CH3), 14.4 (CH3), 19.4, 19.6, 19.9, 23.1 (CH2),
23.2 (CH2), 29.15 (CH2), 29.20 (CH2), 30.3 (CH), 30.5 (CH),
34.14 (CH), 34.41 (CH), 36.7 (CH2), 37.2 (CH2), 43.7 (CH2),
44.0 (CH2), 60.3 (CH2), 119.3 (C2H), 119.8 (C2H), 154.9
(C3H), 155.3 (C3H), 167.1 (CdO), 167.2 (CdO); GC-MS:
19.52 min - m/z 43, 53, 55, 57, 67, 68, 69 (100%), 81, 82,
83, 84, 95, 96, 97, 98, 99, 100, 101, 109, 113, 213, 125,
128, 129, 138, 141, 142, 143, 169, 181, 184, 197, 211, 226
(M•+, 0.66%); 19.64 min - m/z 43, 53, 55, 57, 67, 68, 69
(100%), 81, 82, 83, 84, 95, 96, 97, 98, 99, 100, 101, 109,
1
mmHg. H NMR (500.1 MHz, CDCl3) E-isomer: δ (ppm)
0.92 (t, J ) 7.2 Hz, 3H, H8), 1.28-1.48 (m, 4H, H6 and
H7), 2.10-2.13 (m, 5H, H1 and H5), 2.17 (s, 3H, C4(CH3)),
6.07 (s, 1H, H3); GC-MS: 13.73 min - m/z 43 (90%), 55
(75.9%), 69 (43%), 83 (100%), 98 (91%), 111, 125 (34%),
140 (M•+, 0.7%). These data are consistent with those
published.50 The minor Z-isomer50 eluted at 12.93 min - m/z
43 (100%), 55 (56%), 69, 82, 97, 111, 125 140 (M•+, 5%).

148 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Lengkeek et al.
4-Methyloctan-2-one (31). A solution of 30 (5.02 g,
35.8 mmol) in MeOH (50 mL) was stirred with 10% Pd/C
(∼ 200 mg) under 10 atm of H2 in an autoclave overnight.
The suspension was filtered though a pad of Celite and
washed with MeOH. The solvent was evaporated to give 31
(ppm) [NB: integrals meaningless in this case because of
mixture of diastereomers] 0.80-1.05 (m), 1.18-1.41 (m),
1.55-1.71 (m), 1.86-2.02 (m), 2.10-2.36 (m), 4.66-5.21
(m, )CH); 13C NMR (500 MHz, CDCl3): δ (ppm) major
isomer (2,3-ene) 14.3 (CH3), 18.8, 19.6, 20.72, 20.78, 23.2
(CH2), 29.7 (CH2), 32.3, 37.0 (CH2), 42.2 (CH2), 124.9 (C)),
127.2 (C)); minor component (3,4-ene) 13.6 (CH3), 21.5,
21.7, 21.8, 23.1 (CH2), 29.9 (CH2), 32.1, 37.0, 37.8, 129.3
()CH), 139.2 (C)); GC-MS: 13.05 min - m/z 42, 55, 69
(100%), 83, 111, 125, 153, 168 (M•+, 10.2%); 13.63 min -
m/z 43, 55, 69 (100%), 84, 111, 125 168 (M•+, 12.0%): 14.69
min - m/z 43, 55, 69, 83 (100%), 111, 125, 152, 168 (M•+,
25.2%); GC-EI-HRMS: C12H24 requires 168.1878 found
168.1881.
1
as a colorless liquid, (4.46 g, 82%). H NMR (500.1 MHz,
CDCl3): δ (ppm) 0.881 (t, J ) 7.1 Hz, 3H, H8), 0.885 (d, J
) 6.7 Hz, 3H, C4(CH3)), 1.21-1.30 (m, 6H, H5-H7),
1.95-2.00 (m, 1H, H4), 2.12 (s, 3H, H1), 2.19-2.23 (AA′B,
2H, H3); GC-MS: 12.26 min - m/z 43 (100%), 57, 58 (82%),
69, 71, 85 (36%), 99, 113, 127, 142 (M•+, 3.8%). These data
are consistent with those published.51
2,3,5-Trimethylnonan-3-ol (32). A solution of 31 (1.32
g, 9.28 mmol) in dry Et2O (200 mL) was cooled in an ice
bath and a 0.62 M solution of i-PrMgBr in Et2O (20 mL,
12.3 mmol) was added dropwise via syringe. After stirring
at 0 °C for 2 h, the mixture was allowed to warm to room
temperature and stirring was continued overnight. The
reaction was quenched by the cautious addition of saturated
aqueous NH4Cl (10 mL) followed by H2O (50 mL). The Et2O
fraction was collected, and the aqueous fraction was extracted
with Et2O (2 × 100 mL). The combined organic fraction
was dried (MgSO4) and evaporated, giving a pale yellow
oil (1.37 g) which was subjected to careful Kugelrohr
distillation. At 0.1 mmHg and ∼50 °C, unreacted 31 (162
mg) distilled, and at 75-100 °C, 32 distilled as a colorless
oil (675 mg). GC-MS analysis of the 2,3,5-trimethylnonan-
3-ol fraction revealed it was ∼90% pure. The viscous yellow
distillation residue (537 mg) was subjected to RSF. Elution
with Et2O/ hexane (1:19), followed by Et2O/ hexane (1:4)
The mixture of isomeric alkenes was dissolved in DCM
(20 mL), and the solution was stirred with 10% Pd/C (22
mg) under a balloon of H2. After 5 h, GC-MS indicated that
the reaction was complete. The suspension was vacuum-
filtered though a pad of Celite, and washed through with
DCM. The filtrate was evaporated giving 33 as a colorless
1
liquid (211 mg, 92%). H NMR (500.1 MHz, CDCl3): δ
(ppm) 0.82-1.03 (m, 15H), 1.17-1.44 (m, 8H), 1.58-1.69
(m, 3H); GC-MS: 13.77 min - m/z 43, 57, 71 (100%), 85,
98, 113, 127, 141, 155, 170 (M•+, 0.46%): 13.90 min - m/z
43 (100%), 57, 71, 85, 98, 113, 127, 141, 155, 170 (M•+,
0.54%) GC-EI-HRMS: C12H26 requires 170.2035 found
170.2035.
General Procedures for the Synthesis of the HBA
Series. Domino HWE Reactions. Diethyl 2-oxopropy-
lphosphonate (12) (8 equiv) was added dropwise to a
suspension of oil-free NaH (9 equiv) in dry toluene (5
mL per mmol) at 0 °C. After the vigorous evolution of
H2 had subsided, the mixture was allowed to warm to room
temperature, whereupon a precipitate formed. The result-
ing slurry was treated with the appropriate ketone (1 equiv)
and then heated at 100 °C, causing dissolution of the
precipitate. During the course of the reaction, diethyl
phosphoric acid separated as a viscous, dark-orange layer.
When GC-MS indicated adequate conversion, the reaction
mixture was cooled to room temperature, and the toluene
phase was diluted with H2O (200 mL) and then extracted
with Et2O (3 × 250 mL). The extract was dried (MgSO4),
and the solvent was evaporated to give a yellow oil, which
was dissolved in Et2O and vacuum-filtered through a short
plug of silica gel. Evaporation of the filtrate afforded the
mixture of (polyen)ones 34.
Catalytic Hydrogenation. A solution of 34 in MeOH was
stirred with 10% Pd/C under an atmosphere of H2 until GC-
MS showed the hydrogenation to be complete. The reaction
mixture was vacuum-filtered though a plug of Celite, the
solvent was carefully evaporated, and the residue was
subjected to RSF. Elution with hexane then 1:4 hexane-Et2O
gave the saturated ketones 38.
Grignard Addition. A solution of the appropriate Grig-
nard reagent (2 equiv based on n ) 2) was added to a stirred
solution of the ketones 38 in Et2O (50 mL) at 0 °C under
argon. The mixture was stirred overnight at room temperature
before being quenched by cautious addition of saturated
aqueous NH4Cl (10 mL) and H2O (100 mL). The organic
1
gave 32 as a colorless oil (312 mg, 18%). H NMR (500.1
MHz, CDCl3): δ (ppm) 0.85-0.92 (m, 9H, H1/C2(CH3)/
H9), 0.95 (t, J ) 6.6 Hz, 3H, H9), 1.08 (d, J ) 4.0 Hz, 3H,
H5), 1.10-1.48 (m, 7H, H2/H6/H7/H8), 1.56-1.72 (m, 2H,
H4), 4.09 (m, 1H, OH); 13C NMR (500 MHz, CDCl3): δ
(ppm) 14.3 (CH3), 17.16 (CH3), 17.24 (CH3), 17.7 (CH3),
17.9 (CH3), 22.1 (CH3), 22.2 (CH3), 23.1 (CH2, C8), 23.5
(CH, C2), 23.6 (CH, C2), 28.5 (CH3), 28.7 (CH3), 29.47
(CH2, C7), 29.51 (CH2, C7), 37.6 (CH, C5), 38.3 (CH, C5),
38.9 (CH2, C6), 39.0 (CH2, C6), 46.1 (CH2, C4), 46.6 (CH2,
C4), 75.55 (COH), 75.57 (COH); GC-MS: 16.55 min - m/z
43, 57, 59, 69, 85, 87 (100%), 99, 125, 143, 154, 171; 16.58
min - m/z 43, 57, 59, 69, 85, 87 (100%), 99, 125, 143, 154,
171; CI-HRMS: C12H26O requires 186.1984, found 169.1359
([C12H25]+); IR (thin film): ν (cm-1) 3467 (OH).
2,3,5-Trimethylnonane (33) (1:0.74 Ratio of Diastere-
omers). A solution of 32 (0.300 g, 1.61 mmol) in dry DCM
(10 mL) under argon was cooled in an ice-salt bath, then
treated with BF3.Et2O (0.250 mL, 1.99 mmol), whereupon
the mixture immediately became cloudy. After 15 min a clear
solution had formed and GC-MS revealed that the starting
material had been consumed. The reaction was quenched by
addition of saturated aqueous NaHCO3 (2 mL) followed by
H2O (3 mL). The DCM layer was collected, and the aqueous
layer was extracted with DCM (2 × 5 mL). The combined
organic phase was dried (MgSO4) and evaporated. The
residue was dissolved in pentane, filtered though a short plug
of SiO2, and the filtrate was evaporated yielding a colorless
1
liquid (209 mg, 77%). H NMR (500.1 MHz, CDCl3): δ

Combinatorial Structural Elucidation
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Acknowledgment. This paper is dedicated to Associate
Professor Bob Bucat, on the occasion of his retirement. We
thank Dr. Anthony Reeder for acquisition of HR-MS and
assistance with GC-MS. P.F.G. acknowledges Australian
Research Council (DP0662839) funding for this project.
Supporting Information Available. The ESI includes full
experimental procedures and details, gas chromatograms of
the products of each step for the combinatorial HBA
synthesis, and mass spectra of the final HBA samples for
each series. This material is available free of charge via the
Internet at http://pubs.acs.org.
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