Systematic comparison of sets of 13C NMR spectra that are potentially identical. Confirmation of the configuration of a cuticular hydrocarbon from the cane beetle antitrogus parvulus

Article abstract of DOI:10.1021/jo5012027

A systematic process is introduced to compare ¹³C NMR spectra of two (or more) candidate samples of known structure to a natural product sample of unknown structure. The process is designed for the case where the spectra involved can reasonably

Full text of DOI:10.1021/jo5012027

Article
pubs.acs.org/joc
Open Access on 07/14/2015
13
Systematic Comparison of Sets of C NMR Spectra That Are
Potentially Identical. Confirmation of the Configuration of a Cuticular
Hydrocarbon from the Cane Beetle Antitrogus parvulus
Norazah Basar,† Krishnan Damodaran,‡ Hao Liu,§ Gareth A. Morris,§ Hasnah M. Sirat,†
Eric J. Thomas,*,§ and Dennis P. Curran*,‡
†Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, Skudai, 81310 Johor, Malaysia
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
§School of Chemistry, University of Manchester, Manchester M13 9PL, United Kingdom
S
* Supporting Information
ABSTRACT: A systematic process is introduced to compare 13C
NMR spectra of two (or more) candidate samples of known structure
to a natural product sample of unknown structure. The process is
designed for the case where the spectra involved can reasonably be
expected to be very similar, perhaps even identical. It is first validated
by using published 13C NMR data sets for the natural product
4,6,8,10,16,18-hexamethyldocosane. Then the stereoselective total
syntheses of two candidate isomers of the related 4,6,8,10,16-pentamethyldocosane natural product are described, and the
process is applied to confidently assign the configuration of the natural product as (4S,6R,8R,10S,16S). This is accomplished even
though the chemical shift differences between this isomer and its (16R)-epimer are only 5−10 ppb ( 0.005−0.01 ppm).
compound was 1 or 3 and whether the pentamethyl compound
was 2 or 4.1 (Due to CIP priority changes, 16R-1 corresponds
to 16S-2, while 16S-3 and 16R-4 correspond.)
INTRODUCTION
■
Several years ago, Kitching and co-workers isolated two
polymethylated docosanes from the cuticular extract of the
cane beetle Antitrogus parvulus.1 The compounds were
identified as a 4,6,8,10,16,18-hexamethyldocosane and a
4,6,8,10,16-pentamethyldocosane (Figure 1), and synthesis
established the anti,anti,anti-orientation of the methyl groups
at the 4,6,8,10-positions for both compounds.
For the hexamethyl compound, the 16- and 18-methyl
groups were shown to be syn, but their configuration relative to
the other four methyl groups was not established. Similarly, the
configuration of the 16-methyl group of the pentamethyldoco-
sane relative to the other methyl groups was not elucidated.
Thus, the open questions were whether the hexamethyl
Synthetic chemists soon rallied to this challenge,2 and Herber
and Breit established by head-to-head comparison of synthetic
and natural samples that the natural hexamethyldocosane was
the (4S,6R,8R,10S,16R,18S)-stereoisomer 1, rather than epimer
3.2 Burgess and Negishi also described stereoselective syntheses
of 1.
Meanwhile, in complementary work, one of our groups
tackled the stereoselective syntheses of 2 and 4 to test
methodology and to establish whether that natural product was
the (16S)- or the (16R)-isomer.3
Once the syntheses of 2 and 4 were completed, we faced a
problem because no natural sample was available for head-to-
head comparison. Accordingly, the only option was to compare
tabular lists of 13C NMR chemical shift data for the two
synthetic samples with the natural sample. Not surprisingly,
these data lists are very similar.3 Indeed, so similar that we had
to consider the possibility that the spectra of synthetic 2 and 4
were substantially identical and that any tiny observed
differences were due to error. If that were true, then the
structure of the natural product could not be assigned. Even if
the spectra of 2 and 4 could be proved to be different, how do
we know which is the natural product if we have no natural
sample to compare head-to-head under identical conditions?
Figure 1. Potential structures of cane beetle hydrocarbon natural
products: 4,6,8,10,16,18-hexamethyldocosane is 1 or 3; 4,6,8,10,16-
pentamethyldocosane is 2 or 4.
Received: May 29, 2014
Published: July 14, 2014
© 2014 American Chemical Society
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This type of assignment problem is common for natural
products that have remote stereocenters or local symmetry that
is broken only at a distant point.4 The usual solution is to treat
the distant parts of the molecule independently and to assign
absolute configurations of each part separately.5 However, this
requires derivatization (to make Mosher esters, for example) or
at least mixing with shift reagents. Subsequent recovery of
precious natural or synthetic samples in pure form can be an
issue. At the most basic level, it requires functional groups for
derivatization or complexation, and these are absent in 1−4.
Here we provide a solution to the problem of identifying a
natural product or other unknown compound by matching its
1D 13C NMR spectrum with two spectra from a pair of known
compounds. The solution is generally applicable but is
specifically designed for the case where the spectra of the
two known samples are extremely similar, potentially even
identical. Two common complications are addressed: system-
atic differences in calibration (chemical shift referencing)
between spectra and, importantly, the differential temperature
dependence of 13C chemical shifts.
First, we lay out a stepwise process for comparing pairs of
13C NMR data sets that allows one to decide whether the
spectra are the same or different. If they are different, then the
differences are articulated and applied for structure assignment.
We claim that the method requires only standard tables of 13C
NMR chemical shifts. Second, to validate this claim, we show
that published data sets from Kitching and Breit can be used to
assign the structure of 1 without any head-to-head sample
comparison. Third, we provide full details of the synthesis of 2
and 4, and finally, fourth, we apply the new method to
rigorously show without the aid of a natural sample that the
natural product is (4S,6R,8R,10S,16S)-pentamethyldocosane 2.
Remarkably, the method succeeds even though the largest
difference in chemical shift in the 13C NMR spectra of isomers
2 and 4 is only about 10 ppb! When real differences in chemical
shifts are this small, it is critical to account for possible
differences in sample temperature.
Figure 2. Steps and possible outcomes of a process for comparing
different samples whose 13C NMR spectra are very similar and possibly
identical. Samples S and R are two different candidates of known
structure that are compared to a natural product NP of unknown
structure.
RESULTS AND DISCUSSION
■
The current standard for comparison of 13C NMR spectra of
two similar candidate samples with the spectrum of a natural
sample is simply raw subtraction. The set of chemical shifts of
the natural product spectrum is subtracted from each set of
chemical shifts of the candidate spectra, resulting in two sets of
differences that are typically shown as scatter plots. The two
plots are then compared by standard deviation or other means,
and then the natural product is assigned the structure of the
candidate with the smaller differences.
for rigorous comparison of data sets of 13C NMR spectra of two
samples of known structure with each other and then with a
third sample of unknown structure. The goals are to both assign
the structure of the unknown compound and to confidently
articulate that the assignment is correct. The initial discussion
here presents the generalized process, so it is necessarily
abstract. However, each of the steps of the processes will be
illustrated concretely in the following section on validation.
In Figure 2, the two candidate samples of known structure
(typically isomers made by total synthesis) are generically
called S and R, and the unknown sample (typically a natural
product) is called NP. To the extent possible, the resonances of
the spectra are assigned to their associated carbon atoms by
standard means. The spectra of the synthetic samples must be
recorded under the same conditions and at the same nominal
probe temperature (within about 1 K). The temperature of the
NP spectrum is critical but does not need to be known in
advance because it emerges from the analysis.6
For pairs of spectra from samples like 1/3 or 2/4, this
process is inadequate for at least three reasons. First, it assumes
that there are real and reliable differences in the spectra of the
two candidate isomers, but there may not be. Second, it
assumes without justification that all errors are random and
therefore will tend to cancel in the final comparison. Third, it
treats all differences in chemical shifts as equal in importance,
regardless of the locations of the carbon atoms involved.
However, it is clear, for example, that a difference in chemical
shift in 1/3 or 2/4 at Me10 or Me16 should get more weight
than a difference at the chain terminus methyl groups (C1 or
C22). In other words, some chemical shift differences are more
valuable than others. But which ones? And how do you know?
Systematic Comparison of Very Similar 13C NMR
Spectral Data Sets. Figure 2 illustrates a three-step process
Step 1 is to compare the spectra of the candidate samples R
and S not to the natural product but to each other. The goals are
to determine whether the candidate spectra are the same or
different and, if different, to articulate the differences. Start by
subtracting the chemical shifts of R from S (or the reverse) and
gauge the experimental uncertainty in the chemical shift values.
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13C NMR spectra, the chemical shift differences caused by small
changes in sample temperature could easily exceed the real
differences. Clearly the spectra of the candidate samples have to
be collected at the same sample temperature as the spectrum of
the natural product.
What to do if you identify a temperature difference between
your synthetic samples (sample temperature known) and the
natural product sample (sample temperature unknown)?
Fortunately, the list of the “same” chemical shifts of the
candidate samples allows the sample temperature of the NP
sample to be estimated retrospectively. This process will be
illustrated below.
In the final step 3, simply subtract the “reliably different”
chemical shifts of R and of S from those of the NP. If all of the
subtraction values equal zero within the experimental
uncertainty, then this is the natural product match. If all
subtraction values equal the reliably different values identified
in step 1, then this is the mismatch. No other result is possible;
there cannot be subtractions that neither match (zero) nor
mismatch (reliably different).8
Record duplicate spectra if needed to estimate this. If the
subtractions are all zero within the expected experimental error,
then the spectra are substantially identical. This means that the
two candidate spectra cannot be used to assign the
configuration of NP. Further subtraction of S and R from
NP is pointless, and another means of assignment is needed.
If some subtractions are not zero, then group all resonances
into three categories based on their differences in their chemical
shifts. The chemical shifts of each pair of resonances in S and R
are either (1) the same, (2) uncertain, or (3) reliably different.
Establish chemical shift limits for the three categories based on
the estimated error and common sense analysis of the data.
Going forward, the “same” resonances are used only as
controls; you know that the natural product is one of these
two samples, so it has to have all of the “same” resonances too.
The “reliably different” resonances are used only for assign-
ment; the natural product has either one set or the other. These
values will ultimately be obtained again when the natural
product chemical shifts are subtracted from those of the wrong
candidate isomer, so they are called “mismatch” values. The
“uncertain” resonances are not used at all; this category is
simply a place to cull differences that are too close to call.
Before advancing to step 2, check the carbon atom
assignments of the various resonances, which should pass the
sniff test of chemical common sense. For example, if the
structures are very similar (like 1/3 and 2/4, for example), then
it cannot be that all of the pairs of chemical shifts are reliably
different. Likewise, the “reliably different” and “same”
resonances should not be randomly distributed about the
structures. The carbons of the “reliably different” resonances
should cluster around the parts of the molecules that are
different, while the carbons of the “same” resonances should
cluster in regions that are remote from the differences.
Validation of the Method with Published Breit/
Kitching Data Sets. A corollary of the assignment method
in Figure 2 is that neither new samples nor new experiments are
needed if complete data sets are already published (provided
that the sample temperatures are the same in the data sets to be
compared). Thus, prior to using the method to assign 2/4, we
validated it with the complete data sets published for the related
compounds 1/3 from Breit and Kitching.
Three lists of 13C NMR peaks were used in the validation,
and these are shown in Figure 3a. First, Kitching provided the
In steps 2 and 3, we compare the spectra of the candidate
samples to that of the NP. This is where standard comparisons
usually start; however, we are ahead of the game because we
already know that our comparisons are meaningful (that is, S
and R do not have identical spectra) and we know what to
compare (the reliably different resonances).
In step 2, we control for temperature and calibration
differences of the candidate and natural samples. These controls
are performed by subtracting members of the “same” group of
chemical shifts in S (or R, they are the same after all) from the
corresponding chemical shifts of the natural product NP. In
principle, the subtractions should all be zero. In practice, there
are three possible outcomes: First, if all of the values are zero
(or close to zero), then both the temperature and calibration
errors are small. In that case, proceed directly to step 3 (final
comparison). Second, if the values are small and constant
(either positive or negative), then there is a calibration
difference between the synthetic and natural samples. Stand-
ardize the chemical shifts of NP if the calibration error is
significant compared to the values of the “reliably different”
chemical shifts. Third, if the subtraction values of the “same”
groups give variable values, then there is probably a difference
in sample temperature between the different experiments. This
has to be accounted for when the values of the “same”
subtractions approach or exceed the above “reliably different”
values. Temperature effects on 13C NMR spectra of alkanes are
variable, ranging from 0 to about 20 ppb per degree K in either
direction (that is, upfield or downfield with increasing T),
reflecting the change in conformation populations with
temperature.7 So in two different samples with very similar
Figure 3. (a) Published 13C NMR data sets for hexamethyldocosane
and (b) Breit’s head-to-head comparison of the natural sample with
the synthetic candidates.
spectrum of the isolated natural product and assigned the
various resonances.1 Second, Kitching also provided a spectrum
of a synthetic mixture of four diastereomers: 1, 3, and their
epimers at C10.1 Third, Breit and Herbert stereoselectively
made the two individual candidate isomers 1 and 3 and
recorded their 13C NMR spectra (data in Table 1).2 Kitching
observed in his mixed sample that some of the carbons
appeared as single peaks even though four isomers were
present. This proves a key assumption of our method, that at
least some of the carbons in the isomers have identical chemical
shifts. Kitching also saw various doubled resonances, eight of
which he assigned to the epimers at C16/18. Because Kitching’s
sample was made as a mixture, he could not know which
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Exemplifying the process in Figure 2, step 1 is to compare
the spectra of Breit’s two individual synthetic samples of 1 and
3 to each other. Table 1 shows his complete data lists2 along
with the subtraction results. Breit is correctthe spectra are
strikingly similar. At the 1 ppb level, about half of the
subtraction results are exactly zero, while the largest differences
are less than 20 ppb (+19 ppb for C13 and −17 ppb for C9).
The many zeros show that Breit’s two spectra were recorded
with the same sample temperature and consistently calibrated.
Prior to comparison with the natural product spectrum, the
subtraction values are placed in the three groups: (1) the same
group for <2 ppb difference (15 resonances), (2) the uncertain
group (UC) for 2−6 ppb difference (6 resonances), and (3) the
reliably different group (RD) for >7 ppb difference (6
resonances). The subtraction results from the reliably different
group (RD, in red) and uncertain group (UC, in green) are
placed with their assigned carbon atoms on the hexamethyldo-
cosane structure in Figure 4. Unlabeled carbons are all in the
“same” group.
Table 1. Step 1 of the Comparison Process: Subtraction of
13C NMR Data Set 1 from Set 3 and Classification of the
Chemical Shifts by Magnitude of the Differences
a
C
anti
syn
δ3 − δ1 (ppb)
category
C22
C1
14.181
14.389
19.553
19.570
19.589
19.647
20.080
20.302
23.072
26.928
27.063
27.294
27.294
29.176
29.715
29.982
29.982
29.995
30.346
36.573
36.876
37.876
40.222
45.225
45.552
45.579
46.535
14.181
14.389
19.553
19.570
19.589
19.649
20.080
20.302
23.072
26.940
27.070
27.294
27.294
29.176
29.715
29.982
29.982
30.002
30.365
36.570
36.878
37.885
40.222
45.222
45.550
45.562
46.537
0
0
same
same
same
same
same
UC
b
Me
0
b
Me
0
b
Me
0
b
Me
2
C2
0
same
same
same
RD
c
Me
0
C21
C12
C14
C8
0
12
7
RD
0
same
same
same
same
same
same
RD
C6
0
C20
C4
0
0
C18
C16
C10
C13
C19
C15
C11
C3
0
0
7
19
−3
2
RD
UC
UC
9
RD
0
same
UC
C17
C5
−3
−2
−17
UC
C9
RD
C7
2
UC
a
b
c
UC is uncertain; RD is reliably different. Me groups 4,6,8,10. Me
groups 16,18.
resonances belonged to which isomers, so he could not assign
the natural product structure at that point.
Figure 4. Chemical shift differences (in ppb) and assigned carbon
atoms on the structures of the hexamethyldocosane (top) and
pentamethyldocosane (bottom) candidate isomers. The uncertain
resonances are labeled in green, and reliably different resonances are in
red. The unmarked resonances are in the “same” group.
Breit concluded that assigning the configuration of 3 by the
usual raw subtraction of chemical shifts of synthetic and natural
samples was not possible because the spectra of 1 and 3 were
too similar. Instead, Breit ingeniously inserted a narrow-bore
capillary tube containing the natural product (provided by
Kitching) inside standard-bore NMR tubes containing either of
the two synthetic isomers, then recorded a single spectrum of
the two sample components (Figure 3b). The (16R,18S)
configuration 1 was assigned to the natural product because no
peaks were doubled in the spectrum of the sample of 1 with the
natural product capillary inserted, whereas a lone peak was
doubled in the corresponding spectrum of 3 with the capillary.
The tube-in-tube experiments suggest that the stereoisomers 1
and 3 have 27 chemical shifts that are the same and only one
that is significantly different; however, we show presently that
more differences can be identified.
Together, the data sets provide an extremely rare (perhaps
the only) case study where spectra of pairs of diastereomers
with similar spectra have been collected in three different ways:
as individual, pure samples (Breit), truly mixed (Kitching, but
admixed with two other isomers), and artificially mixed (Breit,
tube-in-tube). Our goal was to do what was not possible by raw
subtraction: to confidently assign the structure of the
hexamethyldocosane natural product from the data sets of the
individual samples alone.
Notice how the reliably different resonances are not
randomly distributed or clustered at the ends. Instead, they
cluster in the region C9−C14. This makes sense given the
structural difference between the two isomers. Further, even the
“uncertain” resonances cluster immediately on either side of the
reliably different resonances, implying that these tiny differ-
ences (2−6 ppb) may also be real. Still, the six reliably different
resonances suffice for the analysis.
Strikingly, most of the uncertain and reliably different
resonances in the hexamethyldocosane isomers 1 and 3 belong
to methylene carbons. Every methylene group along the chain
from C5 to C20 lights up as UC or RD. In contrast, only one of
the six methines (C10 RD class) and one of the six methyl
groups (not shown because it was not assigned, UC class) lights
up in this analysis.
In step 2, calibration, we subtract the “same” chemical shifts
identified in Table 1 on the synthetic samples from the
corresponding chemical shifts of the natural product. These and
the remaining subtraction tables are shown in the Supporting
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Information. The result is a small, constant difference of about
3 ppb. This means that Breit’s and Kitching’s spectra were
recorded at the same sample temperature and that 3 ppb is the
calibration correction. We applied this correction going
forward; however, the same final result is obtained without it
because the calibration error (3 ppb) is smaller than the
differences in values for the reliably different resonances ( 7−
19 ppb).
Finally, to complete the retrospective assignment in step 3,
we subtract the reliably different chemical shifts of Breit’s pure
samples from Kitching’s natural product, with the results shown
in columns four (NP − 1) and five (NP − 3) of Table 2. For
The Breit/Kitching data sets do not match perfectly; one
reliably different resonance from Breit is not listed as doubled
in Kitching’s mixture (C10, which is very close to C16 and C18
making firm assignment difficult in the mixture spectrum), and
one pair of resonances in Kitching is classed as uncertain rather
than reliably different (C15, +13 ppb difference in Kitching, +2
ppb difference in Breit). This simply shows that having more
reliably different resonances increases the confidence of the
method. It is not important to find all of the real differences,
only that the differences found are reliable.
In summary, the standard raw subtraction method for
assignment could not be used with Breit’s samples 1 and 3 to
assign the configuration of the natural product. However, the
method outlined in Figure 2 succeeded. This success was
enabled in no small part by the high quality of the published
data sets from both Breit and Kitching. Breit has already
assigned 1 securely by the tube-in-tube method, so here it is the
validation of the method that counts.
Strikingly, the new method of controlled subtraction of the
data was comparable in effectiveness to recording spectra of
true mixtures in identifying different (doubled) resonances and
was considerably better than the tube-in-tube method. Indeed,
the tube-in-tube method identified only one of the six
resonances with differences >6 ppb. We speculate that this
may be due to the poorer field inhomogeneity inevitable with
two tubes. Regardless, the results show in hindsight that no
mixing of the candidate and natural samples (either real or
artificial) is needed. By careful, controlled comparison of
published data sets, we could identify differences in chemical
shift at the low ppb level, close to the experimental level of
resolution. The upshot is a secure structure confirmation
without access to a natural sample and without new
experiments.
Table 2. Retrospective Assignment of Hexamethyldocosane
by the Comparison Process
a
C
mismatch
category NP − 1 NP − 3 Kitching mixture
a
Me
2
12
7
UC
RD
RD
RD
RD
UC
UC
RD
UC
UC
RD
UC
2
0
2
12
5
3
C12
C14
C10
C13
C19
C15
C11
C17
C5
14
6
−2
0
7
7
b
19
−3
2
0
19
−4
4
21
b
−1
2
13
10
b
9
0
9
−3
−2
−17
2
−1
−3
0
−4
−5
−17
6
b
C9
−20
3
C7
4
a
b
From the comparisons in steps 1 and 2, taken from Table 1. Not
doubled in Kitching’s mixture.
Total Synthesis of Pentamethyldocosane Candidate
Isomers. The Manchester group has recently communicated
the synthesis of the candidate isomers 2 and 4 of the
pentamethyldocosane natural product.3 The synthesis is
summarized here with additional details. Complete exper-
imental information and compound characterization data are
found in the Supporting Information.
The two epimers 2 and 4 were made convergently with a late
stage formation of the C(11)−C(12) bond. The synthesis of
the requisite C(1)−C(11) fragment is based on chemistry
developed for the stereoselective synthesis of hydrocarbons
with methyl substituents disposed at 1,3,5-positions down an
aliphatic chain.9 The key step in this synthesis is the reaction of
(E)-5-benzyloxy-2,4-dimethylpent-2-enyl bromide with alde-
hyde 9. Such reactions are selective for the formation of (E)-
1,5-anti-products when mediated by the low valence bismuth
species formed by reduction of bismuth(III) iodide with zinc
powder.9,10
The synthesis of the left-half C1−C11 is summarized in
Scheme 1. Ozonolysis of the tert-butyldimethylsilyl ether 611 of
(S)-citronellol with a reductive workup gave (S)-6-tert-
butyldimethylsilyloxy-4-methylhexanol 7.12 Elimination of
hydrogen iodide from the corresponding iodide followed by
desilylation and hydrogenation gave (S)-3-methylhexanol 8.13
Oxidation then gave the aldehyde 913 that was used
immediately. This synthesis of 9 is straightforward and scalable.
The bismuth-mediated reaction of aldehyde 9 with the pent-
2-enyl bromide 109 gave a major product identified on the basis
of precedent,10 as the (3E,6S)-2,6-anti-2,4,8-trimethylundec-3-
en-6-ol 11. Minor products were detected at the 5% level but
evaluation purposes, we include both the UC and RD
resonances; however, for assignment we use only the RD set.
From Figure 2, we expect that one of the two sets of values will
be the match and one will be the mismatch. In principle, the
match subtraction results are all zero, while the mismatch
results are the values δ3 − δ1 (from Table 1 or Figure 4). The
actual values match the expected results in both columns within
about 2 ppb; NP − 1 is the match and NP − 3 is the
mismatch. Without question, the hexamethyldocosane is 1.
Now let us compare our method of identifying different
peaks to Breit’s and Kitching’s mixture experiments. Specifi-
cally, are the reliably different resonances identified by this
method real? Recall that Breit’s artificial mixture method (tube-
in-tube) identified only one different resonance, which is that of
C13. Indeed, at +19 ppb this has the largest magnitude of any
difference. Separate resonances were not observed in Breit’s
tube-in-tube experiments for C9 or C12 even though these
differ by −17 and +12 ppb, respectively, reflecting the price
paid in spectral resolution for the use of concentric samples.
The last column of Table 2 lists the ppb differences in the
doubled resonances in Kitching mixture sample. These should
equal the mismatch values in column 2 (Breit’s two synthetic
isomers) and column 5 (NP − 3, the difference between the
natural product and the wrong isomer). Of the eight doubled
resonances assigned to C16,18 epimers in Kitching’s mixture,
five are identified as reliably different and three as uncertain.
The magnitudes of the differences match within about 2 ppb.
This cannot be coincidence. Clearly Kitching assigned these
resonances properly, and we identified them faithfully from
Breit’s data set.
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The remaining methyl group was introduced by treatment of
the toluene p-sulfonate 17, prepared from the alcohol 16, with a
higher order methyl cuprate.15 This reaction proceeds with
inversion to provide the anti,anti,anti-2,4,6,8-tetramethylunde-
canyl silyl ether 19. The yield of the cuprate reaction was low
(21%), perhaps because of steric hindrance due to the flanking
4- and 8-methyl substituents, but sufficient product was
obtained to complete the syntheses. Desilylation gave the
alcohol 20 that was converted into the iodide 22 via the toluene
p-sulfonate 21.
Scheme 1. Synthesis of the 1-Iodo-2,4,6,8-tetramethyl-
undecane 22
a
The syntheses of the enantiomeric C(12)−C(22) fragments
and completion of the syntheses of the 16-epimeric 4,6,8,10,16-
pentamethyldocosanes 2 and 4 are outlined in Scheme 2.
Scheme 2. Completion of Syntheses of the 4,6,8,10-
a
Pentamethyldocosanes 2 and 4
a
Reagents and conditions: (i) TBSCl, imid., THF, rt, 16 h (98%); (ii)
O3, DCM, MeOH, −78 °C, 2 h, NaBH4, −78 °C to rt, 3 h (98%); (iii)
(a) I2, Ph3P, imid., DCM, rt, 2 h; (b) KOtBu, THF, rt, 16 h; (c) 4 M
aq HCl, THF, rt, 3 h; (d) H2, Pd/C, THF, rt, 16 h (60% from 7); (iv)
Dess−Martin periodinane, DCM, NaHCO3, rt, 30 min; (v) BiI3, Zn
powder, THF, rt, 2 h, add 9 and 10, THF, reflux, 2 h (60%); (vi) 4-
O2NC6H4CO2H, Ph3P, DIAD, THF, rt, 16 h (70%); (vii) 2 N aq
NaOH, THF, 50 °C, 1 h (70%); (viii) naphth., Li, THF, −25 °C, add
11, 2 h (78%); (ix) TIPSCl, imid., THF, rt, 16 h (94%); (x)
[Rh(NBD)Diphos-4]BF4 (cat.), DCM, H2, 950 psi, rt, 5 h (16, 70%;
18, 16%); (xi) TsCl, DMAP, THF, rt, 16 h (93%); (xii) CuI, MeLi·LiI,
0 °C, 17, 0 °C−rt, 16 h (21%); (xiii) 4 M aq HCl, dioxane, THF, rt, 16
h (91%); (xiv) TsCl, DMAP, DCM, rt, 16 h (85%); (xv) NaI, acetone,
reflux, 16 h (90%).
a
Reagents and conditions: (i) nBuS(O)2Ph, THF, DMPU, nBuLi, −40
°C, 30 min, 23, −40 °C to rt, 16 h (24, 95%; 31, 90%); (ii) O3, DCM,
MeOH, −78 °C, then NaBH4, −78 °C to rt, 16 h (25, 85%; 32, 87%);
(iii) Na/Hg, MeOH, rt, 16 h [(S)-26, 73%; (R)-26, 70%]; (iv) TsCl,
DMAP, DCM, rt, 16 h [(S)-27, 99%; (R)-27, 98%]; (v) NaI, acetone,
reflux, 2 h [(S)-28, 90%; (R)-28, 92%]; (vi) MeS(O)2Ph, THF, nBuLi,
−40 °C, 30 min, add 28, rt, 16 h [(S)-29, 73%; (R)-29, 75%]; (vii)
nBuLi, hexane, THF, DMPU, −40 °C, 30 min, add 22, −40 °C to rt,
16 h (30, 45%; 33, 34%); (viii) Na/Hg, MeOH, rt, 16 h (2, 83%; 4,
85%).
could not easily be separated. The (3E,6S)-undecenol 11 was
converted into its (3E,6R)-epimer 15 by treatment with 4-
nitrobenzoic acid under Mitsunobu conditions followed by
hydrolysis of the intermediate 4-nitrobenzoate 14. The
(3E,6R)-epimer 15 could be distinguished from the (3E,6S)-
undecenol 11 by H NMR and was shown to be about 5% of
the product mixture from the reaction between the aldehyde 9
and the bromide 10.
1
Reductive cleavage of the benzyl ether 11 followed by
selective silylation of the primary alcohol 12 gave the
triisopropylsilyl ether 13. Following precedents established by
Evans14 and used in preliminary studies,9 hydrogenation of the
alkenol 13 using [Rh(NBD)diphos-4]BF4 as the catalyst gave a
mixture of the 4-epimers of the 2,4,8-trimethylundecan-6-ols 16
and 18, in isolated yields of 75% and 16%, respectively.
Structures were assigned to these products by analogy with our
earlier work9 and were confirmed by comparison of the 13C
NMR spectra of later intermediates, in particular of the 2,4,6,8-
tetramethylundecanol 20, with published data.2
Alkylation of butyl phenyl sulfone using the (R)- and (S)-
iodides (R)-23 and (S)-2316 that are available from the
corresponding enantiomers of citronellol gave the dodecenyl
sulfones 24 and 31 as mixtures of epimers at C(4).
The alkenes in 24 and 31 were ozonized with a reductive
workup to give the alcohols 25 and 32, and then reduction by
sodium amalgam gave the enantiomeric 4-methyldecanols (S)-
and (R)-26.17 These were converted into the sulfones (S)- and
(R)-29 via the corresponding toluene p-sulfonates and
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iodides,18 and alkylation of these sulfones using the 1-iodo-
2,4,6,8-tetramethylundecane 22 gave the 12-phenylsulfonylpen-
tamethyldocosanes 30 and 33. Reductive removal of the
phenylsulfonyl group gave the 4,6,8,10,16-pentamethyldoco-
sanes 2 and 4. These final samples have H NMR spectra at
700 MHz that are indistinguishable, but the subsequent 13C
NMR analysis showed that their isomeric purity is at least 95%.
Assignment of the Structure of the Natural Pentam-
ethyldocosane. The data sets used to assign the pentam-
ethyldocosane structure are summarized in Figure 5. Again
Table 3. Matching and Mismatching by Subtraction of the
Reliably Different Chemical Shifts of Spectra of the
Pentamethyldocosane Natural Product (NP) with the
a
Synthetic Samples 2 (16S) and 4 (16R) (data in ppb)
3
1
resonance
2 − 4
NP − 2
NP − 4
Me-10
Me-16
C14
6
7
0
−1
−1
−1
−2
−1
−1
6
7
5
6
C10
5
4
C13
10
6
8
C11
5
C9
−9
−10
a
Standardization corrections before rounding in ppb are 2.3 and 1.6
(see Supporting Information). Prior to subtraction, values of synthetic
sample peaks were rounded to 1 ppb to match the natural product
(NP) spectrum.
left and right of the reliably different resonances along the
chain. This time, only half (5) of the reliably different and
uncertain resonances belong to methylene groups. The other
half are methyl groups (3) and methines (2).
Validation that these tiny subtraction differences are real and
not error again comes from the relevant mixture sample of
Kitching. The pentamethyldocosane mixture is again four
isomers, epimers at C16 (the relevant center) and C10.
Kitching assigned seven doubled peaks to C16 isomers, and
these are the same seven resonances that differ by ≥5 ppb in
our subtraction. Thus, Kitching again correctly identified the
peaks that differ in the natural product and its C16 epimer.
At 187 MHz, Kitching did not observe doubling of any of the
three peaks that differ by 3−5 ppb in our spectra. We suspect
that these differences are meaningful because they show up
reliably when subtracting the duplicate spectra recorded at 175
MHz. However, the final assignment ultimately comes back to
comparison with Kitching’s published spectra of the natural
product. He observed doubled peaks in 2 wherever chemical
shift differences were >5 ppb, so we used that level as the cutoff
for a reliable difference in further comparisons. This error level
is crucial; if it is raised to just 10 ppb (0.01 ppm), then the
spectra of 2 and 4 are identical.
In short, by comparing in step 1 the various new spectra of
samples 2 and 4, we proved that the samples had very similar
but not identical spectra and we deduced that differences >5 ppb
were meaningful for comparisons with published data lists.
Indeed, the spectra are so similar that even small differences in
sample temperatures (as low as 2−3 K) can complicate
comparisons because the magnitudes of temperature effects on
chemical shifts can exceed the actual differences (see below).
Moving to step 2, we compared the new 298 K spectra of 2
and 4 to Kitching’s spectrum for the natural product.5b First, we
ascertained that Kitching’s spectrum and ours were recorded at
the same temperature by comparing the group of 20 resonances
with the “same” chemical shifts. These resonances had the same
chemical shifts ( 2 ppb) in all three samples, so the natural
product spectrum was recorded at the same temperature as the
spectra of the two synthetic samples. These data were corrected
for small calibration errors (see Supporting Information),
though again the correction is not crucial to the outcome.9
Then in step 3 we compared the subtraction data for the
seven reliably different resonances, as shown in Table 3. The
results of subtractions NP − 2 and NP − 4 are shown in
columns 3 and 4. In NP − 2 all of the values are zero or nearly
Figure 5. Four 13C NMR data sets used to assign the
pentamethyldocosane.
there are data sets of the natural product and the four-isomer
mixture from Kitching.1 We also had the originally published
data sets for 2 and 4 at the time of communication.3 To
complete the assignment, we recorded eight new data sets on
the same two samples used for the original data sets.
To control for both temperature effects and inherent
reproducibility, we recorded four new 13C NMR spectra on
synthetic samples 2 and 4 (two each, 1 week apart) at 175 MHz
in CDCl3 with a nominal probe temperature of 298 K. These
data are fully tabulated in the Supporting Information alongside
those of the published spectra of isomers 2 and the natural
product. Comparing the spectra of the same samples recorded
1 week apart gave an idea of the random error of the
experiments, which was strikingly low. We could reproduce the
list of chemical shifts of each isomer to the level of about
1
ppb. To control for temperature, we also recorded duplicate
pairs of data sets at 293 K; again these were reproducible to the
level of about 1 ppb.
We work first with the new data sets at 298 K. The step 1
subtraction revealed that the differences between the candidate
isomers of 2 and 4 are considerably smaller than those of 1 and
3. Seven of the 27 resonances differed by 5−10 ppb, and these
“reliably different” resonances are shown in red adjacent to
their assigned carbon atoms in Figure 4 (bottom) and also
listed in Table 3. At the next level down, three additional
resonances in the “uncertain” group shown in green differed by
3−4 ppb. The remaining 17 resonances in the “same” set
differed by <2.5 ppb (most by <1.5 ppb).
As before, all of the resonances with the differences
exceeding 2.5 ppb belong to carbons within or between the
groups of stereocenters of 2, and none belongs to carbons on
either end of the long chain (Figure 4). This is sensible. The
largest difference of all, 10.3 ppb, belongs to C13, which is
halfway between the stereocenters at C10 and C16. This is the
same carbon that gave the largest difference in 1/3, but in that
pair of compounds the difference was about twice as large (+19
ppb). Also as before, the uncertain resonances are just to the
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zero; this is the match. In NP − 4, the values are very close to
the reliably different values established in step 1 (column 2);
this is the mismatch. Clearly the natural product is 2, not 4.
Accordingly, the hexa- and pentamethyldocosane natural
products 1 and 2 have the same configuration at C16.
Easy Assignment of the Docosanes by the Difference-
of-Differences Method. The usual way to compare spectra of
two very similar samples to an unknown that is presumed to
match one and not the other is to subtract pairs of the same
chemical shifts in different samples, as we did in Table 2. We have
previously suggested that subtraction of pairs of different
chemical shifts in the same sample from each other is also a
valuable tool.4d This tool is simple because the whole
assignment is reduced to comparison of one number from
each sample. Because two chemical shifts are subtracted, it gives
the largest possible ppb difference in the spectrum, and most
importantly, any calibration error cancels in the subtraction. So
this method works without standardization of the spectra being
compared.
comparing the “same” set of resonances in the original and new
spectra of 2 and 4; many of them are not the same.
To retrospectively estimate the sample temperature of the
published spectrum of 4, we recorded pairs of 13C NMR spectra
of both candidate isomers at 293 K (5 K lower sample
temperature), 1 week apart. Again, the spectra of the same
samples recorded 1 week apart were identical down to the 1−2
ppb level. The subtraction values for 4 are shown in Figure 6;
the values for 2 are very similar (see Supporting Information).
Figure 6. Differences in chemical shifts for spectra of 4 recorded with
sample temperatures 5 K apart. The values are listed as δ 298 K − δ
293 K in ppb.
In the 2/4 pair, the largest difference is obtained by
subtracting the resonance of C9 (the only resonance with a
negative value) from C13 (the resonance with the largest
positive value). This difference is 15.222 ppm for 2 and 15.240
for 4. The natural product difference is 15.222 ppm, matching
2.
Such subtractions of the absolute values give two large
numbers that when compared have a small difference. Because
only the difference is meaningful, it may be more convenient to
look at the difference of differences in values of the chemical
shifts. In other words, subtract the differences of C13−C9 in 2
and 4 from each other.19 At four decimal places: 15.2239 −
15.2215 = 0.0194 ppm, or 19.4 ppb. This is the mismatch
result, rounded to 19 ppb for comparison with the natural
product. As usual, the match result is zero. Now without any
standardization, subtracting the NP value from 2 gives −1 ppb
(match result) and subtracting the NP value from 4 gives 18
ppb (mismatch result).
Likewise, for hexamethyldocosane, the same two carbons
give an almost double difference of differences of 36 ppb.
Subtracting the natural product value from 1 gives 0 ppb
(match result) and subtracting the NP value from 3 gives 36
ppb (mismatch result).
Temperature Effects. When comparing pairs of spectra
with such tiny chemical shift differences, it is crucial to account
for possible differences in sample temperature. We show this by
comparing the newly recorded sets of spectra of 2 and 4 to the
original published spectra.3 As is common, these original
spectra were recorded at ambient temperature, without variable
temperature control.
By subtracting the chemical shifts obtained from the pairs of
new spectra at 293 and 298 K from each other, we learned that
21 of the 27 resonances of 4 shifted by ≥5 ppb (≥1 ppb K−1).
At 56 and 57 ppb (>10 ppb K−1), the resonances for C6 and
C8 exhibit the largest temperature effects. Notice that these
difference are more than 5 times larger than the largest real
difference (10 ppb) in the spectra of the two isomers shown in
Figure 4 and Table 2. Most of the other shifts were positive
(that is, downfield shift with increasing temperature), but the
two end methyl groups (C1 and C22) and one of the
methylene groups (C21) experienced small negative shifts.
These kinds of shifts are typical for other alkanes.4
In the published spectrum of 4, every one of the seven
resonances that did not vary with temperature matched the
corresponding resonances of the new spectra of 4 (within 2
ppb) at both 293 and 298 K, and the 20 temperature-
dependent resonances in the published spectrum fell roughly
40% of the way in between the corresponding resonances of the
new spectra at 293 and 298 K. This means that the published
spectrum of 4 must have been recorded at about 295 K. This
exercise shows how to estimate an unknown sample temper-
ature retrospectively given available candidate sample spectra.
To show the importance of temperature control in candidate
versus natural samples, consider the two deliberately mistaken
subtraction analyses in Figure 7 taken from the new data sets
The originally published spectrum of 2 matched the new
duplicate spectra at 298 K ( 2 ppb) almost as well as the
duplicate spectra matched each other ( 1 ppb). However, the
published spectrum of 4 did not match the new duplicate
spectra of 4 nearly as well as the duplicates matched each other.
Disconcertingly, according to the raw subtraction analysis
(subtract all chemical shifts and calculate a standard deviation),
the published spectrum of 4 is actually closer to the published
spectrum of the natural product than to the new spectra of the
same sample. This is disconcerting because 4 is not the natural
product.
Figure 7. Overwhelming effect of sample temperature. The scatter plot
for the wrong structure at the right temperature (red squares) looks
much better than the plot for the right structure at the wrong
temperature (blue diamonds). Wrong temp is NP (298 K) − 2 (293
K); wrong structure is NP (298 K) − 4 (298 K).
We deduced that the original sample temperature of isomer 2
matched the sample temperature of the new spectra of 2, while
the sample temperature of isomer 4 did not. This is evident by
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and the natural product set. Here we show the scatter plots
from raw subtraction (that is, the current standard method of
data analysis). The results when the new spectrum of 2
recorded at 293 K is subtracted from the NP spectrum at 298 K
are shown with the blue diamonds. This is the case where the
spectra of the correct candidate isomer and the natural product
are compared, but the spectra are recorded at different
temperatures (right structure, wrong temperature).
Now compare this to the subtraction of the wrong candidate
isomer 4 from the natural product with spectra recorded at
identical temperatures, shown with the red boxes. This is the
case where the temperature matches, but the structures do not
(right temperature, wrong structure). By any measure (peak-by-
peak comparison of differences, average difference, standard
deviation), the second pair of spectra (red boxes) “match”
better than the first pair (blue diamonds). In other words, the
usual raw subtraction process assigns the wrong structure to the
natural product because it fails to account for the temperature
effects. Chemical shift differences as a function of temperature
are not random errors and therefore cannot be expected to
cancel in any raw subtraction analysis.
and therefore reliable. NMR probes around the world probably
have ambient temperatures in the range of at least 293−303 K,
a 10 K range. Over this range, the temperature dependence of
13C resonances can change chemical shifts by over 100 ppb
( 0.1 ppm). When spectra recorded at different sample
temperatures are subtracted, real temperature effects (which
are not random) are easily mistaken for random error.
Conservatively, then, whenever chemical shift differences
between candidate and natural product spectra are less than
about 500−1,000 ppb ( 0.5−1 ppm), the sample temper-
ature needs to be accounted for in comparisons.
Given the advantages over the standard raw subtraction
analysis, we suggest that this systematic process should become
standard practice for assignment in cases where two (or more)
candidate structures for a natural product can reasonably be
expected to have very similar or identical spectra.
Finally, we caution that both (or all) of the candidate
samples have to be made for the secure assignment. One
cannot simply make and then match one candidate to the
natural product structure. This is an uncontrolled process. How
do we know which resonances are the same or reliably different
if we do not know whether the candidate and the natural
product are the same or different? Only by circular reasoning.
The spectra of 2 and 4 in this work, for example, easily “match”
the relevant natural product spectrum when compared to it in
isolation (see the “wrong” structure in Figure 7). Only when
the other candidates 1 and 3 are introduced does it become
clear that 2 and 4 are the mismatches and 1 and 3 are the
matches.
CONCLUSIONS
■
In summary, we have postulated, validated, and then applied a
systematic process for comparing 13C NMR spectra of two (or
more) candidate samples of known structure with the spectrum
of another compound of unknown structure (for example, a
natural product). The process is designed for cases where the
spectra of the candidates are very similar, perhaps even
identical. In such cases, raw subtraction with scatter plot
visualization is the current standard for assignment. This
method always come down on the side of one candidate or the
other. Indeed, even if the candidate samples have identical
spectra, an assignment will still result simply because of error.
Accordingly, when spectra are similar, there is a low level of
confidence that an assignment by the raw subtraction method is
correct.
As we have stated previously,4d assigning structures by proof
has the same pitfalls as proving mechanisms. In formal logic, a
structure (or mechanism) can only be disproved, never proved.
The final proof comes from disproof of all sensible structure
candidates (or mechanism candidates) but one.
EXPERIMENTAL SECTION
■
(3S)-1-tert-Butyldimethylsilyloxy-3,7-dimethyloct-6-ene 6.11
Imidazole (479 mg, 7.0 mmol) was added to (S)-citronellol 5 (1.0 g,
6.4 mmol) in THF (25 mL), and the solution stirred at ambient
temperature for 10 min before tert-butyldimethylsilyl chloride (1.06 g,
7.0 mmol) was added. The reaction mixture was stirred at room
temperature for 16 h, diluted with ether (25 mL) and partitioned
between ether (20 mL) and saturated aqueous sodium hydrogen
carbonate. The organic layer was washed with brine (20 mL) and dried
(Na2SO4). After concentration under reduced pressure, chromatog-
raphy of the residue eluting with light petroleum (100%) gave the title
compound 611 (1.7 g, 98%) as a colorless oil, Rf 0.3 (100% light
petroleum), [α]20D −1.7 (c 0.2 in CHCl3); lit.11 value: [α]20D −1.42 (c
1.01 in CHCl3) (found: M+ − C4H9, 213.1675. C12H25OSi requires M,
231.1669); νmax 1462, 1377, 1361, 1254, 1094, 987, 897, 833, and 773
cm−1; δH (500 MHz, CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.82 (3 H, d, J
7, 3-CH3), 0.85 [9 H, s, SiC(CH3)3], 1.11 (1 H, m, 3-H), 1.24−1.32
and 1.51 (each 2 H, m, 4-H2 or 5-H2), 1.55 and 1.63 (each 3 H, s, 8-H3
or 7-CH3), 1.85−1.99 (2 H, m, 2-H2), 3.60 (2 H, m, 1-H2) and 5.04 (1
H, t, J 6.9, 6-H); δC (125 MHz, CDCl3) −5.3, −5.2, 17.7, 18.4, 19.6,
25.5, 25.8, 26.0, 29.1, 37.2, 39.9, 61.5, 124.9 and 131.1; m/z (EI) 213
(M+ − 57, 100%).
In the new method, the spectra of the candidates are first
compared to each other to firmly establish that they are
different and then to articulate the differences. These
differences should be sensible based on the structures being
compared. Next, a subset of the resonances (the “same” group)
is used to standardize the natural product spectrum to the
candidate spectra and to determine whether sample temper-
atures of the spectra are the same. Finally, another subset of
resonances (the “reliably different” group) is used to assign the
structure of the natural product.
The assignment does not rely on a statistical analysis such as
determination of a standard deviation. Instead, all of the key
resonances of the natural product are expected to match one
candidate isomer and not to match the other. The result is both
an assignment of the natural product structure and a high level
of confidence that the assignment is correct. The method
reveals differences that are comparable to those revealed by
recording spectra of mixed samples, a gold-standard process
that is rarely practical either because no natural sample is
available or because the synthetic and natural samples are
simply too precious to mix.
(4S)-6-tert-Butyldimethylsilyloxy-4-methylhexan-1-ol 7.12
Ozone from a generator was bubbled through a solution of the
alkene 6 (1.3 g, 4.8 mmol) in dichloromethane and methanol (1:1; 30
mL) at −78 °C for approximately 2 h until the solution turned blue.
Oxygen was then bubbled through the solution at −78 °C until the
blue color disappeared. Solid sodium borohydride (910 mg, 24 mmol)
was added at −78 °C, and the reaction mixture was allowed to warm
to room temperature and stirred for 3 h. After concentration under
reduced pressure, the residue was partitioned between saturated
The spectra compared in this work have real differences of
only 5−20 ppb. Such small differences are not usually
considered meaningful and are typically ascribed to random
error. However, provided that sample temperature differences
are corrected for, these small differences are demonstrably real
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aqueous sodium hydrogen carbonate (20 mL) and ether (30 mL). The
organic layer was washed with brine (20 mL), dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the residue
eluting with light petroleum/ether (4:1) gave the title compound 712
(1.7 g, 98%) as a colorless oil, Rf 0.5 (1:1 light petroleum/ether),
suspended in a solution of bismuth(III) iodide (637 mg, 1.08 mmol)
in THF (4 mL), and the mixture was stirred vigorously at room
temperature for 1 h during which time the orange/gray suspension
turned black. The 5-benzyloxy-2,4-dimethylpent-2-enyl bromide 109a
(102 mg, 0.36 mmol) and the 3-methylhexanal 9 in THF (2 mL) were
added, and the reaction mixture was stirred under reflux for 2 h. After
cooling to room temperature, the mixture was concentrated under
reduced pressure to give a black slurry. Chromatography of this
residue eluting with light petroleum/ether (7:3) gave the title
compound 11 (67 mg, 60%) as a colorless oil, containing ca. 5% of
its (6R)-epimer 15 (1H, 13C NMR) and other minor components (up
[α]20 +1.2 (c 0.2 in CHCl3) (found: M+, 247.2090. C13H31O2Si
D
requires M, 247.2088); νmax 3325, 1462, 1387, 1361, 1253, 1093, 1006,
938, 896, 833, and 773 cm−1; δH (500 MHz, CDCl3) 0.00 (6 H, s, 2 ×
SiCH3), 0.84 [9 H, s, SiC(CH3)3], 0.86 (3 H, d, J 7.0, 4-CH3), 1.14 (1
H, m, 4-H), 1.30 (2 H, m, 3-H2), 1.53 (4 H, m, 2-H2 and 5-H2) and
3.59 (4 H, m, 1-H2, 6-H2); δC (100 MHz, CDCl3) −5.2, 18.4, 19.7,
26.0, 29.3, 30.3, 33.0, 39.9, 61.4 and 63.4; m/z (ES+) 269 (M+ + 23,
100%) and 247 (M+ + 1, 60).
to 5%), Rf 0.5 (7:3 light petroleum/ether), [α]20 −6.7 (c 0.2 in
D
CHCl3) (found: M+ + Na, 341.2453. C21H34O2Na requires M,
341.2452); νmax 3436, 1454, 1378, 1273, 1205, 1089, 1028, 901, 832,
and 735 cm−1; δH (400 MHz, CDCl3) major epimer 11 0.82 (6 H, m,
8-CH3 and 11-H3), 0.88 (3 H, d, J 7.0, 2-CH3), 1.09 (1 H, m, 7-H),
1.19−1.29 (5 H, m, 8-H, 9-H2 and 10-H2), 1.41 (1 H, m, 7-H′), 1.60
(3 H, s, 4-CH3), 1.75 (1 H, br. s, OH), 1.86 (1 H, dd, J 12.8 and 10.0,
5-H), 2.11 (1 H, dd, J 12.8 and 7.2, 5-H′), 2.69 (1 H, m, 2-H), 3.15 (1
H, dd, J 9.1 and 7.8, 1-H), 3.23 (1 H, dd, J 9.1 and 7.3, 1-H′), 3.63 (1
H, m, 6-H), 4.40 and 4.43 (each 1 H, d, J 12, OHCHPh), 4.97 (1 H, d,
J 8.9, 3-H) and 7.25 (5 H, m, ArH); minor epimer 15 0.92 (3 H, d, J
6.5, 2-CH3), 1.94 (1 H, dd, J 13.6 and 9.1, 5-H) and 4.44 (2 H, s,
OCH2Ph); δC (100 MHz, CDCl3) major epimer 11 14.5, 16.5, 17.4,
20.0, 20.3, 29.5, 33.2, 39.1, 44.6, 48.5, 66.0, 73.0, 75.3, 127.5, 127.6,
128.4, 132.1, 132.6 and 138.5; minor epimer 15 29.1, 40.2, 48.8 and
65.6; m/z (ES+) 341 (M+ + 23, 100%).
(3S)-3-Methylhexan-1-ol 8.13 Iodine (4.21 g, 16.6 mmol) was
added portionwise to triphenylphosphine (4.33 g, 16.6 mmol),
imidazole (1.73 g, 25.4 mmol) and alcohol 7 (3.14 g, 12.7 mmol) in
dichloromethane (70 mL), and the mixture was stirred at room
temperature for 2 h. Saturated aqueous sodium sulfite (30 mL) and
ether (50 mL) were added, and the mixture was partitioned between
water and ether. The organic layer was washed with brine (50 mL),
dried (Na2SO4) and concentrated under reduced pressure. Chroma-
tography eluting with light petroleum gave (4S)-6-tert-butyldimethyl-
silyloxy-4-methyl-1-iodohexane (3.7 g, 82%) as a colorless oil, Rf 0.2
(light petroleum), [α]20 +3.6 (c 0.2 in CHCl3) (found: M+ − C4H9,
D
299.0308. C9H20IOSi requires M, 299.0323); νmax 1462, 1388, 1361,
1254, 1214, 1174, 1094, 1006, 939, 896, 832, and 772 cm−1; δH (500
MHz, CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.86 [9 H, s, SiC(CH3)3],
0.86 (3 H, d, J 7.0, 4-CH3), 1.20 (1 H, m, 4-H), 1.31 (2 H, m, 3-H2),
1.52 (2 H, m, 2-H2), 1.79 (2 H, m, 5-H2), 3.12 (2 H, m, 1-H2) and
3.58 (2 H, m, 6-H2); δC (125 MHz, CDCl3) −5.3(2), 7.5, 18.3, 19.6,
26.0, 28.7, 31.2, 37.9, 39.7 and 61.4; m/z (EI) 299 (M+ − 57, 5%). A
portion of this iodide (3.0 g, 8.4 mmol) was dissolved in THF (40
mL), potassium tert-butoxide (2.9 g, 25 mmol) was added, and the
reaction mixture was stirred at room temperature for 16 h. The
reaction mixture was partitioned between water (70 mL) and ether.
The organic layer was washed with brine (50 mL), dried (Na2SO4)
and concentrated under reduced pressure to yield a colorless oil
identified as (4S)-6-tert-butyldimethylsilyloxy-4-methylhex-1-ene.
Without purification, this alkene was dissolved in THF (30 mL),
and aqueous hydrogen chloride (4 M; 2.2 mL, 9.0 mmol) was added.
The reaction mixture was stirred at room temperature for 3 h,
neutralized using aqueous sodium hydrogen carbonate and partitioned
between saturated sodium hydrogen carbonate (50 mL) and ether.
The organic layer was washed with brine (40 mL), dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of the
residue eluting with petrol/ether (1:1) gave (3S)-3-methylhex-5-en-1-
ol as a colorless oil. This alkene was dissolved in THF (20 mL) and
Pd/C (10% Pd by weight; 150 mg) was added. The reaction mixture
was stirred under an atmosphere of hydrogen at room temperature for
16 h. The suspension was then filtered, and the filtrate was
concentrated under reduced pressure to give the title compound 813
(1.88 g, 60% overall yield) as a colorless oil, Rf 0.5 (1:1 light
petroleum/ether), [α]20 −1.1 (c 0.2 in CHCl3) lit.13 value: [α]20
(3E,2R,6R,8S)-1-Benzyloxy-2,4,8-trimethylundec-3-en-6-ol
15. Di-isopropyl diazodicarboxylate (51 mg, 0.25 mmol) was added to
a suspension of alcohol 11 (40 mg, 0.13 mmol), 4-nitrobenzoic acid
(32 mg, 0.19 mmol) and Ph3P (66 mg, 0.25 mmol) in THF at room
temperature, and the reaction mixture was stirred at room temperature
for 16 h. After concentration under reduced pressure, chromatography
of the residue eluting with light petroleum/ether (90:10) gave the 4-
nitrobenzoate 14 (41 mg, 70%) as a colorless oil, Rf 0.8 (4:1 light
petroleum/ether); δH (400 MHz, CDCl3) 0.60 (3 H, d, J 6.8, 8-CH3),
0.79 (3 H, t, J 7.3, 11-H3), 0.84 (3 H, d, J 6.6, 2-CH3), 1.00−1.33 (6 H,
m, 7-H2, 9-H2 and 10-H2), 1.64 (3 H, s, 4-CH3), 1.70 (1 H, m, 8-H),
2.00−2.40 (2 H, m, 5-H2), 2.56 (1 H, m, 2-H), 3.14 (2 H, m, 1-H2),
4.39 (2 H, s, OCH2Ph), 4.91 (1 H, d, J 9.3, 3-H), 5.34 (1 H, m, 6-H),
7.23 (5 H, m, ArH), 8.10 (2 H, d, J 8.6, ArH) and 8.19 (2 H, d, J 9.1,
ArH).
The ester 14 (41 mg, 0.09 mmol) was dissolved in THF (1.5 mL),
and aqueous sodium hydroxide (2 N; 1 mL) was added. The reaction
mixture was stirred at 50 °C for 1 h then concentrated under reduced
pressure. Chromatography of the residue eluting with light petroleum/
ether (80:20) gave the title compound 15 (41 mg, 70%) as a colorless
oil containing ca. 5% of the (6S)-epimer 11 (1H and 13C NMR), Rf 0.5
(7:3 light petroleum/ether); δH (400 MHz, CDCl3) major epimer 15
0.80−0.84 (6 H, m, 8-CH3 and 11-H3), 0.92 (3 H, d, J 6.6, 2-CH3),
1.03−1.30 (6 H, m, 7-H2, 9-H2 and 10-H2), 1.39 (1 H, m, 8-H), 1.55
(1 H, br. s, OH), 1.61 (3 H, s, 4-CH3), 1.94 (1 H, dd, J 9.1 and 13.6, 5-
H), 2.08 (1 H, dd, J 4.3 and 13.4, 5-H′), 2.68 (1 H, m, 2-H), 3.23 (2
H, m, 1-H2), 3.70 (1 H, m, 6-H), 4.44 (2 H, s, OCH2Ph), 5.02 (1 H, d,
J 9.1, 3-H) and 7.26 (5 H, m, ArH); minor epimer 11 0.88 (3 H, d, J
7.0, 2-CH3) and 1.86 (1 H, dd, J 10.0 and 12.8, 5-H); δC (125 MHz,
CDCl3) major epimer 15 14.4, 16.6, 18.0, 19.3, 20.1, 29.1, 33.2, 40.2,
44.6, 48.8, 66.1, 73.0, 75.2, 127.5, 128.4, 131.8, 132.7 and 138.6; minor
epimer 11 29.5, 39.0, 48.3 and 66.5.
D
D
−0.94 (c 0.91, CHCl3) (found: M+ − H2O, 98.1087. C7H14 requires
M, 98.1090); νmax 3323, 1458, 1378, 1120, 1054, 1008, 960, 836, and
738 cm−1; δH (500 MHz, CDCl3) 0.78 (3 H, t, J 7.0, 6-H3), 0.80 (3 H,
d, J 6.8, 3-CH3), 1.03 (1 H, m, 3-H), 1.16−1.31 (4 H, m, 4-H2 and 5-
H2), 1.50 (2 H, m, 2-H2) and 3.59 (2 H, m, 1-H2); δC (125 MHz,
CDCl3) 14.4, 19.6, 20.0, 29.2, 39.4, 40.0 and 61.3; m/z (EI) 98 (M+ −
18, 10%).
(3E,2R,6S,8S)-2,4,8-Trimethylundec-3-ene-1,6-diol 12. Lith-
ium metal (12 mg, 1.7 mmol) was added in small pieces to
naphthalene (290 mg, 2.3 mmol) in THF (3 mL), and the reaction
mixture was stirred at room temperature until the lithium was
completely dissolved. The resulting dark green solution of lithium
naphthalenide was cooled to −25 °C, and the benzyl ether 11 (90 mg,
0.28 mmol) in THF (2 mL) was added. The reaction mixture was
stirred at −25 °C for 2 h, and saturated aqueous ammonium chloride
(5 mL) and water (5 mL) were added. The mixture was extracted with
ether, and the organic extract was washed with brine (10 mL), dried
(Na2SO4) and concentrated under reduced pressure. Chromatography
(3E,2R,6S,8S)-1-Benzyloxy-2,4,8-trimethylundec-3-en-6-ol
11. Sodium hydrogen carbonate (212 mg, 2.5 mmol) and Dess−
Martin periodinane (261 mg, 0.62 mmol) were added to the alcohol 8
(63 mg, 0.54 mmol) in dichloromethane (5 mL), and the reaction
mixture was stirred at room temperature for 30 min. Saturated
aqueous sodium hydrogen carbonate (4 mL) and sodium bisulfite (4
mL) were added, and the mixture was extracted with dichloromethane
(2 × 10 mL). The organic extract was washed with brine (15 mL),
dried (Na2SO4) and concentrated under reduced pressure to yield
(3S)-3-methylhexanal 9. Zinc powder (80 mg, 1.22 mmol) was
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Article
of the residue eluting with light petroleum/ether (20:80) gave the title
oil, Rf 0.8 (4:1 light petroleum/ether), [α]20 +3.2 (c 0.2 in CHCl3)
D
compound 12 (50 mg, 78%) as a colorless gum, Rf 0.3 (3:7 light
(found: M+ + H, 541.3738. C30H57O4SSi requires M, 541.3741); νmax
1598, 1462, 1362, 1186, 1175, 1096, 1067, 920, 880, 813, 760, and 679
cm−1; δH (400 MHz, CDCl3) 0.72−0.77 (12 H, m, 2-CH3, 4-CH3, 8-
CH3 and 11-H3), 0.98 [21 H, m, 3 × OSiCH(CH3)2], 1.04−1.21 (5 H,
m, 8-H, 9-H2 and 10-H2), 1.27−1.49 (7 H, m, 3-H2, 4-H, 5-H2 and 7-
H2), 1.58 (1 H, m, 2-H), 2.37 (3 H, s, ArCH3), 3.37 (2 H, d, J 6.0, 1-
H2), 4.64 (1 H, m, 6-H), 7.25 (2 H, d, J 7.9, ArH) and 7.72 (2 H, d, J
7.8, ArH); δC (100 MHz, CDCl3) 11.0, 13.2, 15.2, 17.0, 18.5, 18.8,
20.6, 25.6, 27.9, 32.3, 37.7, 39.5, 41.2, 42.3, 68.2, 80.7, 126.7, 128.6,
133.9 and 143.3; m/z (ES+) 563 (M+ + 23, 100%).
petroleum/ether), [α]20 +26.7 (c 0.4 in CHCl3) (found: M+ + Na,
D
251.1983. C14H28O2Na requires M, 251.1982); νmax 3308, 1455, 1378,
1072, 1031, 831, and 739 cm−1; δH (400 MHz, CDCl3) 0.81−0.88 (9
H, m, 2-CH3, 8-CH3 and 11-H3), 0.95−1.30 (6 H, m, 7-H2, 9-H2 and
10-H2), 1.55 (1 H, m, 8-H), 1.57 (3 H, s, 4-CH3), 1.90 (3 H, m, 5-H
and 2 × OH), 2.09 (1 H, dd, J 12.7 and 3.3, 5-H′), 2.60 (1 H, m, 2-H),
3.23 (1 H, dd, J 9.8 and 8.6, 1-H), 3.47 (1 H, dd, J 9.8 and 6.2, 1-H′),
3.72 (1 H, m, 6-H) and 4.91 (1 H, d, J 9.0, 3-H); δC (100 MHz,
CDCl3) 14.4, 16.6, 16.7, 20.0, 20.3, 29.5, 35.4, 39.1, 45.0, 48.5, 66.4,
67.8, 131.2 and 134.2; m/z (ES+) 251 (M+ + 23, 100%).
(2R,4S,6R,8S)-2,4,6,8-Tetramethyl-1-tri-isopropylsilyloxyun-
decane 19. Copper(I) iodide (224 mg, 1.18 mmol) was placed in a
round-bottom flask. The flask was evacuated and purged with nitrogen
three times. Tetrahydrofuran (2 mL) was added followed by methyl
lithium·lithium iodide complex (1.6 M, 1.3 mL, 2.13 mmol) at 0 °C to
produce a clear solution. The toluene p-sulfonate 17 (64 mg, 0.12
mmol) in THF (1 mL) was added. The reaction mixture was stirred at
0 °C for 1 h, allowed to warm to room temperature and then stirred
for 16 h. Saturated aqueous ammonium chloride (10 mL) was added,
and the mixture filtered through a pad of Celite then partitioned
between water and ether. The organic layer was washed with brine (10
mL), dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue eluting with light petroleum (100%)
gave the title compound 19 (10 mg, 21%) as a colorless oil, Rf 0.7
(3E,2R,6S,8S)-2,4,8-Trimethyl-1-tri-isopropylsilyloxyundec-
3-en-6-ol 13. Imidazole (75 mg, 1.1 mmol) was added to the diol 12
(50 mg, 0.22 mmol) in THF (4 mL), and after 10 min, tri-
isopropylsilyl chloride (51 mg, 0.24 mmol) was added at 0 °C. The
reaction mixture was stirred at room temperature for 16 h then
concentrated under reduced pressure. Chromatography of the residue
eluting with light petroleum/ether (4:1) gave the title compound 13
(80 mg, 94%) as a colorless oil, Rf 0.7 (4:1 light petroleum/ether),
[α]20 +9.6 (c 0.2 in CHCl3) (found: M+ + H, 385.3503. C23H49O2Si
D
requires M, 385.3496); νmax 1461, 1381, 1089, 1065, 1013, 995, 881,
785, 680, and 658 cm−1; δH (400 MHz, CDCl3) 0.83 (6 H, m, 8-CH3
and 11-H3), 0.87 (3 H, d, J 7, 2-CH3), 0.98 [21 H, m, 3 ×
OSiCH(CH3)2], 1.10−1.35 (6 H, m, 7-H2, 9-H2 and 10-H2), 1.54 (1
H, m, 8-H), 1.61 (3 H, s, 4-CH3), 1.86 (1 H, dd, J 12.8 and 9.8, 5-H),
1.88 (1 H, s, OH), 2.10 (1 H, dd, J 12.8 and 3.2, 5-H′), 2.54 (1 H, m,
2-H), 3.37 and 3.42 (each 1 H, dd, J 6.9 and 9.2, 1-H), 3.64 (1 H, m, 6-
H) and 4.96 (1 H, d, J 9.1, 3-H); δC (100 MHz, CDCl3) 12.0, 14.4,
16.6, 17.0, 18.0, 20.0, 20.2, 29.5, 35.8, 39.1, 44.4, 48.5, 66.0, 68.4, 132.1
and 132.4; m/z (ES+) 407 (M+ + 23, 100%).
(100% petrol), [α]20 +14.7 (c 0.2 in CHCl3) (found: M+ − C3H7,
D
341.3229. C21H45OSi requires M, 341.3234); νmax 1461, 1378, 1098,
1067, 1012, 994, 918, 881, and 783 cm−1; δH (500 MHz, CDCl3) 0.74
(9 H, m, 3 × CH3), 0.82 (6 H, m, 2 × CH3), 0.99 [21 H, m, 3 ×
OSiCH(CH3)2], 0.95−1.28 (8 H, m, 6-H, 7-H2, 8-H, 9-H2 and 10-H2),
1.42 (1 H, m, 4-H), 1.48−1.54 (4 H, m, 3-H2 and 5-H2), 1.64 (1 H, m,
2-H), 3.35 (1 H, dd, J 6.2 and 9.3, 1-H) and 3.45 (1H, dd, J 6.2 and
9.3, 1-H′); δC (100 MHz, CDCl3) 11.0, 13.4, 15.8, 17.1, 18.5(2), 18.6,
19.1, 26.2, 26.3, 28.7, 32.5, 39.2, 40.4, 44.5, 45.6 and 68.2; m/z (EI)
341 (M+ − 43, 100%).
(2R,4R,6S,8S)- and (2R,4S,6S,8S)-2,4,8-Trimethyl-1-tri-isopro-
pylsilyloxyundecan-6-ol 16 and 18. The alkene 13 (80 mg, 0.21
mmol) followed by [Rh(NBD)Diphos-4]BF4 (7.5 mg, 0.01 mmol)
and DCM (3 mL) were added to a boiling tube with stirrer bar, and
the tube was placed inside a steel screw-cap high pressure bomb. The
pressure gauge block was attached, and the bomb was flushed three
times with hydrogen and then filled with hydrogen to 950 psi. The
reaction mixture was stirred at room temperature for 5 h then
concentrated under reduced pressure. Chromatography of the residue
eluting with light petroleum/ether (4:1) gave the title compound 18
(15 mg, 16%) as a colorless oil, Rf 0.5 (4:1 light petroleum/ether),
[α]20D +4.2 (c 0.2 in CHCl3) νmax 3351, 1462, 1380, 1100, 1067, 1013,
996, 882, 787, 680, and 658 cm−1; δH (500 MHz, CDCl3) 0.81−0.86
(12 H, m, 2-CH3, 4-CH3, 8-CH3 and 11-H3), 0.99 [21 H, m, 3 ×
OSiCH(CH3)2], 1.04−1.33 (10 H, m, 3-H2, 5-H2, 7-H2, 9-H2, and 10-
H2), 1.50 (1 H, m, 8-H), 1.62−1.72 (2 H, m, 2-H and 4-H), 3.36 (1 H,
dd, J 6.6 and 9.5, 1-H), 3.47 (1 H, dd, J 5.7 and 9.5, 1-H′) and 3.73 (1
H, m, 6-H); δC (100 MHz, CDCl3) 12.0, 14.4, 17.5, 18.1, 20.0, 20.2,
26.6, 29.4, 33.4, 39.1, 42.0, 44.9, 46.2, 67.6 and 68.7; m/z (ES+) 409
(M+ + 23, 100%). The second fraction was the title compound 16 (61
(2R,4S,6R,8S)-2,4,6,8-Tetramethylundecan-1-ol 20.2b The
silyl ether 19 (75 mg, 0.19 mmol) was dissolved in THF (2 mL),
aqueous hydrogen chloride (4 M, 0.24 mL, 0.96 mmol) in dioxane was
added, and the mixture was stirred at room temperature for 16 h. The
mixture was concentrated under reduced pressure, and chromatog-
raphy of the residue eluting with light petroleum/ether (7:3) gave the
title compound 202b (40 mg, 91%) as a colorless oil, Rf 0.5 (60:40 light
petroleum/ether), [α]20 +30 (c 0.2 in CHCl3), lit.2b value: [α]20
D
D
+22.7 (c 1.01 in CHCl3) (found: M+ − H2O, 210.2342. C15H30
requires M, 210.2342); νmax 3335, 1463, 1379, 1037, 812, and 735
cm−1; δH (400 MHz, CDCl3) 0.72 (3 H, d, J 7.0, CH3), 0.75 (6 H, d, J
7.0, 2 × CH3), 0.80 (3 H, t, J 6.5, 11-H3), 0.85 (3 H, d, J 6.5, 2-CH3),
0.89−1.28 (10 H, m, 5-H2, 6-H, 7-H2, 8-H, 9-H2 and 10-H2), 1.41 (1
H, m, 4-H), 1.48−1.56 (2 H, m, 3-H2), 1.66 (1 H, m, 2-H), 3.35 (1 H,
m, 1-H) and 3.40 (1 H, m, 1-H′); δC (100 MHz, CDCl3) 14.4, 16.8,
19.5(2), 19.6, 20.1, 27.3(2), 29.7, 33.5, 40.3, 41.5, 45.6, 46.6 and 69.2.
(2R,4S,6R,8S)-2,4,6,8-Tetramethylundecyl Toluene p-Sulfo-
nate 21. Toluene p-sulfonyl chloride 20 (25 mg, 0.13 mmol) and
DMAP (19 mg, 0.15 mmol) were added to the alcohol 20 (20 mg,
0.088 mmol) in dichloromethane (2 mL), and the mixture was stirred
at room temperature for 16 h. The reaction mixture was concentrated
under reduced pressure, and chromatography of the residue eluting
with light petroleum/ether (4:1) gave the title compound 21 (28 mg,
mg, 70%) as a colorless oil, Rf 0.45 (4:1 light petroleum/ether), [α]20
D
+7.8 (c 0.2 in CHCl3) (found: M+ + Na, 409.3486. C23H50O2SiNa
requires M, 409.3473); νmax 3325, 1461, 1379, 1245, 1100, 1067, 1012,
995, 918, 881, 784, 679, and 658 cm−1; δH (400 MHz, CDCl3) 0.81−
0.84 (12 H, m, 2-CH3, 4-CH3, 8-CH3 and 11-H3), 0.99 [21 H, m, 3 ×
OSiCH(CH3)2], 1.05−1.35 (10 H, m, 3-H2, 5-H2, 7-H2, 9-H2 and 10-
H2), 1.40 (1 H, br. s, OH), 1.53 (1 H, m, 8-H), 1.61−1.70 (2 H, m, 2-
H and 4-H), 3.38 (1 H, dd, J 9.8 and 6.1, 1-H), 3.43 (1 H, dd, J 9.8 and
6.1, 1-H′) and 3.73 (1 H, m, 6-H); δC (100 MHz, CDCl3) 12.0, 14.4,
16.4, 18.1, 19.2, 20.0, 20.4, 26.8, 29.3, 33.5, 38.9, 40.4, 45.8, 46.6, 67.9
and 69.4; m/z (ES+) 409 (M+ + 23, 100%).
85%) as a colorless oil, Rf 0.7 (80:20 light petroleum/ether), [α]20
D
+9.5 (c 0.2 in CHCl3) (found: M+ + Na, 405.2433. C22H38O3NaS
requires M, 405.2434); νmax 1596, 1458, 1360, 1188, 1174, 1098, 962,
812, 665, and 654 cm−1; δH (400 MHz, CDCl3) 0.65, 0.68, 0.74, and
0.77 (each 3 H, d, J 7.0, 2-CH3, 4-CH3, 6-CH3 or 8-CH3), 0.80 (3 H, t,
J 7.3, 11-H3), 0.86−1.45 (13 H, m, 3-H2, 4-H, 5-H2, 6-H, 7-H2, 8-H, 9-
H2 and 10-H2), 1.78 (1 H, m, 2-H), 2.38 (3 H, s, ArCH3), 3.72 (1 H,
dd, J 6.8 and 9.3, 1-H), 3.77 (1 H, dd, J 5.8 and 9.3 1-H′), 7.25 (2 H, d,
J 7.8, ArH) and 7.72 (2 H, d, J 8.3, ArH); δC (100 MHz, CDCl3) 14.4,
16.4, 19.2, 19.4, 19.6, 20.1, 21.7, 27.0, 27.2, 29.7, 30.3, 40.2, 40.8, 45.5,
46.1, 75.8, 127.9, 129.8, 133.2 and 144.6; m/z (ES+) 405 (M+ + 23,
100%).
(2R,4R,6S,8S)-2,4,8-Trimethyl-1-tri-isopropylsilyloxyunde-
can-6-yl Toluene p-Sulfonate 17. Toluene p-sulfonyl chloride (205
mg, 1.1 mmol) and 4-dimethylaminopyridine (202 mg, 1.65 mmol)
were added to the alcohol 16 (143 mg, 0.37 mmol) in dichloro-
methane (4 mL) at room temperature, and the reaction was stirred at
room temperature for 16 h. After concentration under reduced
pressure, chromatography of the residue eluting with light petroleum/
ether (4:1) gave the title compound 17 (185 mg, 93%) as a colorless
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(2R,4S,6R,8S)-1-Iodo-2,4,6,8-tetramethylundecane 22. So-
dium iodide (22 mg, 0.15 mmol) was added to the toluene p-
sulfonate 21 (28 mg, 0.07 mmol) in acetone (2 mL), and the mixture
was stirred under reflux for 16 h. The mixture was then partitioned
between hexane and water, and the organic layer was washed with
brine (10 mL), dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with light petroleum
(100%) gave the title compound 22 (21 mg, 90%) as a colorless oil, Rf
0.8 (100% light petroleum), [α]20D +12 (c 0.2 in CHCl3) (found: M+,
338.1462. C15H31I requires M, 338.1465); νmax 1457, 1378, 1193, 962,
816, and 739 cm−1; δH (500 MHz, CDCl3) 0.73 (9 H, m, 3 × CH3),
0.82 (3 H, t, J 7.0, 11-H3), 0.90 (3 H, d, J 6.5, 2-CH3), 0.92−1.28 (11
H, m, 4-H, 5-H2, 6-H, 7-H2, 8-H, 9-H2 and 10-H2), 1.41 (1 H, m, 2-
H), 1.49 (2 H, m, 3-H2), 3.07 (1 H, dd, J 3.2 and 9.5, 1-H) and 3.15 (1
H, dd, J 4.7 and 9.5, 1-H′); δC (125 MHz, CDCl3) 14.4, 18.8, 19.5(2),
19.6, 20.1, 20.4, 27.2, 27.5, 29.7, 32.3, 40.2, 44.8, 45.5 and 46.0; m/z
(EI) 338 (M+, 5%).
became colorless. Sodium borohydride (250 mg, 6.61 mmol) was
added, and the mixture allowed to warm to room temperature and
stirred for 16 h. The mixture was partitioned between ether (20 mL)
and brine (20 mL), and the organic layer washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. Chromatography
of the residue eluting with light petroleum/ether (1:4) gave the title
compound 25 (364 mg, 85%) as a colorless oil, as a 50:50 mixture of
7-epimers (1H and 13C NMR), Rf 0.4 (4:1 light petroleum/ether),
[α]20 −2.9 (c 0.2 in CHCl3) (found: M+ + H, 313.1833. C17H29O3S
D
requires M, 313.1832); νmax 3394, 1447, 1380, 1286, 1141, 1083, 758,
726, and 691 cm−1; δH (500 MHz, CDCl3) 0.75 (1.5 H, d, J 6.9, 4-
CH3), 0.78 (1.5 H, d, J 5.0, 4-CH3), 0.80 (3 H, t, J 7.6, 10-H3), 1.02−
1.58 (11 H, m, 3-H2, 4-H, 5-H2, 6-H2, 8-H2 and 9-H2), 1.71−1.83 (2
H, m, 2-H2), 2.81 (1 H, m, 7-H), 3.54 (2 H, t, J 6.6, 1-H2), 7.50 (2 H,
t, J 7.5, ArH), 7.59 (1 H, t, J 7.5, ArH) and 7.82 (2 H, d, J 7.5, ArH);
δC (100 MHz, CDCl3) 14.0(2), 15.3, 19.3, 19.4, 20.1, 25.4, 29.9,
30.1(2), 32.5, 32.7, 33.8, 33.9, 63.2, 64.6(2), 65.9, 128.8, 129.1, 133.5
and 138.2; m/z (ES+) 335 (M+ + 23, 100%).
(R)- and (S)-8-Iodo-2,6-dimethyloct-2-ene (R)-23 and (S)-
23.16 Sodium iodide (1.83 g, 12.2 mmol) was added to the toluene p-
sulfonate ester of (R)-citronellol20 (1.90 g, 6.1 mmol) in acetone (15
mL). The reaction mixture was stirred under reflux for 16 h then
concentrated under reduced pressure and partitioned between hexane
(30 mL) and aqueous Na2SO3 (15 mL). The organic layer was washed
with brine (20 mL), dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with light petroleum
gave the title compound (R)-2316a (1.44 g, 90%), as a colorless oil, Rf
(S)- and (R)-4-Methyldecan-1-ol (S)-26 and (R)-26.17 Sodium
amalgam (10%; 10.0 g, 34.6 mmol) was added to the sulfone 25 (360
mg, 1.15 mmol) in anhydrous methanol (30 mL), and the mixture was
stirred at room temperature for 16 h. The solution was transferred to
another flask and concentrated under reduced pressure. The residue
was partitioned between saturated aqueous ammonium chloride (40
mL) and ether (40 mL). The organic layer was washed with brine (20
mL), dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue eluting with light petroleum/ether
(4:1) gave the title compound (S)-26 (143 mg, 73%) as a colorless oil,
Rf 0.6 (1:1 light petroleum/ether), [α]20D −3.9 (c 0.3 in CHCl3) lit.17
0.8 (light petroleum), [α]20 −5.2 (c 1.0 in CHCl3) lit.16a value:
D
[α]20 −14.34 (neat) (found: M+, 266.0533. C10H19I requires M,
D
266.0526); νmax 1449, 1377, 1178, 984, 826, and 733 cm−1; δH (400
MHz, CDCl3) 0.82 (3 H, d, J 6.6, 6-CH3), 1.11 (1 H, m, 5-H), 1.27 (1
H, m, 5-H′), 1.49 (1 H, m, 4-H), 1.54 (3 H, s, 2-CH3 or 1-H3), 1.59 (1
H, m, 4-H′), 1.62 (3 H, s, 2-CH3 or 1-H3), 1.83 (1 H, m, 6-H), 1.93 (2
H, m, 7-H2), 3.11 (1 H, m, 8-H), 3.19 (1 H, m, 8-H′) and 5.02 (1 H,
m, 3-H); δC (100 MHz, CDCl3) 5.3, 17.7, 18.7, 25.3, 25.7, 33.6, 36.3,
40.9, 124.5 and 131.5.
value: [α]20 −1.1 (c 5.33 in CHCl3) (found: M+ − H2O, 154.1723.
D
C11H22 requires M, 154.1716); νmax 3314, 1459, 1378, 1057, 898, and
723 cm−1; δH (400 MHz, CDCl3) 0.80 (3 H, d, J 6.6, 4-CH3), 0.81 (3
H, t, J 6.6, 10-H3), 1.01−1.60 (15 H, m, 2-H2, 3-H2, 4-H, 5-H2, 6-H2,
7-H2, 8-H2 and 9-H2) and 3.59 (2 H, t, J 6.8, 1-H2); δC (100 MHz,
CDCl3) 14.1, 19.7, 22.7, 27.0, 29.7, 30.4, 32.0, 32.6, 33.0, 37.0 and
63.5; m/z (EI) 154 (M+ − 18, 5%), 126 (20) and 91 (100).
The same procedure using sodium iodide (2.7 g, 18.3 mmol) and
the toluene p-sulfonate ester of (S)-citronellol21 (2.9 g, 9.2 mmol)
gave the title compound (S)-2316b (2.21 g, 92%), Rf 0.8 (light
The same procedure using the sulfone 32 (540 mg, 1.73 mmol)
gave the title compound (R)-26 (206 mg, 70%), Rf 0.6 (1:1 light
petroleum), [α]20 +7.6 (c 0.6 in CHCl3) (found: M+, 266.0534.
petroleum/ether), [α]20 +4.7 (c 0.3 in CHCl3) (found: M+ − H2O,
D
D
C10H19I requires M, 266.0526), with spectroscopic data identical to
those of the (R)-enantiomer.
154.1714. C11H22 requires M, 154.1716), with spectroscopic data
identical to those of the (S)-enantiomer.
(7R,4RS)-7,11-Dimethyl-4-phenylsulfonyldodec-10-ene 24.
n-Butyllithium (2.94 mL, 1.6 M in hexane, 4.70 mmol) was added
to n-butyl phenyl sulfone (776 mg, 3.91 mmol) in dry THF (14 mL)
and DMPU (2 mL) at −40 °C, and the mixture was stirred for 30 min.
The iodide (R)-23 (1.25 g, 4.7 mmol) in THF (4 mL) was added, and
the reaction mixture was allowed to warm to room temperature and
was stirred for 16 h. Saturated aqueous ammonium chloride (10 mL)
was added, and the mixture was partitioned between water (10 mL)
and ether (20 mL). The organic layer was washed with brine (20 mL),
dried (Na2SO4) and concentrated under reduced pressure. Chroma-
tography of the residue eluting with light petroleum/ether (4:1) gave
the title compound 24 (1.23 g, 95%) as a colorless oil, as a 50:50
mixture of 4-epimers (1H and 13C NMR), Rf 0.4 (4:1 light petroleum/
(S)- and (R)-4-Methyldec-1-yl Toluene p-Sulfonate (S)-27
and (R)-27. Toluene p-sulfonyl chloride (166 mg, 0.87 mmol) and
DMAP (127 mg, 1.04 mmol) were added to the alcohol (S)-26 (100
mg, 0.58 mmol) in dichloromethane (8 mL) at room temperature, and
the mixture was stirred at room temperature for 16 h. The mixture was
concentrated under reduced pressure, and chromatography of the
residue eluting with light petroleum/ether (4:1) gave the title
compound (S)-27 (187 mg, 99%) as a colorless oil, Rf 0.7 (7:3 light
petroleum/ether), [α]20 +3.1 (c 0.4 in CHCl3) (found: M+ + Na,
D
349.1812. C18H30O3NaS requires M, 349.1808); νmax 1598, 1465,
1358, 1187, 1174, 1096, 961, 914, and 812 cm−1; δH (400 MHz,
CDCl3) 0.73 (3 H, d, J 6.6, 4-CH3), 0.81 (3 H, t, J 7.0, 10-H3), 0.97−
1.27 (13 H, m, 3-H2, 4-H, 5-H2, 6-H2, 7-H2, 8-H2 and 9-H2), 1.51−
1.65 (2 H, m, 2-H2), 2.38 (3 H, s, ArCH3), 3.94 (2 H, t, J 6.6, 1-H2),
7.28 (2 H, m, ArH) and 7.72 (2 H, m, ArH); δC (100 MHz, CDCl3)
14.1, 19.4, 21.7, 22.7, 26.5, 26.9, 29.6, 31.9, 32.3, 32.5, 36.8, 71.1,
127.9, 129.8, 133.2 and 144.6; m/z (ES+) 349 (M+ + 23, 70%).
The (R)-alcohol (R)-26 (150 mg, 0.87 mmol), toluene p-sulfonyl
chloride (248 mg, 1.3 mmol) and DMAP (191 mg, 1.51 mmol)
similarly gave the (R)-enantiomer (R)-27 (277 mg, 98%), Rf 0.7 (7:3
ether), [α]20 −1.7 (c 1.6 in CHCl3) (found: M+ + H, 337.2194.
D
C20H33O2S requires M, 337.2196); νmax 1446, 1377, 1302, 1143, 1083,
1024, 998, 756, 725, and 690 cm−1; δH (500 MHz, CDCl3) 0.73 (1.5
H, d, J 6.3, 7-CH3), 0.74 (1.5 H, d, J 6.6, 7-CH3), 0.81 (3 H, t, J 7.3, 1-
H3), 0.98−1.54 (9 H, m, 2-H2, 6-H2, 7-H, 8-H2 and 9-H2), 1.51 and
1.61 (each 3 H, s, 11-CH3 or 12-H3), 1.70−1.93 (4 H, m, 3-H2 and 5-
H2), 2.80 (1 H, m, 4-H), 4.98 (1 H, m, 10-H), 7.49 (2 H, t, J 7.8,
ArH), 7.58 (1 H, t, J 7.3, ArH) and 7.82 (2 H, d, J 7.5, ArH); δC (100
MHz, CDCl3) 14.0(2), 17.7, 19.2, 19.4, 20.1, 25.4(2), 25.7, 29.9, 30.0,
32.5(2), 33.7, 33.9, 36.5, 36.9, 64.6, 64.7, 124.6(2), 128.8, 129.1,
131.3(2), 133.5 and 138.3; m/z (ES+) 359 (M+ + 23, 100%).
(4R,7RS)-4-Methyl-7-phenylsulfonyldecan-1-ol 25. The alkene
24 (460 mg, 1.37 mmol) was dissolved in dichloromethane and
methanol (1:1, 20 mL), and the solution was cooled to −78 °C.
Ozone was bubbled through the solution until it turned blue. Oxygen
was then bubbled through the solution at −78 °C until the reaction
light petroleum/ether), [α]20 −3.8 (c 0.4 in CHCl3) (found: M+ +
D
Na, 349.1810. C18H30O3NaS requires M, 349.1808), with spectro-
scopic data identical to those of the (S)-enantiomer.
(S)- and (R)-1-Iodo-4-methyldecane (S)-28 and (R)-28.18
Sodium iodide (1.06 g, 7.04 mmol) was added to the toluene p-
sulfonate (S)-27 (1.15 g, 3.52 mmol) in acetone (15 mL), and the
mixture was stirred under reflux for 2 h. The mixture was then
concentrated and partitioned between hexane (30 mL) and saturated
aqueous sodium sulphite (15 mL). The organic layer was washed with
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brine (10 mL), dried (Na2SO4) and concentrated under reduced
reaction mixture was stirred at room temperature for 6 h and then
concentrated under reduced pressure. Saturated aqueous ammonium
chloride (4 mL) was added, and mixture was partitioned between
saturated aqueous ammonium chloride (6 mL) and hexane (6 mL).
The organic layer was washed with brine (10 mL), dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of the
residue eluting with hexane gave the title compound 2 (5 mg, 83%) as
pressure to give the title compound (S)-28 (891 mg, 90%) as a
colorless oil, Rf 0.8 (light petroleum), [α]20 +2.6 (c 0.2 in CHCl3)
D
(found: M+, 282.0837. C11H23I requires M, 282.0839); νmax 1460,
1378, 1234, 1173, 926, and 724 cm−1; δH (400 MHz, CDCl3) 0.79 (3
H, d, J 6.6, 4-CH3), 0.81 (3 H, t, J 6.6, 10-H3), 1.01−1.36 (13 H, m, 3-
H2, 4-H, 5-H2, 6-H2, 7-H2, 8-H2 and 9-H2), 1.65−1.85 (2 H, m, 2-H2)
and 3.10 (2 H, dt, J 2.5 and 7.1, 1-H2); δC (100 MHz, CDCl3) 7.7,
14.1, 19.7, 22.7, 27.0, 29.7, 31.3, 32.0, 32.1, 36.9 and 37.9; m/z (EI)
282 (M+, 5%).
a colorless oil, Rf 1.0 (100% petrol), [α]20 +23.3 (c 1.2 in CHCl3);
D
νmax 1463, 1378, 1260, 1094, 1018, and 799 cm−1; δH (500 MHz,
CDCl3) 0.72−0.82 (21 H, m, 7 × CH3), 0.89−1.07 (10 H, m), 1.13−
1.30 (20 H, m), 1.32−1.42 (2 H, m) and 1.42−1.55 (3 H, m); δC (100
MHz, CDCl3) 14.1212, 14.3854, 19.5518, 19.5682, 19.5882, 19.6502,
19.7286, 20.0803, 22.6990, 27.0508, 27.0672, 27.1128, 27.2933,
29.3003, 29.6987, 29.7169, 30.0012, 30.3457, 31.9639, 32.7567,
37.0948, 37.1003, 37.8848, 40.2229, 45.5496, 45.5660 and 46.5428;
m/z (AP-) 367 (M+ − 13, 100%).
The toluene p-sulfonate (R)-27 (1.73 g, 5.3 mmol) and sodium
iodide (1.6 g, 10.6 mmol) similarly gave the (R)-enantiomer (R)-28
(1.37 g, 92%), Rf 0.8 (light petroleum), [α]20D −1.7 (c 0.2 in CHCl3)
(found: M+, 282.0835. C11H23I requires M, 282.0839), with
spectroscopic data identical to those of the (S)-enantiomer.
(S)- and (R)-1-Phenylsulfonyl-4-methylundecane (S)-29 and
(R)-29. n-Butyllithium (240 mL, 1.6 M in hexane, 0.38 mmol) was
added to methyl phenyl sulfone (50 mg, 0.32 mmol) in THF (3 mL)
at −40 °C. The mixture was stirred for 30 min, and the iodide (S)-28
(108 mg, 0.38 mmol) in THF (1 mL) was added. The reaction
mixture was allowed to warm to room temperature and was stirred for
16 h. Saturated aqueous ammonium chloride (5 mL) was added, and
the mixture was partitioned between water (2 mL) and ether (10 mL).
The organic layer was washed with brine (10 mL), dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of the
residue eluting with light petroleum/ether (4:1) gave the title
compound (S)-29 (72 mg, 73%) as a colorless oil, Rf 0.5 (60:40
light petroleum/ether), [α]20D −6.4 (c 0.2 in CHCl3) (found: M+ + H,
311.2032. C18H31O2S requires M, 311.2040); νmax 1463, 1446, 1377,
1305, 1144, 1086, 1024, 998, 794, 745, 727, and 688 cm−1; δH (400
MHz, CDCl3) 0.73 (3 H, d, J 6.6, 5-CH3), 0.81 (3 H, t, J 7.0, 11-H3),
0.94−1.32 (15 H, m, 3-H2, 4-H2, 5-H, 6-H2, 7-H2, 8-H2, 9-H2 and 10-
H2), 1.55−1.65 (2 H, m, 2-H2), 3.02 (2 H, t, J 8.1, 1-H2), 7.51 (2 H,
m, ArH), 7.59 (1 H, m, ArH) and 7.84 (2 H, m, ArH); δC (100 MHz,
CDCl3) 14.1, 19.5, 22.7, 23.0, 25.8, 27.0, 29.6, 31.9, 32.5, 36.4, 36.9,
56.4, 128.1, 129.3, 133.6 and 139.3; m/z (ES+) 333 (M+ + 23, 100%).
Methyl phenyl sulfone (75 mg, 0.48 mmol) and the (R)-iodide (R)-
28 (162 mg, 0.57 mmol) similarly gave the (R)-enantiomer (R)-29
(7S,4RS)-7,11-Dimethyl-4-phenylsulfonyldodec-10-ene 31.
Following the procedure outlined for the synthesis of sulfone 24,
the iodide (S)-23 (1.9 g, 7.1 mmol) and butyl phenyl sulfone (1.2 g,
5.9 mmol) gave the title compound 31 (1.7 g, 90%) as a 50:50 mixture
of 4-epimers (1H NMR), Rf 0.4 (4:1 light petroleum/ether), [α]20
D
+3.0 (c 1.6 in CHCl3) (found: M+ + Na, 359.2025. C20H32O2NaS
requires M, 359.2016); νmax 3063, 1446, 1378, 1303, 1144, 1084, 757,
726, and 691 cm−1; δH (500 MHz, CDCl3) 0.65 and 0.67 (each 1.5 H,
d, J 6.7, 7-CH3), 0.75 (3 H, t, J 7.3, 1-H3), 0.90−1.55 (9 H, m, 2-H2, 6-
H2, 7-H, 8-H2 and 9-H2), 1.52 and 1.64 (each 3 H, s, 11-CH3 or 12-
H3), 1.72−1.95 (4 H, m, 3-H2 and 5-H2), 2.81 (1 H, m, 4-H), 5.01 (1
H, m, 10-H), 7.51 (2 H, t, J 7.8, ArH), 7.60 (1 H, t, J 7.3, ArH) and
7.85 (2 H, d, J 7.5, ArH); δC (100 MHz, CDCl3) 14.0, 17.7, 19.2, 19.4,
20.1, 25.4(2), 25.7, 25.9, 30.0, 32.3, 32.5, 33.8, 33.9, 36.5, 36.9, 64.6,
64.7, 124.6, 128.8, 129.1, 131.3(2), 133.5 and 138.3; m/z (ES+) 359
(M+ + 23, 100%).
(4S,7RS)-4-Methyl-7-phenylsulfonyldecan-1-ol 32. Following
the procedure outlined for the synthesis of alcohol 25, the alkene 31
(690 mg, 2.1 mmol) gave the title compound 32 (559 mg, 87%), a
colorlesss oil, as a mixture of 7-epimers, Rf 0.4 (4:1 light petroleum/
ether), [α]20 +4.7 (c 0.2 in CHCl3) (found: M+ + H, 313.1831.
D
C17H29O3S requires M, 313.1832); νmax 3490, 1725, 1586, 1447, 1380,
1287, 1140, 1084, 1024, 999, 758, 726, and 690 cm−1; δH (500 MHz,
CDCl3) 0.76 and 0.78 (each 1.5 H, d, J 6.8, 4-CH3), 0.81 (3 H, t, J 7.6,
10-H3), 1.04−1.61 (11 H, m, 3-H2, 4-H, 5-H2, 6-H2, 8-H2 and 9-H2),
1.72−1.84 (2 H, m, 2-H2), 2.82 (1 H, m, 7-H), 3.56 (2 H, t, J 6.6, 1-
H2), 7.49 (2 H, m, ArH), 7.61 (1 H, m, ArH) and 7.82 (2 H, m, ArH);
δC (100 MHz, CDCl3) 14.0(2), 19.2, 19.4, 20.1, 25.4, 29.9, 30.1(2),
30.2, 32.4, 32.7(2), 33.8, 33.9, 63.2, 64.6, 128.8, 129.1, 133.5 and
138.3; m/z (ES+) 335 (M+ + 23, 100%).
(110 mg, 75%), Rf 0.5 (60:40 light petroleum/ether), [α]20 +5.2 (c
D
0.2 in CHCl3) (found: M+ + H, 311.2034. C18H31O2S requires M,
311.2040), with spectroscopic data identical to those of the (S)-
enantiomer.
(7S,11RS,13R,15S,17R,19S)-7,13,15,17,19-Pentamethyl-11-
phenylsulfonydocosane 30. n-Butyllithium (33 mL, 1.6 M in
hexane, 0.053 mmol) was added to the (S)-sulfone (S)-29 (13 mg,
0.044 mmol) in dry THF (0.5 mL) and DMPU (0.5 mL) at −40 °C.
The mixture was stirred for 30 min, and then the iodide 22 (18 mg,
0.053 mmol) in THF (0.5 mL) was added. The mixture was allowed to
warm to room temperature and was then stirred for 16 h. Saturated
aqueous ammonium chloride (3 mL) was added, and the mixture was
partitioned between water (2 mL) and ether (5 mL). The organic layer
was washed with brine (10 mL), dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue eluting with
light petroleum/ether (4:1) gave the title compound 30 (10 mg, 45%)
as a colorless oil, as a mixture of 11-epimers, Rf 0.6 (4:1 light
(7R,11RS,13R,15S,17R,19S)-7,13,15,17,19-Pentamethyl-11-
phenylsulfonyldocosane 33. n-Butyllithium (50 mL, 1.6 M in
hexane, 0.08 mmol) was added to the (R)-sulfone (R)-29 (20 mg, 0.07
mmol) in THF (0.8 mL) and DMPU (0.8 mL) at −40 °C, and the
reaction mixture was stirred for 30 min. The iodide 22 (27 mg, 0.8
mmol) in THF (0.8 mL) was added, and the reaction mixture allowed
to warm to room temperature and stirred for 16 h. Saturated aqueous
ammonium chloride (5 mL) was added, and the mixture was
partitioned between water (3 mL) and ether (8 mL). The organic
layer was washed with brine (15 mL), dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the residue
eluting with light petroleum/ether (4:1) gave the title compound 33
(11 mg, 34%) as a colorless oil, as a mixture of 11-epimers, Rf 0.6 (4:1
light petroleum/ether) (found: M+ + H, 521.4371. C33H61O2S requires
M, 521.4387); νmax 1463, 1378, 1304, 1145, 1086, 727, and 691 cm−1;
δH (500 MHz, CDCl3) 0.63−0.83 (21 H, m, 1-H3, 7-CH3, 13-CH3, 15-
CH3, 17-CH3, 19-CH3 and 22-H3), 0.87−1.80 (33 H, m, 2-H2, 3-H2,
4-H2, 5-H2, 6-H2, 7-H, 8-H2, 9-H2, 10-H2, 12-H2, 13-H, 14-H2, 15-H,
16-H2, 17-H, 18-H2, 19-H, 20-H2 and 21-H2), 2.91 (1 H, br m, 11-H),
7.49 (2 H, t, J 7.5, ArH), 7.58 (1 H, m, ArH) and 7.82 (2 H, d, J 7.5,
ArH); δC (100 MHz, CDCl3) 14.1, 14.4, 19.0, 19.2, 19.6(3), 20.1, 22.7,
24.2, 27.0, 27.2, 27.9, 28.2, 29.7(2), 31.9, 32.5, 36.9(2), 37.0, 40.2,
40.3, 45.6, 45.9, 46.3, 46.7, 62.7, 128.9(2), 129.1, 133.4 and 138.3; m/z
(ES+) 543 (M+ + 23, 100%).
petroleum/ether), [α]20 −3.7 (c 0.2 in CHCl3) (found: M+ + H,
D
521.4380. C33H61O2S requires M, 521.4387); νmax 1462, 1379, 1304,
1145, 1086, 764, 727, and 691 cm−1; δH (500 MHz, CDCl3) 0.64−
0.84 (21 H, m, 1-H3, 7-CH3, 13-CH3, 15-CH3, 17-CH3, 19-CH3 and
22-H3), 0.86−1.80 (33 H, br. m, 2-H2, 3-H2, 4-H2, 5-H2, 6-H2, 7-H, 8-
H2, 9-H2, 10-H2, 12-H2, 13-H, 14-H2, 15-H, 16-H2, 17-H, 18-H2, 19-H,
20-H2 and 21-H2), 2.91 (1 H, m, 11-H), 7.49 (2 H, t, J 7.5, ArH), 7.57
(1 H, t, J 6.9, ArH) and 7.81 (2 H, d, J 7.9, ArH); δC (100 MHz,
CDCl3) 14.1, 14.4, 19.0, 19.4, 19.5, 19.6 (2), 20.1, 22.7, 24.2, 27.0,
27.2, 27.3, 27.9, 28.1, 29.0, 29.7(2), 32.0, 32.5, 36.2, 36.9, 37.0, 40.2,
40.3, 45.8, 46.3, 62.7, 128.9(2), 129.1, 133.5 and 138.3; m/z (ES+)
543 (M+ + 23, 100%).
(4S,6R,8R,10S,16S)-4,6,8,10,16-Pentamethyldocosane 2. So-
dium amalgam (20%; 85 mg, 0.518 mmol) was added to the sulfone
30 (9 mg, 0.017 mmol) in MeOH (2 mL) at room temperature. The
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(4S,6R,8R,10S,16R)-4,6,8,10,16-Pentamethyldocosane 4. So-
dium amalgam (20%; 104 mg, 0.641 mmol) was added to the sulfone
33 (11 mg, 0.021 mmol) in MeOH (2 mL) at room temperature, and
the reaction mixture was stirred at room temperature for 6 h. After
concentration under reduced pressure, saturated aqueous ammonium
chloride (4 mL) was added, and mixture was partitioned between
saturated aqueous ammonium chloride (6 mL) and hexane (6 mL).
The organic layer was washed with brine (10 mL), dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of the
residue eluting with hexane (100%) gave the title compound 4 (6 mg,
85%) as a colorless oil, Rf 1.0 (light petroleum), [α]20D −4.8 (c 1.1 in
CHCl3); νmax 1464, 1378, 1260, 1094, 1018, 799, and 725 cm−1; δH
(500 MHz, CDCl3) 0.72−0.83 (21 H, m, 7 × CH3), 0.89−1.06 (10 H,
m), 1.11−1.30 (20 H, m), 1.41 (2 H, m) and 1.49 (3 H, m); δC (100
MHz, CDCl3) 14.1266, 14.3890, 19.5354, 19.5518, 19.5773, 19.6338,
19.7176, 20.0766, 22.6990, 27.0472, 27.0599, 27.1037, 27.2629,
27.2689, 29.6951(2), 29.9757, 30.3311, 31.9603, 32.7439, 37.0884,
37.0966, 37.8702, 40.2101, 45.5296, 45.5533 and 46.5191; m/z (AP-)
367 (M+ − 13, 100%).
(6) We did not control for concentration of the NMR samples in this
work because the samples are dilute hydrocarbons. However, if
needed, it is possible to correct for differences in concentration
between the natural sample and the synthetic samples just as is
described for temperature in the Supporting Information.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full details of experiments and compound characterization,
copies of spectra on intermediates and final products, and
complete lists of published and new data sets with relevant
subtractions. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(13) Williams, D. R.; Nold, A. L.; Mullins, R. J. J. Org. Chem. 2004,
69, 5374−5382.
Corresponding Authors
*E-mail: e.j.thomas@manchester.ac.uk.
*E-mail: curran@pitt.edu.
(14) (a) Evans, D. A.; Morrissey, M. M.; Dow, R. L. Tetrahedron Lett.
1985, 26, 6005−6008. (b) Evans, D. A.; Morrissey, M. M. J. Am. Chem.
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Notes
The authors declare no competing financial interest.
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Chem. Soc. 1985, 107, 3197−3204. (b) Lipshutz, B. H.; Wilhelm, R. S.;
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ACKNOWLEDGMENTS
■
(16) (a) Mori, K.; Masuda, S.; Suguro, T. Tetrahedron 1981, 37,
1329−1340. (b) Chow, S. Y.; Williams, H. J.; Huang, Q.; Nanda, S.;
Scott, I. A. J. Org. Chem. 2005, 70, 9997−1003.
We thank Profs. Kitching and Breit and their co-workers for
their careful accumulation and compilation of 13C NMR data.
They could never have anticipated that their data would be
subjected to (and stand up to) scrutiny at the low ppb level.
The Manchester work was supported by the Engineering and
Physical Sciences Research Council (grant number EP/
I007989/1), and the Pittsburgh group thanks the NIH NIGMS.
(17) Raederstorff, D.; Shu, A. Y. L.; Thompson, J. E.; Djerassi, C. J.
Org. Chem. 1987, 52, 2337−2346.
(18) For the racemic iodide 28 see: Hedenstrom, E.; Edlund, H.;
̈
Lund, S.; Abersten, M.; Persson, D. J. Chem. Soc., Perkin Trans. 1 2002,
1810−1817.
(19) Adding the absolute values of the two “reliably different”
numbers gives the same number.
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