Assignment of the structure of petrocortyne A by mixture syntheses of four candidate stereoisomers

Article abstract of DOI:10.1021/jo100115h

Two different mixture synthesis routes have been used to make the four stereoisomers of petrocortyne A. A first quick and dirty route provided a mixture of the four isomers in nonselective fashion. Mosher and 2-naphthylmethoxyacetic acid (NMA) ester methods were developed to identify the components, and the mixture was partially resolved on analytical chiral HPLC to give the two pure enantiomers of petrocortyne A and the racemate of its diastereomer. A second fluorous mixture synthesis produced all four isomers of petrocortyne A in individual pure form. Comparison of spectra of Mosher derivatives of the synthetic isomers with two supposedly different natural products showed that both natural samples were instead identical and had the (3S,14S) configuration. Likewise, petrocortynes B, D, and F-H are (3S,14S) and petrocortyne D is (3R,14S). Having access to all possible candidate isomers of both petrocortyne A and its Mosher derivatives provided a secure structure assignment not so much because one of the isomers matched the natural product, but because all of the other isomers did not.

Full text of DOI:10.1021/jo100115h

pubs.acs.org/joc
Assignment of the Structure of Petrocortyne A by Mixture Syntheses of
Four Candidate Stereoisomers
Bin Sui, Edmund A.-H. Yeh, and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
curran@pitt.edu
Received February 4, 2010
Two different mixture synthesis routes have been used to make the four stereoisomers of petrocortyne
A. A first quick and dirty route provided a mixture of the four isomers in nonselective fashion.
Mosher and 2-naphthylmethoxyacetic acid (NMA) ester methods were developed to identify the
components, and the mixture was partially resolved on analytical chiral HPLC to give the two pure
enantiomers of petrocortyne A and the racemate of its diastereomer. A second fluorous mixture
synthesis produced all four isomers of petrocortyne A in individual pure form. Comparison of spectra
of Mosher derivatives of the synthetic isomers with two supposedly different natural products
showed that both natural samples were instead identical and had the (3S,14S) configuration.
Likewise, petrocortynes B, D, and F-H are (3S,14S) and petrocortyne D is (3R,14S). Having access
to all possible candidate isomers of both petrocortyne A and its Mosher derivatives provided a secure
structure assignment not so much because one of the isomers matched the natural product, but
because all of the other isomers did not.
Introduction
Petrocortyne A 1 is a representative natural product of this
class that was first described by Shin and co-workers.5
Fractionation and purification of a 5.5 kg Petrosia sp.
sample collected in 1994 from Korean waters of Komun
Island provided 70 mg of a compound assigned as (3R,14R)-
petrocortyne A (Figure 1). The constitution of the sample
was assigned by a battery of spectroscopic methods. The 46-
carbon chain features a dialkynylol unit (C12-C16) and an
enynol unit (C1-C5) that are common in other petrocor-
tynes. The two remote stereocenters at C3 and C14 were
treated independently, and their configurations were assig-
ned by the “advanced Mosher ester” method.6 The sample
had a modest inhibitory effect on the enzyme phospholipase
A2 (PLA2) (31% at 50 μg/mL).
Marine sponges are rich sources of biologically active
natural products of a myriad of different structures.1 The
genus Petrosia, for example, produces all sorts of long-chain
polyacetylene natural products, including petrocortynes,
petroformynes, and petrosiacetylenes.2 These natural pro-
ducts exhibit diverse biological activities including anti-
microbial, antitumor, antiviral, and antifungal effects.3
The compounds typically consist of a linear carbon back-
bone of 30 to 46 carbons interspersed with functional groups
including alkynes, E- and Z-alkenes, and hydroxy groups.
There has been very little synthetic work directed toward
such compounds.4
On the heels of this work, Jung and co-workers reported
fractionation and purification of a 14.5 kg Petrosia sp.
sample collected in 1995 again off Komun Island.7 This
(1) (a) Keyzers, R. A.; Davies-Coleman, M. T. Chem. Soc. Rev. 2005, 34,
355–365. (b) Yeung, K. S.; Paterson, I. Chem. Rev. 2005, 105, 4237–4313.
(c) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep,
M. R. Nat. Prod. Rep. 2006, 23, 26–78.
(2) (a) Shin, J.; Seo, Y.; Cho, K. W. J. Nat. Prod. 1998, 61, 1268–1273.
(b) Lim, Y. J.; Kim, J. S.; Im, K. S.; Jung, J. H.; Lee, C.-O.; Hong, J.; Kim,
D.-K. J. Nat. Prod. 1999, 62, 1215–1217. (c) Lim, Y. J.; Lee, C.-O.; Hong, J.;
Kim, D.-K.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2001, 64, 1565–1567. (d) Lim,
Y. J.; Park, H. S.; Im, K. S.; Lee, C.-O.; Hong, J.; Lee, M.-Y.; Kim, D.-k.;
Jung, J. H. J. Nat. Prod. 2001, 64, 46–53.
(3) Kim, D.-K.; Lee, M.-Y.; Lee, H. S.; Lee, D. S.; Lee, J.-R.; Lee, B.-J.;
Jung, J. H. Cancer Lett. 2002, 185, 95–101.
(4) Gung, B. W.; Omollo, A. O. Eur. J. Org. Chem. 2008, 4790–4795.
(5) Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J.; Sim, C. J. Tetrahedron 1998,
54, 447–462.
(6) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096. (b) Seco, J. M.; Quinoa, E.; Riguera, R. Tetra-
hedron: Asymmetry 2000, 11, 2781–2791. (c) Hoye, T. R.; Jeffrey, C. S.; Shao,
F. Nat. Protoc. 2007, 2, 2451–2458.
(7) Kim, J. S.; Lim, Y. J.; Im, K. S.; Jung, J. H.; Shim, C. J.; Lee, C. O.;
Hong, J.; Lee, H. J. Nat. Prod. 1999, 62, 554–559.
2942 J. Org. Chem. 2010, 75, 2942–2954
Published on Web 04/16/2010
DOI: 10.1021/jo100115h
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2010 American Chemical Society

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JOCArticle
FIGURE 1. Proposed structures of petrocortyne A.
provided an unspecified amount of petrocortyne A, whose
NMR spectra were identical to those of the sample of Shin,
but the advanced Mosher analysis of this sample suggested
that it was the enantiomer, (3S,14S)-petrocortyne A. Jung’s
petrocortyne A is a potent cytotoxic agent and also exhibits
significant anti-inflammatory and pro-aggregative effects at
noncytotoxic concentrations.8 Significant information about
the cellular targets of petrocortyne is available.
Could the same class of sponge isolated from similar
locations in different years really produce enantiomers of
the same natural product? Or were one or even both of the
structure assignments incorrect? These questions piqued our
curiosity in the context of a program on assigning structures
to natural products when two or more stereoisomers can
reasonably be expected to have substantially identical spec-
tra.9 Would the (3S,14S)/(3R,14R) pair of enantiomers
exhibit the same spectra as the (3R,14S)/(3S,14R) pair?
The pairs are syn/anti diastereomers, but the stereocenters
are remote. If the spectra are the same, then how can the
diastereomers be differentiated? And is the application of
advanced Mosher analysis of petrocortynes a reliable tactic
for assigning configurations?
We have recently communicated the finishing steps of a
fluorous mixture synthesis of the petrocortyne isomers and
validation of a new “short cut” Mosher method for assigning
configurations of stereocenters in nearly symmetric environ-
ments.10 Here we report full details of two separate mixture
syntheses of all four stereoisomers of petrocortyne A. The
first “quick and dirty” synthesis produced a mixture of all
four isomers that was partially separated. The second “fluo-
rous mixture synthesis”11 provided all four individual pure
isomers. Comparison of data from synthetic and natural
samples and Mosher derivatives shows that the two natural
samples are the same and that Jung’s assignment of (3S,14S)-
petrocortyne A is correct. We validate use of Mosher esters
to assign the difficult C14 stereocenter of petrocortynes, but
at the same time we suggest that using 2-naphthylmethoxy-
acetic acid (NMA) esters is more convenient and reliable.
stereoisomers of petrocortyne A for data collection and
comparison with each other and with the natural samples.
Dismissing the traditional approach to making all four stereo-
isomers by serial synthesis as too much effort, we simul-
taneously adopted two mixture synthesis approaches: a quick
and dirty mixture synthesis and a fluorous mixture synthesis.
In the quick and dirty approach, we planned to make a
single mixture of all four stereoisomers by using nonselective
reactions to make each of the two stereocenters. Because the
two stereocenters are remote, we reasoned that we could
make believe that this mixture of true stereoisomers was a
single compound during the body of the synthesis. In other
words, we expected the mixtures not to resolve into diaster-
eomeric components on chromatography nor to give diffe-
rent resonances in the NMR spectra, etc. In the end, this
expectation was realized.
All exercises in make believe have to end sooner or later,
and this one ends at the final mixture sample containing the
four isomers of petrocortyne A. This mixture has to be
resolved (separated) into its four isomeric components, and
the configurations of the four isomers have to be confidently
assigned. The approach is comparable to a classical racemic
synthesis followed by resolution and assignment of enantio-
mers, but with double the level of difficulty. We were
confident that we could solve the identification problem on
intermediate compounds made during the course of synthe-
sis. However, as in racemic synthesis, the solution to the
separation problem is difficult to anticipate because it is a
trial and error process.
To complement the quick and dirty approach, we simul-
taneously pursued a fluorous mixture synthesis approach.
This is somewhat more work because we must individually
prepare each isomer and encode its configuration with a
fluorous tag. However, the bulk of the synthesis again occurs
in a mixture mode, so considerable effort is spared. We again
make believe that this mixture of quasiisomers (“quasi”
because the compounds are not true isomers due to the
fluorous tags12) is a single compound throughout much of
the synthesis. But this time, we know that when the make
believe ends we will be able to resolve the final mixture into
its four individual components by demixing, and we will
know which isomer is which by reading (identifying) the tags.
In essence, a bit of extra work in the beginning could pay big
dividends at the end because there are built-in solutions to
the problems of separation and identification.
Results and Discussion
Mixture Synthesis Strategies. To confidently assign the
structures of the extant petrocortyne A natural products, we
set the goal of making individual, pure samples of all four
(8) Hong, S.; Kim, S. H.; Rhee, M. H.; Kim, A. R.; Jung, J. H.; Chun, T.;
Yoo, E. S.; Cho, J. Y. Arch. Pharmacol. 2003, 368, 448–456.
(9) (a) Curran, D. P.; Zhang, Q. S.; Lu, H. J.; Gudipati, V. J. Am. Chem.
Soc. 2006, 128, 9943–9956. (b) Jung, W.-H.; Guyenne, S.; Riesco-Fagundo,
C.; Mancuso, J.; Nakamura, S.; Curran, D. P. Angew. Chem., Int. Ed. 2008,
47, 1130–1133. and references therein.
(10) Curran, D. P.; Sui, B. J. Am. Chem. Soc. 2009, 131, 5411–5413.
(11) (a) Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science
2001, 291, 1766–1769. (b) Curran, D. P.; Zhang, Q. S.; Richard, C.; Lu, H. J.;
Gudipati, V.; Wilcox, C. S. J. Am. Chem. Soc. 2006, 128, 9561–9573.
Assignment of Stereocenter Configurations by Derivatization.
To start, we undertook a series of model studies with two
overlapping aims. Recall that the configurations of the two
samples of petrocortynes were assigned by the advanced
Mosher method. First, to ensure that these assignments are
(12) Zhang, Q. S.; Curran, D. P. Chem.;Eur. J. 2005, 11, 4866–4880.
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TABLE 1. Assignment of the C3 Stereocenter in Mosher (4) and NMA (5) Esters
protons
7
1
4
5
6
8
9
10
11
Δδ (δS-4S - δS-4R) ppm
Δδ (δR-5S - δS-5S) ppm
0.040
0.114
-0.110
-0.199
-0.061
-0.183
-0.041
-0.152
-0.032
-0.183
-0.052
-0.118
-0.026
-0.092
-0.011
-0.054
0.000
-0.027
SCHEME 1. Synthesis of Alkynyl Alkenyl Carbinol 3 and
Derived MTPA and 2-NMA Esters
correct, we needed to validate that method on samples of
known configuration. Second, if successful, the quick and
dirty synthesis was expected to provide isomers devoid of
stereostructures, so the same model studies could serve as
foundation for derivatization and assignment of the uniden-
tified final products. In the end, this use was not needed
because the fluorous mixture synthesis produced pure stereo-
isomers of defined configuration, but the studies nonetheless
laid a solid foundation for using both Mosher6 and NMA13
ester derivatives to assign petrocortynes. In addition, we
found a third use of the model studies that was not planned at
the outset, which was to assign the configuration of one of
the stereocenters during the fluorous mixture synthesis.
Model studies directed toward validating the Mosher
method for assigning the configuration at C3 are summari-
zed in Scheme 1. We later leveraged this work by using some
of the intermediates to begin the fluorous mixture synthe-
sis. Reduction of readily available alkyne 2 by the S-CBS
reagent14 and then desilylation with TBAF provided S-3 in
73% yield and 94% ee. Likewise, reduction by the R-CBS
reagent provided R-3 in 70% yield and 93% ee. The configu-
rations of these compounds can be confidently assigned from
the prevailing model for CBS reductions, so they are suitable
substrates to validate the advanced Mosher method.
method (δS - δR),16 and the values obtained are shown in
Table 1 in parts per million (ppm). The magnitudes of the
differences are well outside experimental error, and the signs
of the differences (negative to the left of the stereocenter as
drawn, positive to the right) are as expected from the CBS
model.
During the model studies for the C14 stereocenter, we
needed to make R-methoxy-2-naphthylacetic acid (NMA)
esters to validate the Mosher results, so we also made the
NMA esters with 3. We had available only the S-2-NMA
acid, so this was reacted with both R- and S-3, and the
spectra of derivatives S-5S and R-5S were analyzed as usual.
The results of appropriate subtraction are also shown in
Table 1. The signs of the differences match the Mosher esters
as expected, but the magnitudes of the differences are much
larger in the NMA esters, and the measurable differences
extend further down the chain.
Alcohol S-3 was reacted with the R and S Mosher acid
chlorides (MTPA-Cl = R-methoxy-R-trifluoromethylphenyl-
1
acetic acid chloride).6 Integration of the H and 19F NMR
spectra of the resulting samples S-4S15 and S-4R provided
the indicated ee’s for the CBS reductions. The chemical shifts
of pairs of resonances were then subtracted by the usual
(13) (a) Kusumi, T.; Takahashi, H.; Xu, P.; Fukushima, T.; Asakawa, Y.;
Hashimoto, T.; Kan, Y.; Inouye, Y. Tetrahedron Lett. 1994, 35, 4397–4400.
(b) Seco, J. M.; Latypov, S.; Quinoa, E.; Riguera, R. Tetrahedron Lett. 1994,
35, 2921–2924. (c) Kouda, K.; Kusumi, T.; Ping, X.; Kan, Y.; Hashimoto, T.;
Asakawa, Y. Tetrahedron Lett. 1996, 37, 4541–4544. (d) Duret, P.; Waechter,
ꢀ
ꢁ
A.-I.; Figadere, B.; Hocquemiller, R.; Cave, A. J. Org. Chem. 1998, 63, 4717–
4720. (e) For a recent comparison of shielding effects of various Mosher-like
derivatives, see: Hoye, T. R.; Erickson, S. E.; Erickson-Birkedahl, S. L.; Hale,
C. R. H.; Izgu, E. C.; Mayer, M. J.; Notz, P. K.; Renner, M. K. Org. Lett. 2010,
Published online Mar 25, 2010. DOI: 10.1021/ol1003862.
(14) (a) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53,
2861–2863. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1988–2012.
Model studies directed toward validating the Mosher
method for assigning the configuration at C14 are summari-
zed in Scheme 2. The use of Mosher esters to assign the C14
center is much more difficult than assigning C3 for two
reasons. First, the nearest protons on both sides of the
(15) Numbers are coded consistently in the paper as follows: R or S before
the number indicates a stereocenter in the petrocortyne chain; R or S after
the number indicates the stereocenter of the Mosher or NMA ester; rac, a mix-
ture of true racemates; qrac, a mixture of quasiracemates; dim, a mixture of
true diastereomers; qdim, a mixture of quasidiastereomers. Silyl tags are coded
by letters: a, TIPSF9=Si(iPr)2(CH2)3C4F9; b, TIPSF0=Si(iPr)3; c, TIPSF7
=
Si(iPr)2(CH2)3C3F7. When two letters are present, the O3 tag is listed before
the O14 tag. For example, one of the four components of qdim-26a,b/a,c is
26a/c. This has the “a” tag on O3 and the “c” tag on O14.
(16) Where possible, the chemical shifts were taken from the 1D spectra.
When resonances overlapped in the 1D spectra, chemical shifts were taken
from the proton axis of 1H,13C COSY (HMQC) spectra.
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TABLE 2. Assignment of the C14 Stereocenter in Mosher (9) and NMA (10) esters
protons
19
10
17
18
20
21
100
Δδ (δR-9S - δR-9R) ppm
Δδ (δS-10S - δR-10S) ppm
-0.023
-0.151
0.029
0.158
0.023
0.175
0.024
0.152
0.011
0.103
0.002
0.064
0.000
0.022
SCHEME 2. Synthesis of Dialkynyl Carbinol Fragment 8 and
Derived MTPA and 2-NMA Esters
mers R-8 and S-8 were each obtained in 83% ee, in 64% and
70% isolated yield, respectively. Configurations were assig-
ned by the Pu model. We found that the enantiomers were
readily separable on a Chiralcel-OD HPLC column, so the
ee of each sample was upgraded to >99% by preparative
HPLC prior to derivatization.
We then made both MTPA and 2-NMA esters of 8 as
described above. Again the pair of enantiomeric MTPA acid
chlorides was reacted with R-9 to make the pair of Mosher
esters R-9S and R-9R, while the single S-NMA acid was
reacted with the pair of enantiomers S-8 and R-8 to give the
NMA pair S-10S and R-10S. The results of the subtractions
are summarized in Table 2. The expected signs of the
differences are observed for both esters; however, the magni-
tudes are very different. For example, in the Mosher ester 9,
the protons nearest to the stereocenter at C17 (propargylic
position) show a difference of only 0.029 ppm. While this
difference is outside the error of the measurement, it is still
very small, especially when one considers that the natural
product will exhibit two resonances with this small separa-
tion that have to be unambiguously assigned.
The NMA esters 10 exhibit superior spectroscopic proper-
ties, with a chemical shift difference of 0.158 ppm for H17
and an even greater difference for H18 (0.175 ppm). Diffe-
rences for H19 and H20 still exceed 0.1 ppm. The benzylic
protons (H100) 10 atoms away from the stereocenter have
about the same difference (0.022 ppm) in the 2-NMA esters
as the nearest protons (H17) in the Mosher esters. No
differences were measured for the PMB aromatic protons
or methoxy group (H700) of the NMA esters.
Taken together, these results validate the use of the
Mosher method for assigning the configuration at C17, but
at the same time show that the use of the NMA method will
be both easier and more reliable. Since either ester can be
used to assign C3, the 2-NMA ester is accordingly recom-
mended as the single best derivative to simultaneously assign
both stereocenters.
Diastereomer Mixture Synthesis. Having validated the
advanced Mosher method and identified the even better
NMA method for configuration assignment, we decided to
undertake the nonselective synthesis of a mixture of all four
diastereomers with the goal of resolving and identifying the
components of the final mixture. The high level plan for this
synthesis, shown in Figure 2, divides the molecule into one
large component 13 (C22-C46), two medium-sized ones 11
(C1-C13) and 12 (C15-C21), and one small one. The small
dialkynyl carbinol unit (C11-C17) are already three carbon
atoms away from the stereocenter. Second, because of the
quasisymmetry of these units, the propargyl protons on C11
and C17 are chemical shift equivalent in the natural product
and related compounds. Making the Mosher ester separates
the resonances by a very small amount.2 Prior to applying the
Mosher method, the resonances have to be assigned, which is
again difficult due to the quasisymmetry. If the resonances
are mis-assigned, then the stereocenter configuration will be
mis-assigned.
To avoid any possible confusion about assigning pairs of
propargylic methylene protons, we simply chose a model
system with only one propargylic methylene group. Again,
we planned to leverage the chemistry used to make the model
later in the fluorous mixture synthesis. Both enantiomers of
dialkynol 8 were prepared according to Pu by in situ gene-
ration of the zinc alkyne from 6, followed by addition of (R)-
or (S)-BINOL, Ti(OiPr)4, and aldehyde 7.17 The enantio-
(17) (a) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143–
4146. (b) Aschwanden, P.; Carreira, E. M. In Acetylene Chemistry; Diederich, F.,
Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005; pp 101-138.
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FIGURE 2. Retrosynthetic plan for the synthesis of a mixture of true diastereomers of 1.
SCHEME 3. Fragment Couplings and Production of a Mixture of the Four Stereoisomers of Petrocortyne A
component is dimethylformamide, which provides the linch-
pin carbon (C14) to join the 1,4-dialkyne unit.
portantly, the spectroscopic data of dim-1 completely mat-
ched the data reported by both (R,R)-1 and (S,S)-1, so the
synthesis confirms the constitution of petrocortyne A.
Left to secure is its configuration. Toward that end, upon
injection into an analytical Chiralcel OD column (2% iso-
propanol/hexane), the sample of dim-1 was resolved into not
four but three peaks in a ratio of about 1:2:1. We interpreted
this chromatogram as showing that the four isomers were
present in equal amounts; two isomers separated from the
other two, which overlapped each other. This was later
confirmed as described below.
At this juncture, the work on the fluorous mixture synthe-
sis (see below) was well advanced and promised to soon
provide all four pure isomers. Thus, the scan of other chiral
separation methods was terminated, and no derivatizations
were attempted. In the end, the diastereomer mixture synthe-
sis proved the constitution of petrocorytne A and showed
that it was possible to resolve two of the four isomers with a
Chiralcel OD column.
Fluorous Mixture Synthesis. The strategy for the fluorous
mixture synthesis, shown in Figure 3, is similar to the dia-
stereomer mixture synthesis, with one important exception.
To allow for generation of the C14 stereocenter by a Pu
asymmetric addition with a silyl alkyne, we shifted the frag-
ment coupling dissection away from C14 to the C11-C12
bond. This gives the same right-hand fragment 13 as above, the
far-left fragment qrac-17 above, and the center-left fragment
Complete details of the fragment syntheses are provided in
the Supporting Information. Briefly, 12 was made in two
steps and 54% overall yield from 3-heptyn-1-ol (Scheme S2
in Supporting Information), whereas rac-11 was made in six
steps and 34% overall yield from 3-nonyn-1-ol (Scheme S3 in
Supporting Information). Finally, the large right-side frag-
ment 13 was made in 10 steps from 16-hydroxyquindecanoic
acid (Scheme S4 in Supporting Information).
The fragment couplings and completion of the diastereo-
mer mixture synthesis are summarized in Scheme 3. Coup-
ling of 13 and 12 by a Wittig reaction under standard
conditions provided the C21-Z isomer 14 in 73% yield. In turn,
this was formylated with DMF to give aldehyde 15 in 86%.
Deprotonation of fragment rac-11 followed by addition of
aldehyde 15 and careful chromatography gave dim-16 in
38% yield, where the prefix “dim” stands for “diastereoisomer
mixture”. Finally, desilylation with TBAF provides the final
mixture of all four petrocortyne A isomers, dim-1. About 18 mg
of this mixture was produced.
Both samples dim-16 and dim-1 appeared to be single
compounds by the usual means of spectroscopic (high field
1H and 13C NMR) and chromatographic (standard and
reverse phase TLC) analysis. It is inconceivable that coupling
of 11 and 15 provided a single isomer; instead, the pairs of
diastereomers are simply not distinguishably different. Im-
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FIGURE 3. Plan for the fluorous mixture synthesis.
SCHEME 4. Synthesis of Alcohols R,S-18
column. Thus, instead doing two asymmetric alkyne addi-
tions and upgrading the ee’s of those enantiomeric products,
we simply made racemic 20 on a gram scale and resolved it.
The racemate was preparatively resolved to provide the first-
eluting enantiomer R-18 in 47% yield and second-eluting
enantiomer S-18 in 48% yield (combined yield, 97%).
Both samples had ee’s g 99% by chiral HPLC analysis.
The configurations of 18 could be tentatively assigned by
HPLC comparison to samples made by Pu alkynylation,
and the assignments were confirmed by making NMA
esters as above (see Supporting Information for details).
The fragment couplings and completion of the fluorous
mixture synthesis are summarized in Scheme 5. To start, CBS
reduction of ketone 22 by a procedure similar to that in
Scheme 2 provided aklynyl alkenyl carbinols R- and S-21.
Quasienantiomers R-22a and S-22b15 were individually pre-
pared by tagging R-21 with C4F9(CH2)3Si(iPr)2OTf20 and
S-21 with standard TIPSOTf. The resulting products were
mixed in equal amounts to make qrac-22a,b. Removal of the
PMB group followed by treatment of the resulting alcohol
with iodine and triphenylphosphine gave iodide qrac-23a,b15
ready for coupling with the center-left fragment.
In an initial dead-end approach, we tagged the enantio-
mers of left-center fragment 18 (Scheme 4) with two different
silyl groups, but we could not couple the resulting quasir-
acemate (not shown) with qrac-23a,b. Suspecting that this
reaction failed because the protected dialkylcarbynol proton
was deprotonated rather than (or in addition to) the terminal
alkyne proton, we conspired to block this side reaction by
conducting the coupling on a dianion derived from free
alcohol 18. This revised sequence, shown in Scheme 5, has
the same number of synthetic steps as the original plan, but
since the coupling was placed before the tagging, we had to
postpone the mixing. This results in conducting one extra
reaction (two couplings instead of one).
18. These last fragments are closely related to 11 and 12 in
Scheme 3. For the fluorous mixture synthesis, both fragments
17 and 18 have to be made in highly enantioenriched form and
then tagged with different fluorous tags for later separation
and identification. While the earlier model work used a PMB
group on O22,18 this proved difficult to remove, so we changed
to a methylthiomethyl (MTM) group.19
The synthesis of center-left fragment 18 is summarized in
Scheme 4. Initially, we focused on Pu additions of several
alkynes to aldehydes like 19. These results are summarized in
Scheme S5 in the Supporting Information. The observed ee’s
of products like 20, while substantial (78-90%), did not
meet our target levels of >95%. Enantiomeric impurities at
this stage would produce diastereomer impurities down-
stream, and we did not know whether or how the impurities
could be either separated or identified.
Deprotonation of R-18 with 2 equiv of BuLi provided
a dianion that was coupled with qrac-23a,b. The resulting
pair of quasidiastereomers (R-qdim-24a,b) was tagged with
C4F9(CH2)3Si(iPr)2OTf to encode the configuration at C14
in qdim-25a,b/a15 with a perfluorobutyl group. Likewise, the
In analyzing the ee’s from Pu reactions, we soon found that
products like rac-20 were easily resolved on a Chiralcel-OD
(18) Sui, B. Ph.D. Thesis, University of Pittsburgh, 2009. The thesis can
be downloaded in pdf form at http://etd.library.pitt.edu/ETD-db/ETD-
search/search.
(19) (a) Petri, A. F.; Schneekloth, J. S.; Mandal, A. K.; Crews, C. M. Org.
Lett. 2007, 9, 3001–3004. (b) Pojer, P. M.; Angyal, S. J. Aust. J. Chem. 1978,
31, 1031–1040.
(20) Preliminary studies used the more common fluorous silyl tags with
ethylene (rather than propylene) spacers, but these tags proved unstable. See:
Garcia Sancho, A.; Wang, X.; Sui, B.; Curran, D. P. Adv. Synth. Catal. 2009,
351, 1035–1040.
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Sui et al.
JOCArticle
SCHEME 5. Fluorous Mixture Synthesis of Petrocortyne Isomers
pair of quasidiastereomers S-qdim-24a,b from reaction of
qrac-23a,b with S-18 was encoded with the perfluoropropyl
group from C3F7(CH2)3Si(iPr)2OTf to give qdim-25a,b/a,c.
Mixing the pair of tagged products provided the first four-
compound quasiisomer mixture, qdim-25a,b/a,c. Notice that
even though both R stereocenters of qdim-25 are encoded with
the same perfluorobutyl group (tag “a”), there is no redun-
dancy in fluorine content of the final four products and the
coding scheme is therefore unambiguous.21
Removal of the MTM group from 25 followed by Dess-
Martin oxidation provided aldehyde qdim-27, which was
then coupling with Wittig reagent 13 to provide qdim-28, now
ready for demixing. Despite the highly convergent synthesis
plan involving late introduction of stereocenters, the fluorous
mixture synthesis route still saved 15 reactions compared to the
same route conducted in serial or parallel.
The quasiisomer mixture qdim-28 was readily demixed by
preparative fluorous HPLC to provide the four underlying
components in pure form. Unlike the spectra of true pro-
tected isomers dim-16 (Scheme 3), the NMR spectra of these
four isomers were not identical. In addition to the obvious
differences in the resonances originating from the different
tags (TIPS and fluorous TIPS), the two isomers containing
the standard TIPS groups had several small differences in
resonances of backbone protons. Thus, the observed small
differences emanated from the tag differences, not the stereo-
center differences.
This conclusion was confirmed by removing the tags from
the four quasiisomers 28 with TBAF to give the four isomers
of petrocortyne A 1, this time in individual, pure form. The
NMR spectra and chromatographic retention times of all of
the isomers on standard silica gel were the same and were
identical to that of the four-compound mixture qdim-1.
Importantly, the pure isomers could be partly differen-
tiated in complementary ways by optical rotation and chiral
(21) Curran, D. P.; Moura-Letts, G.; Pohlman, M. Angew. Chem., Int.
Ed. 2006, 45, 2423–2426.
2948 J. Org. Chem. Vol. 75, No. 9, 2010

Sui et al.
JOCArticle
HPLC. The optical rotations of the four isomers are shown
in Scheme 5. Two pairs of diastereomers 1 (RR/RS and SS/
SR) have rotations that are too close to differentiate in
practice. So for structure assignment purposes, the sign of
the optical rotation can be used assign the configuration of
C3, but no information is provided about C14. Contribu-
tions to rotation from remote stereocenters are often app-
roximately additive,22 so at this wavelength the C14 stereo-
center apparently contributes a negligible amount to the
total rotation.
Given that two pairs of isomers have almost the same
rotations, how do we know that the four samples of 1 from
the fluorous mixture synthesis are isomerically pure? This
confirmation comes from the chiral HPLC. Injection and
coinjection of the four pure isomers of 1 into the Chiralcel
OD column reproduced the pattern observed for the mixture
sample dim-1 described above. Isomer S,S-1 eluted first,
while its enantiomer R,R-1 eluted last. The isomers S,R-1
and R,S-1 eluted together and between the other two iso-
mers. Thus, the chiral HPLC experiment resolves the dia-
stereomers and further resolves one pair of enantiomers but
not the other. That R,R-1 and S,S-1 give essentially single
peaks on HPLC analysis shows that they are both diastereo-
merically and enantiomerically pure. The results show that S,
R-1 and R,S-1 are diastereopure, and they must also be
enantiopure because the samples were all literally made
together. Thus, this pair is simply not resolved into its
enantiomers by the chiral column.
Structure Assignments. Armed with mixture and indivi-
dual samples of all four isomers and having validated the
Mosher analysis, we are ready to assign configurations to the
petrocortyne natural products. We did not succeed in obtai-
ning samples of either isolate, but both papers provide
extensive information about the natural samples and Mosher
derivatives. On the basis of comparison of our data with the
published data, we conclude that the structure of (3R,14R)-
petrocotyne A is incorrect and that the structure of (3S,14S)-
petrocortyne A is correct.
FIGURE 4. Expansions of portions of the 1H NMR spectra of the
bis-(S)-Mosher esters of (3S,14S)-1 (top) and (3S,14R)-1 (bottom)
with proton assignments.
used (with care) to assign the configuration at C14 in petro-
cortynes and that a new “short cut” Mosher rule can also be
applied for this task.
In practice, however, no rules or subtractions were needed
to assign the configuration of the petrocortyne A Mosher
esters because we had available spectra of all possible
isomers. Setting rules aside, we simply matched our spectra
with those of Shin and Jung. We initially expected that this
matching would require 2D spin lock experiments to differ-
entiate H11 and H17, which are in nearly symmetric environ-
ments. Such assignments were used by both Shin and Jung
for their Mosher analyses, and we also did them for validation.
However, the proper assignment of H11 and H17 was
rendered superfluous because the diastereomers of petrocor-
tyne showed clear differences in their Mosher spectra. Expan-
sions of the spectra of bis-(S)-Mosher esters made from the
synthetic (3S,14S) and (3S,14R) isomers of 1 are shown in
Figure 4 along with assignments of H11 and H17. These
assignments were made by TCOSY experiments and can also
be made by either the advanced Mosher rule or the new short
cut.10 That the spectra of the diastereomers are different
means that the Mosher ester at the C3 stereocenter has an
effect on its counterpart eleven atoms down the chain at C14.
This long-range effect is remarkable, and the differences, if
small, are unmistakable even at lower field strengths than
that shown in Figure 4.
Looking at optical rotations first, the signs and magni-
tudes of the reported optical rotation by both Shin5 (þ6.4,
c=0.25 MeOH) and Jung7 (þ10.8, c=1.9, MeOH) are con-
sistent with the measured optical rotations of either
(3S,14R)-petrocortyne A or (3S,14S)-petrocortyne A. The
rotation of Jung’s sample is “spot on” for the (3S,14S)-
isomer, but as stated above, we maintain that the magnitudes
of rotations of the two diastereomers are too close to
differentiate relative stereochemistry. So the rotation com-
parison confirms the configuration of C3 as S. Accordingly,
Jung’s assignment of this stereocenter is correct and Shin’s is
incorrect. Because the diastereomers of petrocortyne A have
Because all four Mosher spectra of the petrocortyne
isomers were unique, we set aside all the resonance assign-
1
ments and simply matched the 1D H NMR spectra of the
synthetic Mosher esters with those reported by Shin and
Jung. The spectrum of the bis-(S)-Mosher ester of synthetic
(3S,14S)-1 uniquely matched the spectra reported by both
groups.23 In turn, both of their bis-(R)-Mosher spectra
matched those from synthetic (3S,14S)-1 as well. This means
that Shin’s and Jung’s samples are identical, not enantiomers,
and that Jung’s assignment of the 3S,14S configuration is correct.
1
identical H and 13C NMR spectra, the assignment of C14
does not follow from the assignment of C3.
Next, we converted the pair of diastereomers with the (3S)
configuration to both the bis-(R)- and bis-(S)-Mosher esters
and recorded and assigned a complete set of 1D and 2D 1H
NMR spectra. The structures of the Mosher esters and their
entire spectra are shown in the Supporting Information of
the prior communication.10 The analysis of the spectra in
that paper also showed that the advanced Mosher rule can be
(23) In comparing Mosher spectra, we discovered that the magnitudes of
the subtraction values reported in Figure 3 of ref 5 are not correct. Assuming
that the listed values are in ppb, they are exactly one-half of the actual
subtraction values. The original resonances of the Mosher ester spectra are
listed in the Experimental Section of the paper, and these data were used for
the comparison. For the Mosher esters in ref 7, we compared our spectra with
copies of the originals kindly provided by Dr. Jung. With his permission,
these copies are included in the Supporting Information.
(22) Kondru, R. K.; Wipf, P.; Beratan, D. N. Science 1998, 282, 2247–
2250.
J. Org. Chem. Vol. 75, No. 9, 2010 2949

Sui et al.
JOCArticle
It also means that both groups properly assigned H11 and
H17 in their Mosher esters. Jung then properly applied the
advanced Mosher rule to assign the natural product configu-
ration.
In the bigger picture, having access to all possible candi-
date isomers for a given structure is of great value in securing
a hard and fast structure assignment. As we stressed in a
recent paper on murisolins,9b the security of the assignment
comes not so much because one of the isomers “matches” the
natural product, but because all of the other isomers do not.
Unfortunately, Shin must have neglected to recognize the
change in CIP priority attendant with using Mosher acid
chlorides in the advanced Mosher rule.6 In other words, he
did all of the correct assignments and subtractions but reversed
the configurations of the stereocenters of his Mosher esters.
That process reversed both stereocenters in the final assign-
ment. The same group has described the isolation and assign-
ments of a number of other petrocortynes. In reviewing these
assignments, we learned that the same errors were made
consistently. Accordingly, the absolute configurations of petro-
cortynes B,5 D,2a E,2a F,2a G,2a and H2a in the indicated
references need to be reversed, whereas the structures of B,2d
G,2c and H2c in the indicated references are correct.
Experimental Section
General. This experimental section contains details for the
fluorous mixture synthesis as described in Scheme 5 and for
the synthesis of the final Mosher esters. General methods and
experimental details for all other work in the paper are con-
tained in the Supporting Information.
(R,E)-1-(tert-Butyldimethylsilyl)-11-(4-methoxybenzyloxy)undec-
4-en-1-yn-3-ol (R-21). A solution of compound 2 (10.62 g, 25.6
mmol) in THF (90 mL) was added dropwise in 10 min to a solu-
tion of (R)-CBS (7.10 g, 25.6 mmol) and BH3 SMe2 (2.8 mL,
3
29.5 mmol) in THF (30 mL) at 0 °C under Ar. Upon completion
of addition, reaction was cautiously quenched by slow addition
of MeOH (30 mL) at 0 °C. The resulting solution was stirred for
15 min at room temperature, and most organic solvent was
removed under reduced pressure. The residue was purified by
column chromatography (hexane/EtOAc = 17:3) to afford the
title compound R-21 (7.48 g, 70%, 93% ee): [R]25D=-21.7 (c=
1.30, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz,
2 H), 6.88 (d, J=8.7 Hz, 2 H), 5.90 (dtd, J=15.3, 6.6, 0.9 Hz,
1 H), 5.59 (ddt, J = 15.3, 5.7, 1.4 Hz, 1 H), 4.82 (t, J = 6.0 Hz,
1 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.43 (t, J=6.6 Hz, 2 H), 2.06 (q,
J=6.6 Hz, 2 H), 1.80 (d, J=6.3 Hz, 1 H), 1.63-1.55 (m, 2 H),
1.45-1.28 (m, 6 H), 0.94 (s, 9 H), 0.12 (s, 6 H); 13C NMR (75
MHz, CDCl3) δ 158.9, 133.7, 130.6, 129.1, 128.8, 113.6, 105.8,
88.4, 72.3, 69.9, 63.0, 55.1, 31.7, 29.5, 28.8, 28.7, 26.0, 25.9, 16.4,
-4.8; IR (film) 3593, 3419, 2932, 2858, 1612, 1513, 1465, 1363,
1301, 1249, 1091, 1034, 909, 827, 777, 734 cm-1; HRMS (ESI) m/z
(Mþ þNa) calcd for C25H40O3NaSi 439.2644, found 439.2620.
(S,E)-1-(tert-Butyldimethylsilyl)-11-(4-methoxybenzyloxy)undec-
4-en-1-yn-3-ol (S-21). Following the same procedure for R-21,
ketone 2 (9.50 g, 22.9 mmol) was reacted with (S)-CBS (6.35 g,
Conclusions
Two different mixture synthesis routes have been used to
make the four stereoisomers of petrocortyne A. A quick and
dirty route provided a mixture of the four isomers in non-
selective fashion. That the intermediate diastereomers did
not separate and exhibited identical spectra facilitated the
synthesis of the isomers. Both Mosher and NMA derivatiza-
tion methods were developed to identify the final petrocor-
tyne A isomers. The mixture was partially resolved on chiral
HPLC to give two pure enantiomers of the syn diastereomer
along with the racemate of the anti diastereomer. Planned
preparative resolution and derivatization were aborted be-
cause the four pure enantiomers became available through
the fluorous mixture synthesis. However, with hindsight we
conclude that this approach would have succeeded because
the enantiomeric pair that resolved was that of petrocortyne A.
This traditional mixture synthesis is easy but risky. The
risk is in the uncertainty of final separation of the diastereo-
mers, which must be accomplished in order to complete their
identification. That risk is maximized because it is postponed
to the very end of the synthesis. The fluorous mixture synthe-
sis produced all four isomers of petrocortyne in individual
pure form. The extra effort in making precursors in enantio-
pure form and tagging them with fluorous tags paid divi-
dends in the end with easy separation and identification by
fluorous demixing.
Comparison of optical rotations of the four synthetic and
two natural samples of 1 showed that both natural samples
had the C3-(S) configuration but left unresolved the configu-
ration at C14. Comparison of spectra of Mosher derivatives
of the synthetic and natural samples showed that both natu-
ral samples had the (3S,14S) configuration. Because we have
all possible diastereomers and their Mosher esters, this
comparison is accomplished by matching spectra and does
not rely on the advanced Mosher rule. At the same time,
the use of the Mosher rule has been validated for assigning
the difficult C14 stereocenter of the petrocortynes. As we
showed in the communication,10 a “short cut” variant in
which only one Mosher ester is made can also be used for this
stereocenter. Finally, for compounds that differ from petro-
cortyne only in areas remote from the stereocenters, the Mosher
rule again becomes completely unnecessary; it suffices to simply
22.9 mmol) and BH3 SMe2 (2.5 mL, 26.4 mmol), and the title
3
compound S-21 (6.99 g, 73%, 94% ee) was obtained. [R]25
=
D
þ22.1 (c=1.17, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.26 (d,
J=8.1 Hz, 2 H), 6.88 (d, J=8.4 Hz, 2 H), 5.89 (dt, J=15.0, 6.9
Hz, 1 H), 5.59 (dd, J = 15.0, 5.7 Hz, 1 H), 4.82 (t, J = 6.0 Hz,
1 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.43 (t, J=6.6 Hz, 2 H), 2.05 (q,
J=6.6 Hz, 2 H), 1.86 (d, J=6.3 Hz, 1 H), 1.63-1.54 (m, 2 H),
1.45-1.28 (m, 6 H), 0.94 (s, 9 H), 0.12 (s, 6 H); 13C NMR (75
MHz, CDCl3) δ 159.0, 133.9, 130.7, 129.2, 128.8, 113.7, 105.7,
88.7, 72.4, 70.0, 63.2, 55.2, 31.8, 29.6, 28.9, 28.7, 26.0(2C), 16.4,
-4.7; IR (film) 3405, 2931, 2857, 1613, 1513, 1464, 1362, 1302,
1249, 1091, 1035, 910, 828, 776, 733 cm-1; MS (EI) m/z 439 (Mþ
þ Na); HRMS (ESI) m/z (Mþ þ Na) calcd for C25H40O3NaSi
439.2644, found 439.2640.
(R,E)-tert-Butyl(3-(diisopropyl(4,4,5,5,6,6,7,7,7-nonafluorohep-
tyl)silyloxy)-11-(4-methoxybenzyloxy)undec-4-en-1-ynyl)dimethyl-
silane (R-22a). Trifluoromethanesulfonic acid (neat, 1.9 mL,
21.7 mmol) was slowly added to silane C4F9(CH2)3(iPr)2SiH
(neat, 8.67 g, 23.0 mmol) at 0 °C. After being stirred for 20 min at
the same temperature, the mixture was warmed to room tem-
perature and stirred for 15 h. To it CH2Cl2 (24 mL) was added at
-60 °C, followed by a solution of alcohol R-21 (6.00 g, 14.4
mmol) in CH2Cl2 (36 mL) and 2,6-lutidine (3.3 mL, 28.7 mmol).
The resulting mixture was warmed to room temperature and
stirred for further 2 h. Saturated aqueous NH4Cl (75 mL) was
then added to quench the reaction at 0 °C. The mixture was
extracted with Et2O (3 ꢀ 150 mL), and the organic layers were
combined, washed with water, dried over MgSO4, and concentrated
1
make one Mosher ester, record its H NMR spectra, and
match that to the library of spectra reported herein.
2950 J. Org. Chem. Vol. 75, No. 9, 2010

Sui et al.
JOCArticle
in vacuo. The crude product was purified by column chromato-
graphy (hexane/EtOAc = 19:1) to afford the title compound
R-22a (9.94 g, 87%): [R]25D=þ1.1 (c=1.20, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.26 (d, J= 8.4 Hz, 2 H), 6.88 (d, J =8.4
Hz, 2 H), 5.79 (dtd, J=15.0, 6.9, 0.9 Hz, 1 H), 5.51 (dd, J=15.3,
5.7 Hz, 1 H), 4.88 (d, J=6.0 Hz, 1 H), 4.43 (s, 2 H), 3.80 (s, 3 H),
3.43 (t, J=6.6 Hz, 2 H), 2.19-2.00 (m, 4 H), 1.76-1.69 (m, 2 H),
1.61-1.53 (m, 2 H), 1.43-1.28 (m, 6 H), 1.06 (br s, 14 H),
0.93 (s, 9 H), 0.79-0.73 (m, 2 H), 0.09 (s, 6 H); 13C NMR
(75 MHz, CDCl3) δ 159.1, 132.2, 130.8, 129.6, 129.2, 113.8,
106.3, 88.0, 72.5, 70.2, 64.0, 55.3, 34.5 (t, JCF = 21.8 Hz, 1 C),
31.8, 29.7, 29.0, 28.9, 26.0 (2 C), 17.6 (2 C), 17.5 (2 C) 16.5, 14.6,
12.7, 12.6, 11.0 -4.8; IR (film) 3020, 2933, 1514, 1423, 1215,
1133, 1044, 928, 755 cm-1; HRMS (ESI) m/z (Mþ þ Na) calcd
for C38H59O3NaSi2F9 813.3757, found 813.3793.
(S,E)-tert-Butyl(11-(4-methoxybenzyloxy)-3-(triisopropylsilyl-
oxy)undec-4-en-1-ynyl)dimethylsilane (S-22b). 2,6-Lutidine (3.5
mL, 30.1 mmol) and TIPSOTf (7.9 mL, 29.4 mmol) were seq-
uentially added to the solution of alcohol S-21 (6.90 g, 16.6 mmol)
in CH2Cl2 (160 mL) at 0 °C. The resulting mixture was stirred for
2 h at the same temperature. Saturated aqueous NH4Cl (80 mL)
was then added to quench the reaction. The mixture was extracted
with Et2O (3 ꢀ 150 mL), the organic layers were combined and
washed with water, dried over MgSO4, and concentrated in vacuo.
The crude product was purified by column chromatography (hexane/
EtOAc=19:1) to afford the title compound S-22b (8.53 g, 90%):
[R]25D =-1.0 (c=0.92, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.26 (d, J=8.7 Hz, 2 H), 6.88 (d, J=8.7 Hz, 2 H), 5.80 (dtd, J=
15.3, 6.6, 0.9 Hz, 1 H), 5.52 (dd, J=15.0, 5.4 Hz, 1 H), 4.92 (dd, J=
5.1, 0.6 Hz, 1 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.43 (t, J=6.6 Hz, 2 H),
2.04 (q, J=6.6 Hz, 2 H), 1.61-1.54 (m, 2 H), 1.43-1.28 (m, 6 H),
1.15-1.06 (m, 21 H), 0.92 (s, 9 H), 0.09 (s, 6 H); 13C NMR (75
MHz, CDCl3) δ159.1, 131.7, 130.8, 129.9, 129.2, 113.7, 106.8, 87.5,
72.5, 70.2, 63.9, 55.3, 31.8, 29.7, 28.9 (2 C), 26.1 (2 C), 18.0, 16.5,
12.2, -4.7; IR (film) 3019, 2934, 2864, 1514, 1424, 1216, 1039, 928,
756 cm-1; HRMS (ESI) m/z (MþþNa) calcd for C34H60O3NaSi2
595.3979, found 595.3959.
(R,E)-tert-Butyl(3-(diisopropyl(4,4,5,5,6,6,7,7,7-nonafluorohep-
tyl)silyloxy)-11-iodoundec-4-en-1-ynyl)dimethylsilane and (S,E)-
tert-Butyl(11-iodo-3-(triisopropylsilyloxy)undec-4 -en-1-ynyl)di-
methylsilane (qrac-23a,b). DDQ (9.93 g, 43.7 mmol) was added
to the mixture of compound R-22a (9.94 g, 12.6 mmol) and
compound S-22b (7.24 g, 12.6 mmol) in CH2Cl2 (250 mL) and
H2O (13 mL) at room temperature. The reaction was monito-
red by TLC until completion, and then saturated NaHCO3
aqueous solution was added. The mixture was extracted with
CH2Cl2 (3 ꢀ 150 mL), and the organic layers were combined,
washed with saturated NaHCO3 aqueous solution and brine,
dried over MgSO4, and concentrated in vacuo. The crude pro-
duct was purified by column chromatography (hexane/Et2O =
4:1) to afford the title compound, which was contaminated with
a tiny amount of 4-(methoxymethyl)benzaldehyde and was used
in the following step without further purification.
H), 0.79-0.73 (m, 2 H), 0.09 (s, 6 H); 13C NMR (75 MHz,
CDCl3) δ 131.9, 131.4, 130.1, 129.8, 106.8, 106.2, 88.1, 87.6,
64.0, 63.8, 34.5 (t, JCF = 21.8 Hz), 33.5, 31.6, 30.3, 28.7, 28.0,
26.0, 18.0, 17.6, 17.5, 16.5, 14.6, 12.7, 12.6, 12.2, 10.9, 7.1; IR
(film) 2932, 2862, 1464, 1384, 1236, 1133, 1057, 908, 826, 733;
MS (EI) for qrac-23a m/z 737 (Mþ - C3H7); qrac-23b m/z 519
(Mþ-C3H7); HRMS (ESI) qrac-23a m/z (Mþ-C3H7) calcd for
C27H43OF9Si2I 737.1753, found 737.1748; qrac-23b m/z (Mþ -
C3H7) calcd for C23H44OSi2I 519.1976, found 519.1993.
(12R,23R,E)-23-((tert-Butyldimethylsilyl)ethynyl)-29,29,30,30,
31,31,32,32,32-nonafluoro-25,25-diisopropyl-4,24-dioxa-2-thia-25-
siladotriaconta-21-en-10,13-diyn-12-ol and (12R,23S,E)-23-((tert-
Butyldimethylsilyl)ethynyl)-25,25-diisopropyl-26-methyl-4,24-dioxa-
2-thia-25-silaheptacosa-21-en-10,13-diyn-12-ol (R-qdim-24a,b).
n-BuLi (4.0 mL, 1.6 M solution in THF, 6.4 mmol) was slowly
added to the solution of alkyne R-18 (679.0 mg, 3.0 mmol) in
THF (15 mL) at -30 °C. After stirring at the same temperature
for 1 h, the mixture was cooled to -78 °C, and HMPA (1.5 mL)
was added followed by a solution of iodide qrac-23a,b (1.01 g,
1.5 mmol) in THF (7.5 mL). The resulting mixture was stirred
for 2 h at -78 °C and warmed to room temperature. After
stirring at room temperature for overnight, saturated NH4Cl
aqueous solution (20 mL) was added, the organic layer was
separated, and the aqueous layer was extracted with Et2O (3 ꢀ
20 mL). The combined organic layers were washed with water
and brine, dried over MgSO4, and concentrated in vacuo. The
crude product was purified by column chromatography (hexane/
Et2O = 4:1) to afford the mixture R-qdim-24a,b (370.7 mg,
34%), which was contaminated with some inseparable impuri-
ties and was used in the following step without further purifica-
tion. 1H NMR (500 MHz, CDCl3) δ 5.80-5.76 (m, 1 H),
5.55-5.49 (m, 1 H), 5.10-5.08 (m, 1 H), 4.93-4.88 (m, 1 H),
4.63 (s, 2 H), 3.52 (t, J=6.5 Hz, 2 H), 2.23 (quind, J=7.0, 1.5
Hz, 4 H), 2.15 (s, 3 H), 2.12-2.06 (m, 1 H), 2.05 (q, J=6.5 Hz,
2 H), 1.78-1.69 (m, 1 H), 1.64-1.45 (m, 8 H), 1.40-1.25 (m, 6 H),
1.10-1.05 (m, 17.5 H), 0.93 (s, 9 H), 0.78-0.74 (m, 1 H), 0.09 (s,
6 H); HRMS (ESI) R-qdim-24a m/z (Mþ þ Na) calcd for
C42H67O3F9NaSi2S 901.4103, found 901.4134; R-qdim-24b
m/z (Mþ þ Na) calcd for C38H68O3NaSi2S 683.4325, found
683.4340.
(12S,23R,E)-23-((tert-Butyldimethylsilyl)ethynyl)-29,29,30,30,
31,31,32,32,32-nonafluoro-25,25-diisopropyl-4,24-dioxa-2-thia-
25-siladotriaconta-21-en-10,13-diyn-12-ol and (12S,23S,E)-23-
((tert-Butyldimethylsilyl)ethynyl)-25,25-diisopropyl-26-methyl-4,
24-dioxa-2-thia-25-silaheptacosa-21-en-10,13-diyn-12-ol (S-qdim-
24a,b). Following the same procedure as for R-qdim-24a,b, alkyne
S-18 (679.0 mg, 3.0 mmol) was reacted with n-BuLi (4.0 mL, 1.6 M
solution in THF, 6.4 mmol), HMPA (1.5 mL), and iodide qrac-
23a,b (1.01 g, 1.5 mmol). The title mixture S-qrac-24a,b (356.2 mg,
33%) was obtained, which was contaminated with some insepar-
able impurities and was used in the following step without further
purification. 1H NMR (600 MHz, CDCl3) δ 5.82-5.77 (m, 1 H),
5.55-5.49 (m, 1 H), 5.10-5.08 (m, 1 H), 4.92-4.88 (m, 1 H), 4.63
(s, 2 H), 3.52 (t, J=6.6 Hz, 2 H), 2.23-2.20 (m, 4 H), 2.15 (s, 3 H),
2.14-2.09 (m, 1 H), 2.05 (q, J=6.6 Hz, 2 H), 1.76-1.70 (m, 1 H),
1.63-1.43 (m, 8 H), 1.40-1.25 (m, 6 H), 1.11-1.03 (m, 17.5 H),
0.92 (s, 9 H), 0.77-0.74 (m, 1 H), 0.09 (s, 6 H); HRMS (ESI)
S-qdim-24a m/z (MþþNa) calcd for C42H67O3F9NaSi2S 901.4103,
found 901.4072; S-qdim-24b m/z (Mþ þ Na) calcd for C38H68-
O3NaSi2S 683.4325, found 683.4296
To a solution of triphenylphosphine (5.44 g, 20.7 mmol) in
CH2Cl2 (27 mL) was slowly added a solution of iodine (5.26 g,
20.7 mmol) in CH2Cl2 (27 mL), followed by a mixture of
imidazole (1.55 g, 22.8 mmol) and alcohol (5.74 g, 10.2 mmol)
in CH2Cl2 (80 mL) at room temperature. After 2 h, the reaction
was quenched with saturated aqueous NaHCO3 (100 mL). The
mixture was extracted with Et2O (3 ꢀ 100 mL), and the organic
layer was washed with saturated aqueous Na2S2O3 (100 mL),
water, and brine, dried over MgSO4, and concentrated in vacuo.
The crude product was purified by column chromatography
(hexane/EtOAc=99:1) to afford the title compound qrac-23a,b
(12R,23R,E)-23-((tert-Butyldimethylsilyl)ethynyl)-12-(diisopro-
pyl(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)silyloxy)-29,29,30,30,31,31,
32,32,32-nonafluoro-25,25-diisopropyl-4,24-dioxa-2-thia-25-silado-
triaconta-21-en-10,13-diyne and (12R,23S,E)-23-((tert-Butyl-
dimethylsilyl)ethynyl)-12-(diisopropyl(4,4,5,5,6,6,7,7,7-nonafluoro-
heptyl)silyloxy)-25,25-diisopropyl-26-methyl-4,24-dioxa-2-thia-25-
silaheptacosa-21-en-10,13-diyne (qdim-25a,b/a). Trifluoromethane-
sulfonic acid (neat, 72.4 μL, 0.82 mmol) was slowly added to silane
1
(5.62 g, 42% for two steps): H NMR (300 MHz, CDCl3) δ
5.83-5.74 (m, 1 H), 5.52 (dd, J=15.0, 5.1 Hz, 1 H), 4.94-4.88
(m, 1 H), 3.18 (t, J=6.9 Hz, 2 H), 2.19-2.04 (m, 4H), 1.88-1.70
(m, 4H), 1.47-1.27 (m, 8 H), 1.19-1.02 (m, 17.5 H), 1.06 (s, 9
J. Org. Chem. Vol. 75, No. 9, 2010 2951

Sui et al.
JOCArticle
C4F9(CH2)3(iPr)2SiH (neat, 359.0 mg, 0.95 mmol) at 0 °C. After
being stirred for 20 min at the same temperature, the mixture was
warmed to room temperature and stirred for 15 h. To it was added
CH2Cl2 (0.8 mL) at -60 °C, followed by a solution of alcohol
R-qdim-24a,b (200.0 mg, 0.27 mmol) in CH2Cl2 (1.2 mL) and 2,6-
lutidine (0.13 mL, 1.09 mmol). The resulting mixture was warmed
to room temperature and stirred for further 2 h. Saturated aqueous
NH4Cl (10 mL) was then added to quench the reaction at 0 °C. The
mixture was extracted with Et2O (3 ꢀ 10 mL), and the organic
layers were combined, washed with water, dried over MgSO4, and
concentrated in vacuo. The crude product was purified by column
chromatography (hexane/Et2O = 97:3) to afford the title mixture
(m, 3 H), 1.62-1.43 (m, 8 H), 1.40-1.24 (m, 6 H), 1.13-1.05 (m,
31.5 H), 0.92 (s, 9 H), 0.79-0.75 (m, 3 H), 0.09 (s, 6 H); MS (EI)
qdim-26a/a m/z 1215 (MþþNa); qdim-26b/a m/z 998 (MþþNaþ
H); qdim-26a/c m/z 1165 (Mþ þ Na); qdim-26b/c m/z 948 (Mþ þ
Na þ H) HRMS (ESI) qdim-26a/a m/z (Mþ þ Na) calcd for
C53H82O3F18NaSi3 1215.5182, found 1215.5067; qdim-26b/a
m/z (Mþ þ Na) calcd for C49H83O3F9NaSi3 997.5404, found
997.5370; qdim-26a/c m/z (MþþNa) calcd for C52H82O3F16NaSi3
1165.5214, found 1165.5240; qdim-26b/c m/z (Mþ þNa) calcd for
C48H83O3F7NaSi3 947.5436, found 947.5422.
(8R,19R,E)-21-(tert-Butyldimethylsilyl)-8,19-bis(diisopropyl(4,
4,5,5,6,6,7,7,7-nonafluoroheptyl)silyloxy)henicosa-17-en-6,9,20-
triynal, (8R,19S,E)-21-(tert-Butyldimethylsilyl)-8-(diisopropyl(4,
4,5,5,6,6,7,7,7-nonafluoroheptyl)silyloxy)-19-(triisopropylsilyloxy)-
henicosa-17-en-6,9,20-triynal, (8S,19R,E)-21-(tert-Butyldimethyl-
silyl)-19-(diisopropyl(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)silyloxy)-
8-((4,4,5,5,6,6,6-heptafluorohexyl)diisopropylsilyloxy)henicosa-
17-en-6,9,20-triynal, and (8S,19S,E)-21-(tert-Butyldimethylsilyl)-
8-((4,4,5,5,6,6,6-heptafluorohexyl)diisopropylsilyloxy)-19-(triisopro-
pylsilyloxy)henicosa-17-en-6,9,20-triynal (qdim-27a,b/a,c).NaHCO3
(196.2 mg, 2.34 mmol) was added followed by DMP (371.5 mg, 0.88
mmol) to the solution of mixture qdim-26a,b/a,c (270.0 mg, 0.29
mmol) in CH2Cl2 (4.5 mL) at room temperature. The resulting
mixture was stirred at the same temperature for 2 h. Saturated
NH4Cl aqueous solution (15 mL) was added. The organic phase was
separated, and the aqueous phase was extracted with CH2Cl2 (3 ꢀ
10 mL). The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The crude product was
purified by column chromatography (hexane/Et2O=9:1) to afford
the mixture qdim-27a,b/a,c (200.3 mg, 74%): 1H NMR (600 MHz,
CDCl3) δ9.76 (s, 1 H), 5.82-5.76 (m, 1 H), 5.54-5.49 (m, 1 H), 5.20
(s, 1 H), 4.92-4.87 (m, 1 H), 2.44 (t, J=7.2 Hz, 2 H), 2.24 (t, J=6.6
Hz, 2 H), 2.19 (t, J=7.2 Hz, 2 H), 2.14-2.02 (m, 5 H), 1.79-1.70
(m, 5 H), 1.57-1.46 (m, 6 H), 1.38-1.33 (m, 4 H), 1.31-1.25 (m, 2
H), 1.13-1.05 (m, 31.5 H), 0.92 (s, 9 H), 0.79-0.75 (m, 3 H), 0.09
(s, 6 H); HRMS (ESI) qdim-27a/a m/z (Mþ þ Na) calcd for
C53H80O3F18NaSi3 1213.5026, found 1213.5062; qdim-27b/a m/z
(Mþ þ Na) calcd for C49H81O3F9NaSi3 995.5248, found 995.5237;
qdim-27a/c m/z (MþþNa) calcd for C52H80O3F16NaSi3 1163.5058,
found 1163.5033; qdim-27b/c m/z(MþþNa) calcd for C48H81O3F7-
NaSi3 945.5279, found 945.5278.
(10R,21R,E)-21-((7Z,13Z,29Z)-32-(tert-Butyldimethylsilyl)do-
triaconta-7,13,29-trien-1,31-diynyl)-10-((tert-butyldimethylsilyl)-
ethynyl)-1,1,1,2,2,3,3,4,4,27,27,28,28,29,29,30,30,30-octadecafluoro-
8,8,23,23-tetraisopropyl-9,22-dioxa-8,23-disilatriacont-11-en-19-yne,
(5S,16R,E)-16-((7Z,13Z,29Z)-32-(tert-Butyldimethylsilyl)dotri-
aconta-7,13,29-trien-1,31-diynyl)-5-((tert-butyldimethylsilyl)ethy-
nyl)-22,22,23,23,24,24,25,25,25-nonafluoro-3,3,18,18-tetraisopropyl-
2-methyl-4,17-dioxa-3,18-disilapentacos-6-en-14-yne, (9S,20R,E)-
9-((7Z,13Z,29Z)-32-(tert-Butyldimethylsilyl)dotriaconta-7,13,
29-trien-1,31-diynyl)-20-((tert-Butyldimethylsilyl)ethynyl)-1,1,1,
2,2,3,3,26,26,27,27,28,28,29,29,29-hexadecafluoro-7,7,22,22-tetra-
isopropyl-8,21-dioxa-7,22-disilanonacos-18-en-10-yne, and (5S,16S,
E)-16-((7Z,13Z,29Z)-32-(tert-Butyldimethylsilyl)dotriaconta-7,13,
29-trien-1,31-diynyl)-5-((tert-butyldimethylsilyl)ethynyl)-22,22,23,
23,24,24,24-heptafluoro-3,3,18,18-tetraisopropyl-2-methyl-4,17-
dioxa-3,18-disilatetracos-6-en-14-yne (qdim-28a,b/a,c). NaHMDS
(0.63 mL, 1.0 M solution in THF, 0.63 mmol) was added to the
solution of phosphonium bromide 13 (658.9 mg, 0.82 mmol) in
THF (2.1 mL) at 0 °C. The resulting orange solution was stirred at
the same temperature for 10 min and then cooled to -78 °C. The
solution of aldehyde qdim-27a,b/a,c (190.0 mg, 0.21 mmol) in
THF (1.4 mL) was then added. The mixture was stirred at -78 °C
for 2 h. Saturated NH4Cl aqueous solution (10 mL) was added, the
organic phase was separated, and aqueous phase was extrac-
ted with Et2O (3 ꢀ 10 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The crude product was purified by column chromatography
1
qdim-25a,b/a (272.5 mg, 99%): H NMR (600 MHz, CDCl3) δ
5.81-5.77 (m, 1 H), 5.54-5.49 (m, 1 H), 5.21 (s, 1 H), 4.92-4.87
(m, 1 H), 4.62 (s, 2 H), 3.50 (t, J=6.6 Hz, 2 H), 2.23-2.18 (m, 4 H),
2.14 (s, 3 H), 2.12-2.03 (m, 5 H), 1.80-1.73 (m, 3 H), 1.62-1.41
(m, 8 H), 1.40-1.33 (m, 4 H), 1.31-1.25 (m, 2 H), 1.12-1.05 (m,
31.5 H), 0.92 (s, 9 H), 0.79-0.75 (m, 3 H), 0.09 (s, 6 H); MS (EI)
qdim-25a/a m/z 1275 (MþþNa); qdim-25b/a m/z 1057 (MþþNa);
HRMS (ESI) qdim-25a/a m/z (Mþ þ Na) calcd for C55H86O3F18-
NaSi3S 1275.5216, found 1275.5210; qdim-25b/a m/z (Mþ þ Na)
calcd for C51H87O3F9NaSi3S 1057.5438, found 1057.5407.
(12S,23R,E)-23-((tert-Butyldimethylsilyl)ethynyl)-29,29,30,30,
31,31,32,32,32-nonafluoro-12-((4,4,5,5,6,6,6-heptafluorohexyl)-
diisopropylsilyloxy)-25,25-diisopropyl-4,24-dioxa-2-thia-25-sila-
dotriaconta-21-en-10,13-diyne and (12S,23S,E)-23-((tert-Butyl-
dimethylsilyl)ethynyl)-12-((4,4,5,5,6,6,6-heptafluorohexyl)diisopro-
pylsilyloxy)-25,25-diisopropyl-26-methyl-4,24-dioxa-2-thia-25-sila-
heptacosa-21-en-10,13-diyne (qdim-25a,b/c). Following the same
procedure as for R-qdim-24a,b, the mixture S-qdim-24a,b (250.0
mg, 0.34 mmol) was reacted with trifluoromethanesulfonic acid
(neat, 79.6 μL, 0.90 mmol), silane C3F7(CH2)3(iPr)2SiH (neat,
333.6 mg, 1.02 mmol), and 2,6-lutidine (0.14 mL, 1.19 mmol),
and the title mixture qdim-25a,b/c (277.7 mg, 85%) was obtained:
1H NMR (600 MHz, CDCl3) δ 5.80-5.77 (m, 1 H), 5.54-5.50 (m,
1 H), 5.21 (s, 1 H), 4.92-4.87 (m, 1 H), 4.62 (s, 2 H), 3.50 (t, J=6.6
Hz, 2 H), 2.23-2.18 (m, 4 H), 2.14 (s, 3 H), 2.12-2.03 (m, 5 H),
1.80-1.73 (m, 3 H), 1.62-1.43 (m, 8 H), 1.40-1.33 (m, 4 H),
1.31-1.25 (m, 2 H), 1.12-1.05 (m, 31.5 H), 0.92 (s, 9 H), 0.79-0.75
(m, 3 H), 0.09 (s, 6 H); MS (EI) qdim-25a/c m/z 1225 (Mþ þNa);
qdim-25b/c m/z 1008 (Mþ þ Na þ H); HRMS (ESI) qdim-25a/c
m/z (Mþ þ Na) calcd for C54H86O3F16NaSi3S 1225.5248, found
1225.5231; qdim-25b/c m/z (Mþ þ Na) calcd for C50H87O3F7Na-
Si3S 1007.5470, found 1007.5438.
(8R,19R,E)-21-(tert-Butyldimethylsilyl)-8,19-bis(diisopropyl(4,
4,5,5,6,6,7,7,7-nonafluoroheptyl)silyloxy)henicosa-17-en-6,9,20-
triyn-1-ol, (8R,19S,E)-21-(tert-Butyldimethylsilyl)-8-(diisopropyl-
(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)silyloxy)-19-(triisopropylsilyl-
oxy)henicosa-17-en-6,9,20-triyn-1-ol, (8S,19R,E)-21-(tert-Butyl-
dimethylsilyl)-19-(diisopropyl(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-
silyloxy)-8-((4,4,5,5,6,6,6-heptafluorohexyl)diisopropylsilyloxy)-
henicosa-17-en-6,9,20-triyn-1-ol, and (8S,19S,E)-21-(tert-Butyl-
dimethylsilyl)-8-((4,4,5,5,6,6,6-heptafluorohexyl)diisopropylsilyl-
oxy)-19-(triisopropylsilyloxy)henicosa-17-en-6,9,20-triyn-1-ol
(qdim-26a,b/a,c). Solid NaHCO3 (324.4 mg, 3.86 mmol) and
MeI (9.0 mL) were added to the solution of mixture qdim-25a,b/a
(270.0 mg, 0.27 mmol) and qdim-25a,b/c (259.4 mg, 0.27 mmol) in
a mixture of acetone (16.0 mL) and water (0.86 mL). The resulting
suspension was stirred in a sealed tube at 45 °C for 14 h. The
mixture was diluted with water (20 mL) and EtOAc (30 mL). The
organic layer was separated, and the aqueous phase was extracted
with EtOAC (3 ꢀ 20 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The crude product was purified by column chromatography
(hexane/Et2O = 3:1) to afford the mixture qdim-26a,b/a,c (451.0
1
mg, 90%): H NMR (600 MHz, CDCl3) δ 5.82-5.76 (m, 1 H),
5.54-5.49 (m, 1 H), 5.20 (s, 1 H), 4.92-4.87 (m, 1 H), 3.64 (t, J=
6.6 Hz, 2 H), 2.24-2.18 (m, 4 H), 2.14-2.03 (m, 5 H), 1.78-1.73
2952 J. Org. Chem. Vol. 75, No. 9, 2010

Sui et al.
JOCArticle
(hexane/CH2Cl2=9:1) to afford the title compound qdim-28a,b/a,
c (137.2 mg, 44%): 1H NMR (600 MHz, CDCl3) δ 5.96 (dt, J =
10.8, 7.8 Hz, 1 H), 5.83-5.76 (m, 1 H), 5.54-5.47 (m, 2 H),
5.38-5.30 (m, 4 H), 5.21 (s, 1 H), 4.92-4.87 (m, 1 H), 2.32 (q, J=
7.2 Hz, 2 H), 2.20 (q, J = 7.8 Hz, 2 H), 2.15-2.08 (m, 3 H),
2.06-1.98 (m, 10 H), 1.79-1.72 (m, 3 H), 1.53-1.47 (m, 4 H),
1.44-1.25 (m, 36 H), 1.13-1.05 (m, 31.5 H), 0.96 (s, 9 H), 0.92 (s,
9 H), 0.79-0.75 (m, 3 H), 0.13 (s, 6 H), 0.09 (s, 6 H).
Demix the Mixture qdim-28a,b/a,c. The mixture qdim-28a,b/
a,c (137.2 mg, 0.09 mmol) was dissolved in CH3CN/THF (3:2)
(6 mL) and demixed by semipreparative fluorous HPLC (Fluoros-
Flash PFC8 column, CH3CN/THF=100:0 to 85:15 in 45 min,
then 85:15 for another 20 min). The four desired compounds
were obtained. 28b/c: 41.3 mg, tR = 20.3 min. 28b/a: 39.5 mg,
tR = 25.5 min. 28a/c: 16.0 mg, tR = 42.2 min. 28a/a: 19.7 mg,
tR = 52.7 min.
THF, 0.07 mmol), the title compound (3R,14S)-1 (2.1 mg, 41%)
was obtained: [R]25D=-9.0 (c=0.16, CH3OH); 1H NMR (600
MHz, CDCl3) δ 6.00 (dt, J = 10.8, 7.2 Hz, 1 H), 5.91 (dt, J =
15.0, 7.2 Hz, 1 H), 5.62 (dd, J=15.6, 6.0 Hz, 1 H), 5.44 (dd, J=
10.8, 1.2 Hz, 1 H), 5.39-5.31 (m, 4 H), 5.09 (dt, J=7.2, 1.8 Hz,
1 H), 4.84 (t, J=6.0 Hz, 1 H), 3.07 (d, J=1.8 Hz, 1 H), 2.57 (d,
J=1.8 Hz, 1 H), 2.32 (q, J=7.2 Hz, 2 H), 2.23 (qd, J=6.9, 1.8
Hz, 4 H), 2.10 (d, J = 6.6 Hz, 1 H), 2.08 (q, J = 7.2 Hz, 2 H),
2.06-1.99 (m, 8 H), 1.85 (d, J = 6.0 Hz, 1 H), 1.56-1.49 (m, 4
H), 1.46-1.25 (m, 36 H); 13C NMR (150 MHz, CDCl3) δ 146.33,
134.35, 130.22, 130.08, 129.66, 129.31, 128.52, 107.88, 85.05,
85.00, 83.26, 81.12, 80.58, 78.08 (2 C), 74.02, 62.80, 52.55, 31.77,
30.27, 29.77, 29.68 (3 C), 29.66 (3 C), 29.59, 29.45, 29.38, 29.34 (2
C), 29.18, 28.88, 28.73, 28.57, 28.55, 28.51, 28.21, 27.92, 27.24,
27.14, 27,09, 26.66, 18.65, 18.63; IR (film) 3053, 2986, 2929,
1423, 1265, 909, 736, 706; MS (EI) m/z 678 (Mþ þ Na þ H);
HRMS (ESI) m/z (Mþ þ Na) calcd for C46H70O2Na 677.5274,
found 677.5307.
(3R,4E,14R,21Z,27Z,43Z)-Hexatetraconta-4,21,27,43-tetraen-
1,12,15,45-tetrayne-3,14-diol ((3R,14R)-1). Following the same
procedure for (3S,14S)-1, the compound 28a/a (18.5 mg, 0.011
mmol) was reacted with TBAF (0.09 mL, 1.0 M solution in
THF, 0.09 mmol), the title compound (3R,14R)-1 (5.1 mg, 69%)
was obtained: [R]25D=-11.2 (c=0.20, CH3OH); 1H NMR (600
MHz, CDCl3) δ 6.00 (dt, J = 10.8, 7.2 Hz, 1 H), 5.91 (dt, J =
15.6, 6.6 Hz, 1 H), 5.62 (ddd, J=15.0, 6.0, 1.2 Hz, 1 H), 5.44 (d,
J=10.8, 1 H), 5.39-5.31 (m, 4 H), 5.09 (dt, J=7.2, 1.8 Hz, 1 H),
4.84 (t, J=6.0 Hz, 1 H), 3.07 (d, J=1.2 Hz, 1 H), 2.57 (d, J=1.8
Hz, 1 H), 2.32 (q, J=7.2 Hz, 2 H), 2.23 (qd, J=7.2, 1.8 Hz, 4 H),
2.11 (d, J=7.2 Hz, 1 H), 2.08 (q, J=7.2 Hz, 2 H), 2.06-1.99 (m,
8 H), 1.86 (d, J = 6.0 Hz, 1 H), 1.56-1.49 (m, 4 H), 1.46-1.25
(m, 36 H); 13C NMR (150 MHz, CDCl3) δ 146.33, 134.35,
130.22, 130.08, 129.66, 129.31, 128.52, 107.88, 85.04, 84.99,
83.26, 81.13, 80.58, 78.09 (2 C), 74.03, 62.79, 52.55, 31.77,
30.28, 29.77, 29.69 (3 C), 29.66 (3 C), 29.59, 29.45, 29.38,
29.34 (2 C), 29.18, 28.88, 28.73, 28.56, 28.54, 28.50, 28.20,
27.92, 27.24, 27.14, 27,09, 26.66, 18.65, 18.63; IR (film) 3054,
2986, 1423, 1265, 909, 735, 705; MS (EI) m/z 678 (MþþNaþH);
HRMS (ESI) m/z (Mþ þ Na) calcd for C46H70O2Na 677.5274,
found 677.5295.
(3S,4E,14S,21Z,27Z,43Z)-Hexatetraconta-4,21,27,43-tetraen-
1,12,15,45-tetrayne-3,14-diol ((3S,14S)-1). TBAF (0.24 mL, 1.0 M
solution in THF, 0.24 mmol) was added to a solution of compound
28b/c (40.0 mg, 0.029 mmol) in THF (0.6 mL) at room tempera-
ture. The mixture then was stirred for 1 h at this temperature and
quenched with saturated aqueous NH4Cl. The resulting mixture
was extracted with CH2Cl2 (3 ꢀ 5 mL). The organic layers were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The crude product was purified by column chro-
matography (hexane/Et2O = 4:1) to give compound (3S,14S)-1
(11.4 mg, 59%): [R]25D=þ10.5 (c=0.30, CH3OH); 1HNMR(600
MHz, CDCl3) δ 6.00 (dt, J=10.8, 7.2 Hz, 1 H), 5.91 (dt, J=15.0,
7.0 Hz, 1 H), 5.62 (dd, J=15.0, 6.0 Hz, 1 H), 5.44 (dd, J=10.8, 1.2
Hz, 1 H), 5.39-5.31 (m, 4 H), 5.09 (dt, J=7.2, 1.8 Hz, 1 H), 4.84 (t,
J=6.0 Hz, 1 H), 3.07 (d, J=1.8 Hz, 1 H), 2.57 (d, J=2.4 Hz, 1 H),
2.32 (q, J=7.2 Hz, 2 H), 2.23 (qd, J=6.0, 1.2 Hz, 4 H), 2.13 (d, J=
7.2 Hz, 1 H), 2.08 (q, J=7.2 Hz, 2 H), 2.06-1.99 (m, 8 H), 1.88 (d,
J = 6.0 Hz, 1 H), 1.55-1.49 (m, 4 H), 1.46-1.25 (m, 36 H); 13
C
NMR (150 MHz, CDCl3) δ 146.31, 134.32, 130.21, 130.07, 129.65,
129.31, 128.52, 107.88, 85.02, 84.97, 83.26, 81.13, 80.58, 78.10,
78.10, 74.01, 62.77, 52.54, 31.76, 30.26, 29.76, 29.68 (3 C), 29.65 (3
C), 29.57, 29.44, 29.37, 29.33 (2 C), 29.17, 28.87, 28.72, 28.56,
28.54, 28.49, 28.19, 27.92, 27.23, 27.13, 27,09, 26.65, 18.64, 18.63;
IR (film) 3054, 2986, 2929, 2855, 1422, 1265, 909, 740; MS (EI) m/z
678 (Mþ þ Na þ H); HRMS (ESI) m/z (Mþ þ Na) calcd for
C46H70O2Na 677.5274, found 677.5321.
Synthesis of Mosher Esters of (3S,14R)-1 and (3S,14S)-
1. (2R,20R)-((3S,4E,14R,21Z,27Z,43Z)-Hexatetraconta-4,21,27,
43-tetraen-1,12,15,45-tetrayne-3,14-diyl) Bis(3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate). R-MTPA (1.8 mg, 0.0076 mmol) was
added to a solution of alcohol (3S,14R)-1 (1.0 mg, 0.0015 mmol)
in DCM (0.5 mL) at rt, followed by addition of DCC (1.9 mg,
0.0092 mmol) and DMAP (0.2 mg, 0.0015 mmol). The resulting
mixture was stirred for overnight. The solvent was evaporated,
and the crude product was purified by column chromatography
(hexane/EtOAc=9:1) to give title compound (1.0 mg, 62%): 1H
NMR (700 MHz, CDCl3) δ 7.55-7.52 (m, 4 H), 7.41-7.38 (m,
6 H), 6.21 (t, J=2.1 Hz, 1 H), 6.06 (dtd, J=15.4, 7.7, 1.4 Hz, 1 H),
6.02-5.98 (m, 2 H), 5.60 (ddt, J = 15.4, 7.0, 1.4 Hz, 1 H),
5.45-5.43 (m, 1 H), 5.38-5.30 (m, 4 H), 3.59 (s, 3 H), 3.55 (s,
3 H), 3.07 (t, J=1.4 Hz, 1 H), 2.59 (d, J=2.1 Hz, 1 H), 2.32 (qd,
J=7.7, 1.4 Hz, 2 H), 2.23 (td, J=7.0, 2.1 Hz, 2 H), 2.19 (td, J=
7.0, 2.1 Hz, 2 H), 2.08 (q, J=7.0 Hz, 2 H), 2.04-1.99 (m, 8 H),
1.56-1.21 (m, 40 H).
(3S,4E,14R,21Z,27Z,43Z)-Hexatetraconta-4,21,27,43-tetraen-
1,12,15,45-tetrayne-3,14-diol ((3S,14R)-1). Following the same
procedure for (3S,14S)-1, the compound 28b/a (38.0 mg, 0.027
mmol) was reacted with TBAF (0.22 mL, 1.0 M solution in
THF, 0.22 mmol), the title compound (3S,14R)-1 (10.4 mg,
59%) was obtained: [R]25D=þ9.5 (c=0.25, CH3OH); 1H NMR
(600 MHz, CDCl3) δ 6.00 (dt, J=10.8, 7.2 Hz, 1 H), 5.91 (dt, J=
15.6, 7.2 Hz, 1 H), 5.62 (ddd, J=15.6, 6.0, 0.6 Hz, 1 H), 5.44 (dd,
J=10.8, 1.2 Hz, 1 H), 5.39-5.31 (m, 4 H), 5.09 (dt, J=6.6, 1.2
Hz, 1 H), 4.84 (t, J=6.0 Hz, 1 H), 3.07 (d, J=1.8 Hz, 1 H), 2.57
(d, J=1.8 Hz, 1 H), 2.32 (q, J=7.2 Hz, 2 H), 2.23 (qd, J=6.5,
1.2 Hz, 4 H), 2.11 (d, J=7.2 Hz, 1 H), 2.08 (q, J=7.2 Hz, 2 H),
2.06-1.99 (m, 8 H), 1.87 (d, J = 6.0 Hz, 1 H), 1.56-1.49 (m, 4
H), 1.46-1.25 (m, 36 H); 13C NMR (150 MHz, CDCl3) δ 146.32,
134.33, 130.21, 130.07, 129.65, 129.31, 128.51, 107.87, 85.03,
84.98, 83.26, 81.12, 80.58, 78.09, 78.08, 74.02, 62.78, 52.54,
31.77, 30.26, 29.76, 29.68 (3 C), 29.66 (3 C), 29.58, 29.44,
29.37, 29.33 (2 C), 29.17, 28.87, 28.72, 28.56, 28.54, 28.50,
28.20, 27.91, 27.23, 27.13, 27,09, 26.65, 18.65, 18.63; IR (film)
3054, 2986, 2929, 2855, 1423, 1265, 909, 736; MS (EI) m/z 678
(Mþ þ Na þ H); HRMS (ESI) m/z (Mþ þ Na) calcd for
C46H70O2Na 677.5274, found 677.5267.
(2S,20S)-((3S,4E,14R,21Z,27Z,43Z)-Hexatetraconta-4,21,27,
43-tetraen-1,12,15,45-tetrayne-3,14-diyl) Bis(3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate). Following the above procedure, the
compound (3S,14R)-1 (1.0 mg, 0.0015 mmol) was reacted with
S-MTPA (1.8 mg, 0.0076 mmol) in the presence of DCC (1.9 mg,
0.0092 mmol) and DMAP (0.2 mg, 0.0015 mmol), and the title
1
(3R,4E,14S,21Z,27Z,43Z)-Hexatetraconta-4,21,27,43-tetraen-
1,12,15,45-tetrayne-3,14-diol ((3R,14S)-1). Following the same
procedure for (3S,14S)-1, the compound 28a/c (12.5 mg, 0.008
mmol) was reacted with TBAF (0.07 mL, 1.0 M solution in
compound (0.8 mg, 50%) was obtained: H NMR (700 MHz,
CDCl3) δ 7.56-7.52 (m, 4 H), 7.43-7.38 (m, 6 H), 6.21 (t, J =
2.1 Hz, 1 H), 6.03-5.97 (m, 3 H), 5.49 (ddt, J=15.4, 7.0, 1.4 Hz,
1 H), 5.45-5.43 (m, 1 H), 5.38-5.29 (m, 4 H), 3.59 (s, 3 H), 3.59
J. Org. Chem. Vol. 75, No. 9, 2010 2953

Sui et al.
JOCArticle
(s, 3 H), 3.07 (t, J=0.7 Hz, 1 H), 2.63 (d, J=2.1 Hz, 1 H), 2.32
(qd, J=7.7, 1.4 Hz, 2 H), 2.21 (td, J=7.7, 2.1 Hz, 2 H), 2.20 (td,
J=7.0, 2.1 Hz, 2 H), 2.05-1.99 (m, 10 H), 1.52-1.21 (m, 40 H).
(2R,20R)-((3S,4E,14S,21Z,27Z,43Z)-Hexatetraconta-4,21,27,
43-tetraen-1,12,15,45-tetrayne-3,14-diyl) Bis(3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate). Following the above procedure, the
compound (3S,14S)-1 (1.0 mg, 0.0015 mmol) was reacted with
R-MTPA (1.8 mg, 0.0076 mmol) in the presence of DCC (1.9 mg,
0.0092 mmol) and DMAP (0.2 mg, 0.0015 mmol), and the title
S-MTPA (1.8 mg, 0.0076 mmol) in the presence of DCC (1.9 mg,
0.0092 mmol) and DMAP (0.2 mg, 0.0015 mmol), and the title
1
compound (0.7 mg, 44%) was obtained: H NMR (700 MHz,
CDCl3) δ 7.55-7.52 (m, 4 H), 7.43-7.38 (m, 6 H), 6.21 (t, J=1.4
Hz, 1 H), 6.03-5.97 (m, 3 H), 5.49 (dd, J = 15.4, 7.0 Hz, 1 H),
5.44-5.43 (m, 1 H), 5.37-5.29 (m, 4 H), 3.59 (s, 3 H), 3.59 (s,
3 H), 3.06 (d, J=1.4 Hz, 1 H), 2.63 (d, J=2.1 Hz, 1 H), 2.32 (q,
J=7.0 Hz, 2 H), 2.23 (td, J=7.0, 2.1 Hz, 2 H), 2.19 (td, J=7.0,
2.1 Hz, 2 H), 2.05-1.99 (m, 10 H), 1.52-1.21 (m, 40 H).
1
compound (1.1 mg, 69%) was obtained: H NMR (700 MHz,
CDCl3) δ 7.56-7.54 (m, 4 H), 7.43-7.38 (m, 6 H), 6.21 (t, J=2.1
Hz, 1 H), 6.05 (dtd, J = 15.4, 7.0, 1.4 Hz, 1 H), 6.02-5.98 (m,
2 H), 5.59 (ddt, J=15.4, 7.0, 1.4 Hz, 1 H), 5.45-5.43 (m, 1 H),
5.37-5.29 (m, 4 H), 3.59 (s, 3 H), 3.55 (s, 3 H), 3.06 (d, J =
0.7 Hz, 1 H), 2.59 (d, J=2.1 Hz, 1 H), 2.32 (qd, J=7.7, 1.4 Hz,
2 H), 2.22 (td, J = 7.0, 2.1 Hz, 2 H), 2.20 (td, J = 7.0, 2.1 Hz,
2 H), 2.07 (q, J = 7.0 Hz, 2 H), 2.04-1.99 (m, 8 H), 1.52-1.21
(m, 40 H).
(2S,20S)-((3S,4E,14S,21Z,27Z,43Z)-Hexatetraconta-4,21,27,
43-tetraen-1,12,15,45-tetrayne-3,14-diyl) Bis(3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate). Following the above procedure, the
compound (3S,14S)-1 (1.0 mg, 0.0015 mmol) was reacted with
Acknowledgment. We thank the National Institutes of
Health, National Institute of General Medical Sciences
(NIH NIGMS) for funding this work. We also thank Dr.
Jung for copies of NMR spectra of petrocortyne and its
Mosher esters.
Supporting Information Available: Complete experimental
procedures and compound characterization for all compounds
not in the experimental section along with copies of key spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
2954 J. Org. Chem. Vol. 75, No. 9, 2010