Ruthenium-catalyzed olefin metathesis after tetra-n-butylammonium fluoride-mediated desilylation

Article abstract of DOI:10.1016/j.tetlet.2012.09.035

One-pot procedures expedite organic synthesis but pose challenges in that many reagents must be compatible with each other. We discovered that the presence of ⁿBu₄NF hindered ruthenium-catalyzed olefin metathesis when ⁿBu<

Full text of DOI:10.1016/j.tetlet.2012.09.035

Tetrahedron Letters 53 (2012) 6637–6640
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ruthenium-catalyzed olefin metathesis after tetra-n-butylammonium
fluoride-mediated desilylation
⇑
Sami Osman, Kazunori Koide
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot procedures expedite organic synthesis but pose challenges in that many reagents must be com-
patible with each other. We discovered that the presence of nBu4NF hindered ruthenium-catalyzed olefin
metathesis when nBu4NF-mediated desilylation and olefin metathesis were performed in one pot. This
problem could be solved by the addition of (TMS)2O to remove fluoride anions in order to facilitate
the ruthenium-catalyzed olefin metathesis.
Received 27 August 2012
Revised 7 September 2012
Accepted 10 September 2012
Available online 24 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Metathesis
Ruthenium
Fluoride
Silicon
One-pot
Small molecule inhibitors of pre-mRNA splicing are an
emerging class of molecules that can be used as chemical probes
and drug candidates.1–9 Direct inhibitors of the spliceosome
known to date are pladienolides,4,10–12 herboxidiene,13–15 and
FR9014642,16–18 and its analogs.3,19,20 While many of these splicing
inhibitors are widely used in biochemical studies,1–5,21–23 their
with diene 6 in the presence of nitro-Grela reagent Ru-1 yielded
meayamycin B in 44% yield.
We reasoned that the replacement of the hydrogen atom in
the conversion of 2 into 3 with tritium should allow us to incor-
porate the radioactive atom in 4 and eventually in meayamycin B.
In order to develop a one-pot procedure for the conversion of
alkene 1 into meayamycin B to minimize purification steps, the
alkene was treated with Hg(OAc)2 and NaBH4 (Scheme 1b).
para-Nitrobenzaldehyde was added to the resulting mixture to
trap excess hydride. Subsequently, TBAF was added to furnish
alcohol 5 without complications. Finally, diene 6 and Ru-1 were
added in this order in the same flask; however, the final cross-
coupling reaction did not take place.
drug development lags behind.
A pladienolide analog was
advanced to phase I studies,6 but none of the FR901464 analogs
advanced to the same level. In our laboratory, we reported an
in vivo study of meayamycins; these FR901464 analogs, despite
high potency in vitro, showed poor pharmacokinetics in mice.8 In
order to design meayamycin analogs that are active in vivo, the
absorption, distribution, metabolism, and excretion (ADME) of
meayamycins must be elucidated.
This problem raised a question about whether the presence of
any of the preexisting molecules could interfere with the final step.
Previously, Caulton and co-workers reported that treatment
A classic approach to the ADME studies of small molecules re-
quires a highly sensitive method to detect the parent compound
and its derivatives. The most common method is to label the par-
ent compound with a radioisotope. However, organic synthesis of
radioactive compounds imposes a challenge in that purification
steps must be minimized.
Our previously reported synthetic scheme for meayamycin B is
shown in Scheme 1a.19,20 Briefly, alkene 1 was subjected to oxym-
ercuration-reduction conditions to form tetrahydrofuran 4 in 76%
yield. The subsequent deprotection of the triethylsilyl (TES) group
using tetra-n-butylammonium fluoride (TBAF) provided alcohol 5
in 97% yield. Finally, the cross-olefin metathesis of this alcohol
of
a
ruthenium dimer [Ru(PiPr3)2HCl]2 with Me4NF yields
[Ru(PiPr3)2HF]2.24 We hypothesized that fluoride ions from the
use of TBAF in excess might interfere with the metathesis reaction
through the possible displacement of chloride of Ru-1 with fluo-
ride. To test our hypothesis, we compared the ring closing metath-
esis of the model substrate 725 in the presence of Ru-1. Indeed, the
addition of TBAF reduced the yield of 8 from 78% (Table 1, entry 1)
to 15% (entry 2), supporting our hypothesis. Previous investigation
of the effects of halogens in the olefin metathesis suggested that
the catalyst’s activities decrease as the halogens are changed from
Cl to Br to I, due to the increase in trans influence and the size of
halogens.26 Based on these results we would expect that fluorine
on the ruthenium-based catalyst would have an increase in the
⇑
Corresponding author.
E-mail address: koide@pitt.edu (K. Koide).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.035

6638
S. Osman, K. Koide / Tetrahedron Letters 53 (2012) 6637–6640
(a)
OH
O
O
O
O
Hg(OAc)2
NaBH4
TBAF
HgOAc
HgH
TESO
TESO
TESO
TESO
HO
O
1
O
O
O
O
2
3
4
5
76% yield
97% yield
N
N
Mes
Cl
Me s
Ru-1
Ru
O
Cl
NO2
O
O
O
N
O
O
O
O
N
H
HO
N
O
O
6
O
O
meayamycin B
O
44% yield
N
H
(b)
CHO
6, Ru-1
NO2
4
Hg(OAc)2
NaBH4
1
2
3
5
meayamycin B
TBAF
0% yield (no additive)
21% yield (with excess (TMS)2O)
Scheme 1. (a) Original protocol to prepare meayamycin B. (b) Preparation of meayamycin B from 1 using the one-pot procedure.
Table 1
(entry 3). With this protocol in hand, we were able to convert
Ring closing metathesis of the model substrate 7
alkene 1 into meayamycin B in one pot by adding (TMS)2O in the
final step as determined by HPLC and 1H NMR spectroscopic
analyses (Scheme 1b and Fig. 1).
EtO2C CO2Et
EtO2C CO2Et
Ru-1 (2.5 mol%)
CH2Cl2, 26 °C
Additives
In conclusion, we discovered that fluoride anions interfere with
ruthenium-catalyzed olefin metathesis reactions. Subsequently,
we developed a protocol to effect the ruthenium-catalyzed olefin
cross-metathesis after TBAF was used in the same flask. This study
allowed us to establish potential access to tritium-labeled meaya-
mycin B with one purification step. The use of (TMS)2O may find
other applications in which olefin metathesis is carried out imme-
diately after the use of TBAF.
7
8
Entry
Additives
(TMS)2O (equiv)
Yielda
TBAF (equiv)
1
2
3
0
1
1
0
0
1.2
78%b
15%c
quant.
a
Yields were determined by 1H NMR spectroscopic analysis of the reaction
Protocol to prepare meayamycin B from alcohol 1
mixture that contained PhCHO as an internal standard.
b
Yield taken from Ref. 25.
7 was the remaining 85%.
Alcohol 1 (10 mg, 34
10-mL round-bottomed flask. The flask was cooled to 0 °C, and
Hg(OAc)2 (13 mg, 41 mol) was added. The resulting solution
lmol) and THF (0.3 mL) were placed in a
c
l
catalyst’s activity; however, this was not the case in our experi-
ment. Meanwhile, recent theoretical investigations suggested that
was stirred under a nitrogen atmosphere and slowly warmed to
26 °C over 5 h. The mixture was then cooled to À78 °C, then NaBH4
a
r
-withdrawing group would decrease the catalyst’s activity.27
(1.3 mg, 34 lmol) and Et3B (1.0 M in THF, 37 lL, 37 lmol) were
Since fluorine atoms are highly electronegative, our results are in
agreement with this suggestion.
added. The mixture was stirred while warming to À40 °C over
3.5 h, followed by the addition of para-nitrobenzaldehyde
In order to couple alcohol 5 and diene 6 after the TBAF-
promoted deprotection of the TES group in one pot, it became nec-
essary to remove fluoride ions. To this end, we treated the mixture
of TBAF and the model substrate 7 with ditrimethylsilyl ether
(TMS)2O28–31 with the anticipation that the fluoride ions would
be trapped as fluorotrimethysilane (bp 16 °C), which can be readily
removed due to its high volatility. As anticipated, the ring-closing
metathesis proceeded to form cyclopentene 8 in quantitative yield
(51 mg, 340 lmol). After this step, all of the experiments were car-
ried out in an air atmosphere. The mixture was warmed to 26 °C
and stirred at the same temperature for 2.5 h. The mixture was
then cooled to 0 °C, and TBAF (1.0 M in THF, 60
added at the same temperature, followed by warming to 26 °C over
4 h. Afterward, (TMS)2O (110 mg, 860 mol) was added, and the
lL, 60 lmol) was
l
mixture was stirred at the same temperature for 11 h. The mixture
was then treated with a pH 7 buffer (1.23 M potassium phosphate,

S. Osman, K. Koide / Tetrahedron Letters 53 (2012) 6637–6640
6639
Figure 1. 1H NMR spectrum of meayamycin B from the one-pot protocol (top) and authentic meayamycin B (bottom).
0.25 mL), a solution of diene 6 (5 mg, 10
l
mol) in 1,2-dichloroeth-
recipient of a Graduate Excellence Fellowship from the University
of Pittsburgh.
ane (0.1 mL), and Ru-1 (4 mg, 6 mol). The mixture was stirred in a
l
45 °C oil bath for 27 h, then passed through a short plug of silica
gel. The filtrate was concentrated in vacuo, and the resulting
residue was initially purified by preparative TLC (80% EtOAc in
hexanes), then preparative HPLC (absorption at 232 nm. Elution
conditions: flow rate = 10.0 mL/min, gradient: 60 ? 100% MeCN
in water over 15 min, then 10 min with 100% MeCN. Column:
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