Divergent Approach to a Family of Tyrosine-Derived Ru-Alkylidene Olefin Metathesis Catalysts

Article abstract of DOI:10.1021/acs.joc.5b01091

A simple and generic approach to access a new family of Ru-alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda-Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions.

Full text of DOI:10.1021/acs.joc.5b01091

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Article
Divergent Approach to a Family of Tyrosine-
derived Ru-Alkylidene Olefin Metathesis Catalysts
Ellen C Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea Jane Robinson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01091 • Publication Date (Web): 23 Jun 2015
Downloaded from http://pubs.acs.org on July 2, 2015
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Divergent Approach to a Family of Tyrosine-derived Ru-
Alkylidene Olefin Metathesis Catalysts
Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson and Andrea J. Robinson*
School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
Email: andrea.robinson@monash.edu
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Abstract
A simple and generic approach to access a new family of Ruꢀalkylidene olefin
metathesis catalysts with specialised properties is reported. This strategy utilises a late
stage, utilitarian Hoveydaꢀtype ligand derived from tyrosine, which can be accessed
via a multiꢀgram scale synthesis. Further functionalisation allows catalyst properties
to be tuned, giving access to modified second generation HoveydaꢀGrubbs type
catalysts. This divergent synthetic approach can be used to access solidꢀsupported
catalysts and catalysts that function under solventꢀfree and aqueous conditions.
Introduction
1
Olefin metathesis has provided a powerful tool for the formation of CꢀC bonds. The
exceptional functional group tolerance, selectivity and stability of well defined
commercially available Ruꢀalkylidene catalysts such as 1 and 2 (Figure 1) have
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allowed application of this reaction to a broad range of substrates. Notable recent
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4
developments in this field include Zꢀselectivity, efficient ethenolysis, alternative
5
6
metal centers and alternative operating solvents. The latter case is of significant
7
importance for developing more environmentally benign olefin metathesis processes.
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Furthermore, modification of parent architectures has enabled efficient olefin
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metathesis reactions under aqueous and solventꢀfree conditions, as well as
10
recoverable or recyclable catalyst systems. Toꢀdate, synthetic strategies used to
access modified Ruꢀbased catalysts have adopted a targetꢀorientated approach,
focusing on incorporating one specific catalyst property (for example water solubility
or solidꢀsupported) rather than a generic or divergent approach to access a tuneable
catalyst family.
1
1
As part of our studies on improving olefin metathesis technology, we envisaged that
a rationally designed ligand precursor would allow a divergent and highly tuneable
approach to catalyst preparation. We designed Hoveydaꢀtype ligand precursor 3
(
Figure 1) to examine this approach. Notably, 3 can be prepared from readily
available ꢀtyrosine and possesses chemically distinguishable amine and carboxylic
L
acid groups for further manipulation. In this paper, we disclose the generality of this
strategy through the preparation of three Ruꢀalkylidene based catalysts 4ꢀ6.
Specifically, functionalising the amine and carboxylic acid groups with hydrophilic
PEG groups should provide a water soluble Ruꢀcomplex 4 suitable for olefin
metathesis in aqueous media. Conversely, addition of hydrophobic alkane groups onto
the amino acid handles should provide a highly organic soluble catalyst 5 suitable for
solventꢀfree conditions. Finally, incorporation of 3 into a solid support via solid phase
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peptide synthesis (SPPS) should provide access to a potentially recyclable preꢀcatalyst
system 6.
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Figure 1 Divergent strategy for synthesis of catalysts 4, 5 and 6
Results and Discussion
Herein we demonstrate a highly tuneable synthetic strategy to access a range of Ruꢀ
based olefin metathesis catalysts through the use of 3 as a common ligand precursor.
Studies commenced with the preparation of the parent ligand 3 from commercially
available
Lꢀtyrosine derivative 7 (Scheme 1). Allylation of 7 with allyl bromide
afforded the diꢀallyl analogue 8. Thermally induced Claisen rearrangement gave the
1
2
orthoꢀsubstituted phenol 9. Alkylation of 9 with 2ꢀiodopropane delivered the desired
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ether 10. Finally, ester hydrolysis followed by isomerisation/deprotection using
t
KO Bu provided the isoꢀpropoxystyrene ligand 3, which could be easily accessed on
multiꢀgram scale.
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Scheme 1 Preparation of parent ligand precursor 3.
With the key ligand precursor 3 in hand, we sought to utilise the amine and carboxylic
acid groups as synthetic handles to tune catalyst properties via incorporation of useful
functionalities. We first studied tethering hydrophilic functionalities to ligand
precursor 3 to access a water soluble Ruꢀalkylidene catalyst (Scheme 2). Towards this
end, 3 was reacted with the acyl chloride 11 to afford the amide 12. Esterification
using the tosylate 13 under basic conditions gave the required ester 14. Subsequent
coꢀordination of 14 to catalyst 1 provided the target Ruꢀalkylidene complex 4.
Purification of 4 was achieved in a straightforward manner via alumina column
chromatography.
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Scheme 2 Preparation of water soluble complex 4
The activity of PEG catalyst 4 was assessed using substrates 15ꢀ18 (Table 1).
12
Unfortunately, catalyst 4 showed limited solubility in pure water. Attempted ringꢀ
closing metathesis (RCM) of 15 with catalyst 4 in pure water at 40 °C under
ultrasonication, gave poor conversion to product 19 (Table 1, Entry 2). However,
using a water/methanol mixture (1:1) provided a suitable medium for aqueous
metathesis. Using a loading of 2.5 mol% of 4, the RCM of dienes 15, 16 and 17 gave
complete conversion to cyclised products 19, 20 and 21 respectively. The crossꢀ
metathesis (CM) of allyl alcohol (18) also proceeded quantitatively to give the diol
2
2.
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Table 1 Selected scope for catalyst 4
a
Entry
1
Substrate
Product
Conv. (%)
0
1
2
3
4
5
6
7
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9
0
1
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3
4
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9
0
1
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0
b
2
5
c
>95
2
c
>95
3
4
c
c
>95
>95
a
1
b
Conversions were determined by HꢀNMR spectroscopy. Metathesis reactions
were performed using 2.5 mol% 4 under ultrasonication for 2 h then at 40 °C for 16
1
c
h. Conversions were determined by HꢀNMR spectroscopy. Metathesis reactions
were performed using 2.5 mol% 4 in 1:1 H O:MeOH at 40 °C for 16 h.
2
Next, we were interested in transforming styrene 3 into a catalyst suitable for
metathesis under solventꢀfree conditions with highly nonꢀpolar substrates. Hence,
lipophilic groups were attached to the amine and carboxylic acid termini. Acylation of
3
with stearoyl chloride (23) gave amide 24 (Scheme 3). The carboxylic acid was next
converted to the ester 25 derivative by treatment with 1ꢀbromooctadecane (26) under
basic conditions. Finally, coꢀordination of 25 to catalyst 1 gave the target lipophilic
Ruꢀalkylidene complex 5. Notably, complex 5 was prepared from the key precursor 3
in three facile steps.
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O
Br
23
26
Cl
16
17
O
O
4
M NaOH(aq), acetone
rt, 16 h
NaHCO , DMF
3
rt, 16 h
O
OH
OH
69% over 2 steps
H N
N
2
1
6 H
O
O
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3
24
N
O
N
Mes
Cl
Mes
Cl
Ru
1, CuI,
CH2Cl2
0 °C, 30 min
O
O
4
O
59%
O
O
N
N
1
6 H
17
16 H
17
O
O
25
5
Scheme 3 Preparation of lipophilic Ruꢀalkylidene complex 5
The CM activity of 5 was investigated using solventꢀfree conditions by studying the
dimerisation of 1ꢀdecene (27). The optimal catalyst loading was studied and
compared with the commercially available catalyst 2 (Table 2). Initially, optimisation
studies were completed at room temperature (Table 2, entries 1ꢀ3). Catalyst 5 showed
significantly higher reactivity than catalyst 2 under solventꢀfree conditions. This can
be attributed to the differences in solubility of 5 compared with catalyst 2. Addition of
5
to 1ꢀdecene (27) instantly resulted in a homogenous reaction mixture. In contrast,
catalyst 2 was largely insoluble in the neat substrate. By elevating the temperature to
0 °C, catalyst loading could be further reduced (Table 2, entries 4ꢀ6). Optimal
4
conditions were observed at 0.5 mol% of 5 at 40 °C, providing 91% conversion to the
dimerised product 28.
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Table 2 Optimisation of CM conditions using
5
0
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a
a
Entry
Loading (mol%)
Temp (°C)
20 (r.t)
20 (r.t)
20 (r.t)
40
Catalyst
5
Catalyst 2
1
2
3
4
5
6
1.0
0.5
83%
11%
54%
7%
10%
0.1
3%
0.5
91%
16%
5%
ꢀ
ꢀ
ꢀ
0.25
0.1
40
40
a
Metathesis reactions were performed using
5 or 2 in neat 27. Conversions
1
were determined by HꢀNMR spectroscopy.
With optimised conditions in hand, we studied the dimerisation of other alkene
substrates with catalyst 5 (Table 3). Selfꢀmetathesis of homologous terminal alkenes,
1
ꢀoctene and 1ꢀhexene, provided excellent conversions to their respective crossꢀ
products (entries 1ꢀ2). High conversions were also observed for the CM of nonꢀpolar
alcohol ωꢀundecylenyl alcohol (entry 3) and 1ꢀvinyl cyclohexanol (entry 4). Crossꢀ
metathesis between allylbenzene (29) and cisꢀ1,4ꢀdiacetoxyꢀ2ꢀbutene (30) under
solventꢀfree conditions gave the corresponding crossꢀproduct in modest isolated yield
(
entry 5). Catalyst 5 also mediated good conversion of 1,5ꢀcyclooctadiene in a ringꢀ
opening metathesis polymerisation (ROMP) reaction (entry 6). Finally, solventꢀfree
RCM of dienes 31 and 32 both proceeded with excellent conversion without
formation of polymeric byꢀproducts (entries 7 and 8).
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Table 3 Selected scope for catalyst
5
a
Entry
Substrate
Conv. (%)
95
1
2
3
4
1ꢀoctene
1ꢀhexene
>95
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
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ωꢀundecylenyl alcohol
1ꢀvinyl cyclohexanol
>95
90
b
5
6
57
1,5ꢀcyclooctadiene
83
7
8
>95
88
a
Metathesis reactions were performed using 0.5 mol%
5
in neat substrate at
o
1
b
4
0 C. Conversions were determined by HꢀNMR spectroscopy. Isolated
yield
Lastly, we explored the development of a solidꢀsupported recyclable catalyst via the
incorporation of ligand precursor 3 into a peptide sequence using established SPPS
technology. Reaction of 3 with FmocꢀOSu provided the required NꢀFmoc analogue 33
(Scheme 4). SPPS began with FmocꢀGlyꢀWang resin and sequential coupling of
FmocꢀGlu, NꢀFmocꢀprotected analogue 33, FmocꢀTyr, and FmocꢀSer delivered the
solidꢀsupported pentaꢀpeptide 34. Subsequent coꢀordination of 34 to catalyst 1
1
3
afforded the solidꢀsupported Ruꢀalkylidene complex 6 as green resin beads.
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Fmoc-OSu, NaHCO3
O
O
acetone, H O
2
rt, 16 h
SPPS
8
5%
OH
OH
H N
FmocHN
2
O
O
0
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33
N
N
Mes
Cl
Mes
Cl
Ru
1
, CuI
O
O
CH Cl2
O
O
2
40 °C, 1 h
OtBu
H
N
OtBu
H
N
O
O
H
H
N
N
O
O
AcHN
N
N
H
AcHN
N
N
H
H
H
O
O
O
O
O
O
OtBu O
OtBu
OtBu O
OtBu
3
4
6
Scheme 4 Preparation of solidꢀsupported olefin Ruꢀalkylidene complex
6
The catalytic activity of 6 was assessed with the RCM reaction of diethyl
diallylmalonate 31 (Table 4, entry 1). At 5 mol% loading of 6 the reaction proceeded
o
to 95% after 0.5 h at 45 C. Significantly, removal of the solidꢀsupported catalyst
from the reaction mixture was achieved via a simple filtration of the resin beads; the
resulting filtrate was only faintly coloured (Figure 2). In contrast, after an analogous
reaction performed using 5 mol% 2, the resultant reaction mixture was visibly darker
due to higher Ruꢀcontamination (Figure 2). The filtered and washed resinꢀbound
catalyst was reused in five subsequent RCM reactions with no loss of activity (Table
4
, entries 1ꢀ6). Additionally, three more catalyst cycles were performed with extended
reaction times to provide excellent ringꢀclosure of diethyl diallylmalonate (31)
14
(
entries 7ꢀ9).
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Table 4 RCM of 31 catalysed by a single batch of resinꢀbound catalyst
6
10
11
12
13
14
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17
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19
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23
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a
b
Runs
Time (h)
Conv. (%)
Ru (ppm)
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
1
95
95
95
95
95
95
92
90
90
45
45
33
36
24
12
19
20
16
1
1
1.5
1.5
2
a
Metathesis reactions were performed using 5 mol%
2 2
6 in CH Cl at 45 °C.
1
Conversions were determined by HꢀNMR spectroscopy. A single batch of
b
catalyst
6
was used across runs 1ꢀ9. Ru analysis performed using ICPꢀMS.
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Figure 2 left) RCM reaction of 31 using 5 mol%
of 31 using 5 mol% (after filtration)
2 and right) RCM reaction
6
The attachment of the Ruꢀcomplex to the solid support via the labile Hoveyda ligand
0
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relies on a catchꢀrelease or ‘boomerang’ mechanism, which is still widely disputed.
If this mechanism is highly operational yet inefficient, such catalysts can potentially
suffer from significant leaching of the active Ru species into the reaction medium.
Consequently, we were also interested in determining the amount of Ru contaminant
present in the product. Ru analysis of the filtrate from each reaction (entries 1ꢀ9) was
performed using ICPꢀMS (Table 4). Our results show a sustained leaching of Ru into
the reaction medium, losing a total of 20% of the initial Ru content over the nine
reaction cycles. This amount of leaching is comparable with supported Ruꢀalkylidene
1
0d
catalysts previously reported by Lee and coworkers
and Bannwarth and
10j
coworkers.
Conclusions
In summary, a generic and simple approach has been developed to prepare a family of
specialist Ruꢀalkylidene catalysts for olefin metathesis. Preparation of the key ligand
precursor 3 was achieved via five facile and high yielding steps from commercially
available Lꢀtyrosine 7. Further functionalization of 3 provides access to modified
second generation HoveydaꢀGrubbs type catalysts. Through this single synthetic
approach, ruthenium alkylidene catalysts for use in solventꢀfree reactions, aqueous
media and recycling have been prepared. We envisage that this general strategy could
be adopted by other organic synthesis research groups in need of bespoke olefin
metathesis catalysts. Current work is underway to utilise this generic approach to
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access other tailored catalyst systems which may address current synthetic challenges
of olefin metathesis.
Experimental Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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Dichloromethane (CH
and tetrahydrofuran (THF) were distilled over potassium prior to use. Acetic acid
AcOH), acetone, dimethylformamide (DMF) ethyl acetate (EtOAc), hexane and
2 2 2 2
Cl ) was distilled over CaH prior to use. Diethyl ether (Et O)
(
methanol (CH
3
OH), copper(I) chloride (CuCl), CbzꢀLꢀtyrosine, oꢀdichlorobenzene,
t
dimethyl sulfoxide (DMSO), 2ꢀiodopropane, potassium tertꢀbutoxide (KO Bu), stearic
acid were used as supplied. Benzylidene [1,3ꢀbis(2,4,6ꢀtrimethylphenyl)ꢀ2ꢀ
imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium was used as supplied
by SigmaꢀAldrich.
Allyl
(S)-3-(4-(allyloxy)phenyl)-2-
(
((benzyloxy)carbonyl)amino)propanoate 8
Potassium carbonate (17.5 g, 127 mmol) and allyl bromide (11.0 mL, 15.4 g, 127
mmol) were added to a solution of Cbzꢀ ꢀtyrosine 7 (10.0 g, 31.7 mmol) in acetone
150 mL). The reaction mixture was vigorously stirred for 5 min before TBAI (11.7 g,
L
(
3
1.7 mmol) was added in portions over 20 min. The resulting suspension was then
sealed and heated at 45 °C for 48 h. The reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The colourless residue was
resuspended in EtOAc (200 mL), filtered and the filtrate concentrated under reduced
pressure. The residue was then purified by silica chromatography (8:1,
hexane:EtOAc) to give titled compound 8 as a colourless solid (11.7 g, 93%), m.p.
3
6.9ꢀ38.6 °C. IR νmax 3345m, 3067m, 3033m, 2937m, 1718s, 1611m, 1509s, 1455m,
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ
1 1
1239s, 1219s, 1177s cm . H NMR (400 MHz, CDCl
3
):
.00 (m, 2H), 6.84ꢀ6.80 (m, 2H), 6.05 (ddt, J = 17.2, 10.4, 5.4 Hz, 1H), 5.92ꢀ5.82 (m,
H), 5.44ꢀ5.24 (m, 5H), 5.14ꢀ5.07 (m, 2H), 4.68ꢀ4.61 (m, 3H), 4.51 (dt, J = 5.4, 1.2
δ 7.38ꢀ7.29 (m, 5H), 7.03ꢀ
7
1
1
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 2H), 3.12ꢀ3.02 (m, 2H). C{ H} NMR (150 MHz, CDCl
3
):
δ 171.4, 157.8. 155.7,
1
6
3
36.3, 133.3, 131.5, 130.4, 128.6, 128.2, 128.1, 127.8, 119.1, 117.7, 114.9, 68.8, 67.0,
+
+
+
5
6.0, 55.0, 37.4. HRMS (ESI , MeOH): m/z 396.1801 [M + H] , C23H26NO requires
96.1805.
Allyl
((benzyloxy)carbonyl)amino)propanoate 9
Compound 9 was prepared according to a modified procedure by Grela and
(S)-3-(3-allyl-4-hydroxyphenyl)-2-
(
14
coworkers. A solution of ether 8 (9.34 g, 23.6 mmol) in oꢀdichlorobenzene (20 mL)
was added to a microwave vessel. The vessel was thoroughly flushed with nitrogen,
sealed and irradiated (100 W, 210 °C) for 4 h. The resultant reaction mixture was
concentrated under reduced pressure and the residue was then purified by silica
column chromatography (3:1, hexane:EtOAc) to give titled compound 9 as a
colourless oil (7.78 g, 83%). IR νmax 3356brs, 3070m, 3032m, 2945m, 1696s, 1508s,
ꢀ1
1
1
5
3
3
438m, 1340m, 1260s, 1189s cm . H NMR (400 MHz, CDCl ): δ 7.38ꢀ7.29 (m,
H), 6.85ꢀ6.82 (m, 2H), 6.67 (d, J = 8.0 Hz, 1H), 6.02ꢀ5.85 (m, 2H), 5.37ꢀ5.25 (m,
H), 5.15ꢀ5.06 (m, 4H), 4.68ꢀ4.61 (m, 3H), 3.39ꢀ3.30 (m, 2H), 3.09ꢀ2.99 (m, 2H) (OH
13
1
not observed due to exchange). C{ H} NMR (100 MHz, CDCl
3
): 171.6, 155.9,
1
1
53.4, 136.5, 136.2, 131.5, 131.2, 128.6, 128.4, 128.3, 128.1, 127.4, 126.0, 119.1,
+
16.2, 115.8, 67.2, 66.2, 55.1, 37.5, 34.6. HRMS (ESI , MeOH): m/z 396.1801 [M +
+
+
5
H] , C23H26NO requires 396.1805.
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Allyl
(
S
)-3-(3-allyl-4-isopropoxyphenyl)-2-(((benzyloxy)carbonyl)
amino)propanoate 10
Compound 10 was prepared according to a modified procedure by Grela and
1
4
coworkers. Potassium carbonate (10.6 g, 76.9 mmol) and 2ꢀiodopropane (4.80 mL,
8.17 g, 48.1 mmol) were added to a stirred solution of the phenol 9 (7.58 g, 19.2
mmol) in acetone (100 mL). The reaction mixture was vigorously stirred for 5 min
before TBAI (7.10 g, 19.2 mmol) was added in portions over 10 min. The resultant
suspension was sealed and heated to 45 °C for 24 h. The reaction mixture was
concentrated under reduced pressure. The residue was resuspended in EtOAc (100
mL), filtered and the filtrate concentrated under reduced pressure. The residue was
purified by silica column chromatography (9:1, hexane:EtOAc) to give titled
compound 10 as a colourless oil (6.75 g, 80%). IR νmax 3338brs, 3067m, 2976m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1 1
2
936m, 1719s, 1496s, 1454m, 1382m, 1339m, 1246s, 1189m cm . H NMR (400
MHz, CDCl ): 7.38ꢀ7.29 (m, 5H), 6.90ꢀ6.86 (m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 5.98ꢀ
.82 (m, 2H), 5.33ꢀ4.99 (m, 7H), 4.66ꢀ4.60 (m, 3H), 4.51 (sept, J = 6.0 Hz, 1H), 3.36ꢀ
3
δ
5
3
13
1
.26 (m, 2H), 3.04 (d, J = 5.6 Hz, 2H), 1.32 (d, J = 6.0 Hz, 6H). C{ H} NMR (100
): 171.5, 155.8, 154.9, 137.1, 136.5, 131.7, 131.0, 130.0, 128.6, 128.3,
128.2, 128.0, 127.2, 119.0, 115.5, 113.1, 70.2, 67.0, 66.1, 55.1, 37.5, 34.5, 22.3.
MHz, CDCl
3
δ
+
+
+
HRMS (ESI , MeOH): m/z 438.2288 [M + H] , C H NO requires 438.2275.
26
32
5
(S,E)-2-Amino-3-(4-isopropoxy-3-(prop-1-en-1-yl)phenyl)propanoic acid 3
An aqueous solution of 1 M LiOH (15 mL) was added to 10 (0.50 g, 1.1 mmol) in
THF (15 mL) and the mixture was stirred at room temperature for 16 h. The reaction
mixture was concentrated to half volume under reduced pressure, acidified to pH 2
with aqueous 1 M HCl and extracted with EtOAc (3 x 50 mL). The combined organic
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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3
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4
4
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4
4
4
4
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5
5
5
5
5
5
5
6
layers were dried with Na
2
SO
4
, filtered and concentrated under reduced pressure. The
t
residue was then redissolved in DMSO (26 mL). KO Bu (0.58 g, 5.2 mmol) was
o
added and the resultant mixture was stirred at 50 C for 16 h. The mixture was
concentrated under reduced pressure. The residue was dissolved in H O (5 mL) and 1
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
M HCl was added to reach pH 6. The precipitate was collected by filtration and
washed with H
yellow solid (0.26 g, 87%), m.p. 187.4ꢀ189.1°C. IR νmax 3448brs, 3200brs, 3038s,
975s, 2933m, 2913m, 1605s, 1586s, 1489s, 1437m, 1397s, 1332s, 1242s, 1110s,
2 2
O (10 mL) and Et O (10 mL) to provide titled compound 3 as a
2
ꢀ1 1
954s cm . H NMR (400 MHz, MeOD):
δ
7.36 (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 8.4,
.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.67 (dq, J = 15.8, 1.6 Hz, 1H), 6.28 (dq, J =
5.8, 6.8 Hz, 1H), 4.55 (sept, J = 6.0 Hz, 1H), 3.73 (dd, J = 8.8, 4.0 Hz, 1H), 3.23 (dd,
2
1
J = 14.6, 4.0 Hz, 1H), 2.93 (dd, J = 14.6, 8.8 Hz, 1H), 1.87 (dd, J = 6.8 Hz, 1.6 Hz,
3
2
H), 1.31 (d, J = 6.0 Hz, 6H) (COOH and NH not observed due to exchange).
1
3
1
C{ H} NMR (100 MHz, MeOD):
δ
173.9, 155.3, 129.9, 129.6, 129.1, 128.5, 127.1,
ꢀ
1
27.0, 116.0, 72.0, 57.7, 37.6, 22.5, 19.0. HRMS (ESI , MeOH): m/z 262.1445 [M ꢀ
ꢀ
ꢀ
3
H] , C15H20NO requires 262.1448.
(S,E)-3-(4-Isopropoxy-3-(prop-1-en-1-yl)phenyl)-2-(3,4,5-tris(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)benzamido)propanoic acid 12
Thionyl chloride (1.00 mL, 13.8 mmol) was added to 3,4,5ꢀtris(2ꢀ(2ꢀ(2ꢀ
methoxyethoxy)ethoxy)ethoxy)benzoic acid (1.14 g, 1.87 mmol) and the mixture was
sonicated for 1.5 h. Excess SOCl
acid chloride 11. In a separate round bottom flask, an aqueous solution of 2 M NaOH
7 mL) was added to amino acid 3 (0.70 g, 2.6 mmol) in THF (7 mL) at 0 °C. Acid
2
was removed under reduced pressure to provide
(
chloride 11 in THF (5 mL) was added dropwise to the amino acid 3 solution. The
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reaction mixture was allowed to warm to room temperature and stirred for 16 h. The
solution was acidified to pH 1 with aqueous 1 M HCl and THF was removed under
reduced pressure. The aqueous solution was extracted with EtOAc (3 x 100 mL), and
the combined organic extract was dried with Na SO , filtered and concentrated under
2
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
reduced pressure. The residue was purified by silica column chromatography
100:5:1, CH Cl :MeOH:AcOH) to give titled compound 12 (1.49 g, 93%) as a
yellow oil. IR νmax 2912s, 2874s, 1735m, 1638w, 1580m, 1491m, 1347m, 1243m,
(
2
2
ꢀ1 1
1
201m, 1094s cm . H NMR (400 MHz, CDCl
3
): δ 7.21 (d, J = 1.6 Hz, 1H), 6.95ꢀ
6.94 (m, 4H), 6.72 (d, J = 8.4 Hz, 1H), 6.60 (dq, J = 16.0. 1.6 Hz, 1H), 6.08 (dq, J =
1
6.0, 6.8 Hz, 1H), 4.87 (q, J = 6.4 Hz, 1H), 4.42 (sept, J = 6.2 Hz, 1H), 4.17ꢀ4.07 (m,
H), 3.79 (t, J = 4.8 Hz, 4H), 3.75 (t, J = 5.2 Hz, 2H), 3.70ꢀ3.66 (m, 6H), 3.63ꢀ3.59
6
(m, 12H), 3.53ꢀ3.50 (m, 6H), 3.34 (s, 3H), 3.33 (s, 6H), 3.23ꢀ3.07 (m, 2H), 1.79 (dd, J
=
6.8, 1.6 Hz, 3H), 1.28 (d, J = 6.2 Hz, 6H) (COOH not observed due to exchange).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
):
δ
173.7, 167.1, 153.7, 152.5, 141.6, 129.0, 128.5,
1
28.2, 128.1, 127.6, 126.1, 125.8, 114.4, 107.1, 72.4, 72.0, 70.8, 70.73, 70.68, 70.64,
0.57, 70.54, 70.52, 70.4, 69.8, 69.0, 59.0, 54.3, 36.5, 22.30, 22.28, 19.0 (1 carbon
7
+
+
environments overlapping). HRMS (ESI , MeOH): m/z 876.4349 [M + Na] ,
+
C H NO Na requires 876.4358.
43
67
16
2
-(2-(2-Methoxyethoxy)ethoxy)ethyl (S,E)-3-(4-isopropoxy-3-(prop-1-en-1-
yl)phenyl)-2-(3,4,5-tris(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)benzamido)propanoate 14
K CO (71.0 mg, 520 ꢁmol) was added to a solution of 12 (120 mg, 141 ꢁmol) and
2
3
tosylate 13 (49.0 mg, 150 ꢁmol) in DMF (3 mL). The reaction was stirred at room
temperature for 16 h. The mixture was diluted with H
2
O (50 mL) and extracted with
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
EtOAc (3 x 50 mL). The combined organic extracts were washed with 10% (w/v)
aqueous CuSO
Na SO , filtered and concentrated under reduced pressure. The residue was purified
by silica column chromatography (20:1, CH Cl :MeOH) to give titled compound 14
4 2
(2 x 50 mL), H O (1 x 50 mL) and brine (1 x 50 mL), then dried with
2
4
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(128 mg, 91%) as a colourless oil. IR νmax 2873brs, 1741m, 1662m, 1582m, 1490m,
ꢀ
1 1
1
450w, 1490m, 1350m, 1243m, 1095s cm . H NMR (400 MHz, CDCl
2.2 Hz, 1H), 6.92 (s, 2H), 6.89 (dd, J = 8.4, 2.2 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H),
.59 (dq, J = 16.0, 1.6 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.06 (dq, J = 16.0, 6.4 Hz,
1H), 4.97ꢀ4.92 (m, 1H), 4.43 (sept, J = 6.4 Hz, 1H), 4.28ꢀ4.25 (m, 2H), 4.15ꢀ4.09 (m,
3
): δ 7.14 (d, J
=
6
6
3
H), 3.81ꢀ3.73 (m, 6H), 3.68ꢀ3.65 (m, 8H), 3.61ꢀ3.57 (m, 18H), 3.50ꢀ3.47 (m, 8H),
.32 (s, 3H), 3.31 (s, 6H), 3.30 (s, 3H), 3.16 (A of ABX, J = 13.8, 5.6 Hz, 1H), 3.10
(B of ABX, J = 13.8, 5.6 Hz, 1H), 1.79 (dd, J = 6.6, 1.6 Hz, 3H), 1.28 (dd, J = 6.2 Hz,
13
1
1.2 Hz, 6H). C{ H} NMR (100 MHz, CDCl
3
):
δ 171.7, 166.4, 153.7, 152.5, 152.3,
1
7
2
41.6, 129.2, 128.4, 128.1, 128.0, 127.7, 127.5, 126.0, 125.8, 114.3, 106.8, 101.7,
2.4, 71.9, 70.8, 70.7, 70.61, 70.55, 70.5, 69.7, 69.0, 68.8, 64.5, 59.0, 53.7, 36.9,
+
2.22, 22.20, 18.9 (6 carbon environments overlapping). HRMS (ESI , MeOH): m/z
+
+
1022.5286 [M + Na] , C50H81NO19Na requires 1022.5300.
Aqueous Catalyst 4
Complex 1 (143 mg, 168 ꢁmol), CuCl (17.0 mg, 171 ꢁmol) and 14 (171 mg, 171
mol) in CH Cl (2 mL) were added to a flameꢀdried Schlenk vessel under N
ꢁ
2
2
2
atmosphere. The reaction was stirred at 45 °C for 0.5 h. The dark green mixture was
concentrated under reduced pressure and the residue was purified by neutral alumina
column chromatography using a N flow (16:4:1 Et O:hexane:MeOH) to yield
2
2
complex 4 (115 mg, 46%) as a green oil. IR νmax 3339w, 2872s, 1739m, 1655m,
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8
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ꢀ
1
1
1581m, 1485s, 1449m, 1421m, 1256m, 1095s, 1029s cm . H NMR (400 MHz,
CD OD): 16.48 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H),
.14 (s, 2H), 7.00ꢀ6.92 (m, 5H), 6.71 (d, J = 2.0 Hz, 1H), 4.93ꢀ4.93 (m, 1H), 4.73ꢀ
.68 (m, 1H), 4.29ꢀ4.27 (m, 4H), 4.18ꢀ4.16 (m, 8H), 3.89ꢀ3.84 (m, 6H), 3.76ꢀ3.72 (m,
δ
3
7
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6H), 3.71ꢀ3.62 (m, 16H), 3.60ꢀ3.48 (m, 12H), 3.37 (s, 3H), 3.36 (s, 6H), 3.35ꢀ3.34 (m,
1
3
1
2
H), 3.33 (s, 3H), 2.54ꢀ2.35 (m, 18H), 1.23 (dd, J = 6.0, 1.2 Hz, 6H). C{ H} NMR
150 MHz, CD OD): 298.1, 211.2, 172.7, 168.8, 153.9, 153.7, 152.6, 146.7, 142.5,
40.1, 132.5, 131.6, 131.0, 130.3, 130.0, 123.8, 114.4, 107.8, 76.4, 73.7, 73.6, 73.0,
(
3
δ
1
72.9, 71.7, 71.64, 71.56, 71.5, 71.4, 70.8, 70.0, 69.9, 65.7, 59.1, 56.3, 36.2, 22.5, 21.7,
+
2
1.3 (8 carbon environments overlapping). HRMS (ESI , MeOH): m/z 1472.5513 [M
+
102+
+
Na] , C69
H
103Cl
2
N
3
NaO19Ru
requires 1472.5504.
General Procedure for Olefin Metathesis in water/MeOH mixture using
Catalyst 4
The complex 4 (7.5 mg, 0.052 mmol, 0.25 mol%) was dissolved in degassed MeOH
2
(1 mL) and added to a solution of substrate (0.21 mmol) in degassed H O (1 mL). The
homogenous mixture was stirred at 40 °C for 16 h. The reaction mixture was
1
concentrated in vacuo, dissolved in D O and analysed by H NMR spectroscopy.
2
Octadecyl
oxooctadecyl)aminopropanoate 25
Thionyl chloride (361 ꢁL, 592 mg, 4.98 mmol) was added to stearic acid (118 mg,
.42 mmol) and the mixture was sonicated for 1.5 h. Excess SOCl was removed
(S,E)-3-(4-isopropoxy-3-(prop-1-en-1-yl)phenyl)-2-N-
(
0
2
under reduced pressure to provide acid chloride 23. In a separate round bottom flask,
amino acid 3 (100 mg, 0.38 mmol) and NaOH (61 mg, 1.52 mmol) were dissolved in
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a H
2
O (5 mL) and acetone (3 mL) mixture. A solution of 23 in acetone (3mL) was
added to the reaction mixture at room temperature. The reaction was stirred for 16 h.
The mixture was then acidified with aqueous 1 M HCl until pH 2 and extracted with
EtOAc (3 x 50 mL). The combined organic phases were dried with MgSO , filtered
4
0
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9
0
and concentrated under reduced pressure to give amide 24 which was used in the
3
subsequent step without further purification. NaHCO (128 mg, 1.52 mmol) and 1ꢀ
bromooctadecane (253 mg, 0.76 mmol) were added at room temperature to a solution
of 24 in DMF (3 mL). The reaction was stirred at room temperature for 16 h. The
mixture was diluted with H O (50 mL) and was extracted with Et O (3 x 50 mL). The
2
2
combined organic extracts were washed with H O (2 x 50 mL) and brine (1 x 50 mL),
2
4
dried with MgSO and concentrated under reduced pressure. The residue was purified
by silica column chromatography (11:1, hexane:EtOAc) to afford titled compound 25
o
as a colourless solid (206 mg, 69%), m.p. 69.2 – 72.5 C. IR νmax 3254w, 2914s,
ꢀ1 1
2849s, 1736m, 1638m, 1542m, 1491m, 1467m, 1372w, 1244s, 1112m, 967m cm . H
NMR (400 MHz, CDCl ): 7.11 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.4, 2.4 Hz, 1H),
.75 (d, J = 8.4 Hz, 1H), 6.66 (dq, J = 15.6, 1.6 Hz, 1H), 6.16 (dq, 15.6, 6.6 Hz, 1H),
.88 (d, J = 8.0 Hz, 1H), 4.84 (dt, J = 7.7, 5.6 Hz, 1H), 4.47 (sept, J = 6.0 Hz, 1H),
3
δ
6
5
4.11ꢀ4.06 (m, 2H), 3.04 (d, J = 6.0 Hz, 2H), 2.18ꢀ2.15 (m, 2H), 1.88 (dd, J = 6.6, 1.6
Hz, 3H), 1.60ꢀ1.57 (m, 4H), 1.33 (d, J = 6.0 Hz, 6H), 1.29ꢀ1.22 (m, 58H), 0.89ꢀ0.86
13
1
(
m 6H). C{ H} NMR (75 MHz, CDCl
27.6, 126.1, 126.0, 114.4, 71.0, 65.8, 53.2, 37.5, 36.8, 32.1, 29.85, 29.81, 29.76,
29.7, 29.6, 29.5, 29.44, 29.40, 28.7, 26.0, 25.8, 22.8, 22.4, 19.0, 14.2 (19 overlapping
3
): δ 172.7, 172.1, 153.9, 128.4, 128.3, 127.9,
1
+
+
+
carbon environments). HRMS (ESI , MeOH): m/z 782.7018 [M + H] , C H NO
4
5
1
92
requires 782.7026.
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Solvent-Free Catalyst 5
Complex 1 (100 mg, 0.116 mmol), CuCl (12.7 mg, 0.128 mmol) and a solution of 25
100 mg, 0.113 mmol) in CH Cl (4 mL) were added to a flameꢀdried Schlenk vessel
(
2
2
under N atmosphere. The reaction was stirred at 45 °C for 0.5 h. The dark green
2
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24
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60
mixture was concentrated under reduced pressure and the residue was purified by
silica column chromatography using a N
2
flow (4:1, hexane:Et
2
O ꢀ 1:4,
hexane:Et
2
O) to give complex 5 as a green solid (108 mg, 69%), m.p. 120.6 – 127.8
o
C. IR νmax 3320w, 2920s, 2851s, 1736m, 1672m, 1518m, 1487m, 1420m, 1262s,
ꢀ
1 1
1221m, 1198m, 1133m, 1105m cm . H NMR (400 MHz, C
.16 (m, 4H), 7.10 (dd, J = 8.4, 2.0 Hz, 1H), 7.03 (s, 2H), 6.97ꢀ6.96 (m, 3H), 6.34 (d,
J = 8.4 Hz, 1H), 5.57 (d, J = 7.6 Hz, 1H), 5.02ꢀ4.96 (m, 1H), 4.48 (sept, J = 6.4 Hz,
6 6
D ): δ 16.70 (s, 1H),
7
1
1
H), 4.03ꢀ4.39 (m, 2H), 3.44 (s, 4H), 3.17ꢀ3.08 (m, 2H), 2.59ꢀ2.40 (m, 18H), 1.83ꢀ
13
1
.66 (m, 4H), 1.64ꢀ1.58 (m, 2H), 1.36ꢀ1.25 (m, 60H), 0.94ꢀ0.90 (m, 6H). C{ H}
): 292.0, 212.7, 172.3, 171.9, 151.7, 145.9, 138.9, 130.5,
29.8, 129.3, 128.5, 127.6, 123.5, 113.0, 75.2, 65.5, 54.1, 51.3, 37.4, 36.2, 32.4,
NMR (150 MHz, C
6
D
6
δ
1
3
0.27, 30.25, 30.2, 30.1, 30.0, 29.9, 29.7, 29.6, 28.8, 26.2, 25.9, 23.2, 21.4, 21.3, 14.4
+
(20 overlapping carbon environments). HRMS (ESI , MeOH): m/z 1254.7068 [M +
+
+
Na] , C H Cl N NaO Ru requires 1254.7044.
70
113
2
3
4
General Procedure for Solvent-Free Olefin Metathesis using Catalyst 5
The complex 5 (3.0 mg, 0.002 mmol, 0.5 mol%) was added to the neat substrate (0.49
mmol) under an inert atmosphere and heated at 40 °C for 16 h. The reaction mixture
1
was dissolved in CDCl and analysed by H NMR spectroscopy.
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(
(
E
)-2-((((9
H
-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-isopropoxy-3-
prop-1-en-1-yl)phenyl)propanoic acid 33
3
Amino acid 3 (200 mg, 759 ꢁmol) and NaHCO (255 mg, 3.04 mmol) were dissolved
in a mixture of H O (7.5 mL) and acetone (3 mL). A solution of FmocꢀOSu (230 mg,
2
0
1
2
3
4
5
6
7
8
9
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2
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722 ꢁmol) in acetone (4.5 mL) was added at room temperature and the reaction was
stirred for 16 h. The mixture was acidified to pH 2 with aqueous 1 M HCl and acetone
was removed under reduced pressure. The resulting solution was extracted with
EtOAc (40 mL) and organic phase washed with brine (40 mL). The organic phase was
dried with MgSO , filtered and concentrated under reduced pressure. The residue was
4
purified by silica column chromatography (60:40:1, hexane:EtOAc:AcOH) to give
titled compound 33 as a colourless solid (315 mg, 85%). IR νmax 3294m, 3067w,
ꢀ1
1
2
984w, 2850w, 1691s, 1543m, 1490m, 1430m, 1297m, 1247s, 735s cm . H NMR
(400 MHz, CDCl ): 7.76 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.39 (t, J =
3
δ
7.6 Hz, 2H), 7.32ꢀ7.27 (m, 2H), 7.22 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.8
Hz, 1H), 6.66 (dd, J = 15.8, 1.6 Hz, 1H), 6.19 (dq, J = 15.8, 6.6 Hz, 1H), 5.21 (d, J =
8
.0 Hz, 1H), 4.70ꢀ4.65 (m, 1H), 4.50ꢀ4.32 (m, 3H), 4.20 (t, J = 7.2 Hz, 1H), 3.16 (A
of ABX, J = 14.2, 6.4 Hz, 1H), 3.06 (B of ABX, J = 14.2, 6.4 Hz, 1H), 1.85 (dd, J =
6.6, 1.6 Hz, 3H), 1.33 (d, J = 6.0 Hz, 6H) (COOH not observed due to exchange).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
): δ 175.3, 154.1, 143.9, 141.4, 141.3, 128.53,
1
4
28.55, 127.9, 127.5, 127.4, 127.2, 126.5, 125.9, 125.2, 120.1, 114.5, 71.0, 67.4, 54.8,
+
+
7.3, 37.2, 22.4, 19.1. HRMS (ESI , MeOH): m/z 508.2092 [M + Na] ,
+
C
30
H
31NO
5
Na requires 508.2094.
Peptide ligand 34
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Manual Fmoc SPPS of 34 (0.05 mmol) was performed in polypropylene Terumo
syringes (5 mL) fitted with a porous polyethylene filter. FmocꢀGlyꢀWang resin was
2 2
swollen with CH Cl /DMF (1:1) prior to synthesis. Sequential deprotection (20%v/v
piperadine in DMF), coupling (0.05 mmol amino acid, 0.05 mmol HATU, 0.10 mmol
10
11
12
13
14
15
16
17
18
19
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23
24
25
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31
32
33
34
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60
NMM, 3 mL DMF) and final capping (94:5:1, DMF:Ac O:NMM) provided the
2
+
desired solidꢀsupported peptide 34. LRMS (ESI , MeCN:H
2
O:HCOOH): m/z 742.3
+
+
[
48 5
M + H] , C36H N O12 requires 742.3. RPꢀHPLC (Agilent Vydac C18 analytical
R
column, 15ꢀ50% MeCN over 35 min): t = 12.7 min.
Solid-supported catalyst 6
Copper (I) chloride (3 mg, 0.030 mmol) and 1 (30 mg, 0.035 mmol) were added to a
2
stirred suspension of 34 (0.030 mmol) in CH Cl (2 mL) under an atmosphere of N .
2
2
The flask was heated to 45 °C for 1 h. The suspension was filtered via canula and the
resin beads washed (3 x 5 mL) with fresh CH Cl . The resin beads were dried under
2
2
+
+
vacuum to afford 6 as a green solid. LRMS (ESI , MeOH): 1193.3 m/z [M + H] ,
102+
C
55
H
70
N
7
O12Ru
requires 1192.3.
General Procedure for Olefin Metathesis using Solid-Supported Recyclable
Catalyst 6
A degassed solution of diethyl diallylmalonate 31 (0.12 mL, 0.5 mmol) in CH Cl (2
2
2
mL) was added to the supported catalyst 6 (0.025 mmol, 5 mol%). The mixture was
stirred at 45 °C for 0.5ꢀ2 h. Removal of the catalyst 6 from the reaction was achieved
2 2
via canula filtration. The solidꢀsupported catalyst was washed further with CH Cl (2
x 5 mL) and dried in vacuo. The resultant filtrate was concentrated in vacuo,
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1
dissolved in CDCl
MQ H
3
and analysed by H NMR spectroscopy. The filtrate was diluted in
2
O (100 mL) and Ru content analysed by ICPꢀMS.
Associated Content
Author Information
Corresponding Author
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Email: andrea.robinson@monash.edu
Notes
The authors declare no competing financial interest
Acknowledgments
The authors acknowledge the financial support of the Australian Research
Council (DP120104169) and the Australian postꢀgraduate research award to
ECG and ZJW.
Supporting Information
1
13
1
Copies of H, C{ H} NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org/.
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