Solid-phase olefin cross-metathesis promoted by a linker

Article abstract of DOI:10.1021/ol702415x

(Chemical Equation Presented) Olefin cross-metathesis couples two alkenes to form complex molecules and has been widely used in solution-phase organic synthesis. However, this powerful method has rarely been used in solid-phase organic synthesis. Herein w

Full text of DOI:10.1021/ol702415x

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5235-5238
Solid-Phase Olefin Cross-Metathesis
Promoted by a Linker
Amanda L. Garner and Kazunori Koide*
Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue,
Pittsburgh, PennsylVania 15260
koide@pitt.edu
Received October 3, 2007
ABSTRACT
Olefin cross-metathesis couples two alkenes to form complex molecules and has been widely used in solution-phase organic synthesis.
However, this powerful method has rarely been used in solid-phase organic synthesis. Herein we report that olefin cross-metathesis is a
synthetically viable method particularly when a traceless longer linker is inserted between solid support and reacting olefins.
Carbon-carbon double bond formations are important in
organic synthesis. Among these reactions is olefin metathesis,
which is a very powerful method for the construction of
complex alkenes.1 As such, olefin metathesis has been used
in the syntheses of a variety of molecules in solution phase.2
In solid-phase synthesis, although ring-closing olefin me-
tathesis has been widely used,3 olefin cross-metathesis has
been rarely used4,5 despite its potential for the convergent
synthesis of complex alkenes. In a rare example, Testero and
Mata showed that â-lactam analogues could be prepared on
solid support using olefin cross-metathesis between alkenes
on polymer and alkenes in solution, in which the yields of
the metathesis ranged from 35 to 78%.4 As apparent in our
study described below, their success may be due to the large
distance between the polymer and the reacting olefins, which
may not apply to other cases. In related cases, two spatially
separated alkenes, both on the same solid support, were
coupled by olefin metathesis, but these examples are, strictly
speaking, intramolecular reactions.6 Broadly applicable solid-
phase olefin cross-metathesis would be valuable because
homodimers and byproducts in solution can easily be
removed by simple filtration and the process can be
(1) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim,
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S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606.
(c) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.;
He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature
1997, 387, 268. (d) Koide, K.; Finkelstein, J. M.; Ball, Z.; Verdine, G. L.
J. Am. Chem. Soc. 2001, 123, 398.
(5) Chang, S.; Na, Y.; Shin, H. J.; Choi, E.; Jeong, L. S. Tetrahedron
Lett. 2002, 43, 7445.
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3, 1185. (b) Liao, Y.; Fathi, R.; Yang, Z. J. Comb. Chem. 2003, 5, 79. (c)
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(d) Tang, Q.; Wareing, J. R. Tetrahedron Lett. 2001, 42, 1399.
(4) Testero, S. A.; Mata, E. G. Org. Lett. 2006, 8, 4783.
10.1021/ol702415x CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/15/2007

automated.5 Herein, we report a general solution to the
challenging solid-phase olefin cross-metathesis.
In our synthetic efforts toward the development of biologi-
cally active compounds on solid support, we chose olefin
cross-metathesis as a convergent coupling method. Olefin
cross-metathesis is a mild transformation catalyzed by various
ruthenium reagents such as 1a7 and 1b8 (Figure 1) and
the analysis of compounds synthesized on the solid support
upon cleavage. As a complex olefin in solution, we chose
quinine because it presents high functionality, is com-
mercially available, and has been used as an antimalarial
drug.16 Unexpectedly, treatment of 2 with quinine (5.0 equiv)
and 1b (5 mol %) at 40 °C did not yield the desired alkene
3 as determined by crude 1H NMR analysis (Scheme 1). We
speculated that the ruthenium alkylidene complex of 2 might
be catalytically inactive because of chelation with the epoxide
oxygen atom. On the basis of this speculation, the above
reaction of 2 and quinine was employed in the presence of
Ti(OiPr)4 (20 mol %),17 which proceeded but to less than
20% which was still unsatisfactory. No intrabead ho-
modimerization was observed in either of these experiments.
In light of these poor results and the lack of systematic
studies in the literature, we decided to study cross-metathesis
reactions using model systems on solid support to further
the use of this method in solid-phase organic synthesis. We
noted that the olefin in 2 was much closer to the polymer
than those substrates reported in the literature.4 Although
change in linker length has been shown to be nonessential
in other solid-phase reactions,18 the proximity of the olefin
to the solid support could impact cross-metathesis because
the steric bulk of the polymer may block the catalyst’s access
to the olefin and the steric bulk of the catalyst may prevent
it from entering further into the polymer to react with shorter
carbon chains. Conversely, too long of a carbon chain would
facilitate the formation of undesired homodimers on the same
bead as previously shown by others.6
Figure 1. Metathesis catalysts.
tolerates many functional groups.9 Olefins themselves are
stable for long-term storage and compatible with many
synthetic transformations such as carbonyl addition reactions.
In addition to carbon-carbon double bonds as key retrosyn-
thetic disconnection sites, we became interested in epoxides
as featured synthetic intermediates and final products. As
intermediates, the regioselectivity of nucleophilic additions
to sterically and/or stereoelectronically differentiated ep-
oxides is predictable. As final compounds for biological
screenings, since epoxides are present in over eight thousand
biologically active natural products and can specifically form
covalent bonds with proteins,10 they should facilitate sub-
sequent chemical genetic studies (e.g., trapoxin B,11 fum-
agillin,12 epoxomicin).13 Furthermore, a range of enantio-
merically enriched epoxides is synthetically available.14
Our epoxide-based library synthesis project commenced
with trityl ether 2 (Scheme 1), which was derived from trityl
To study the distance-dependent solid-phase olefin cross-
metathesis, we prepared compounds 4a-d (Table 1). For
Table 1. Proximity Effect on Solid-Supported Olefin
Cross-Metathesis
Scheme 1. Solid-Phase Olefin Cross-Metathesis with Epoxide
2
entry
substrate
n
% yield
1
2
3
4
5
6
7
8
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
1
2
3
4
1
2
3
4
1
2
3
4
12 (<10a)
62 (48a)
70b (52a)
>95c (60a)
37
52
chloride resin and the corresponding epoxy alcohol. The
epoxy alcohol was prepared according to our previous work
(see Supporting Information).15 A trityl ether was chosen
because the readily cleavable linker provided a handle for
80b
83c
9
37
10
11
12
42
50b
(7) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(8) (a) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.;
Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318. (b) Grela, K.;
Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed. 2002, 41, 4038.
70c
a Yield using 1a instead of 1b. b Yield, 6:1 E:Z. c Yield, 5:1 E:Z.
5236
Org. Lett., Vol. 9, No. 25, 2007

our model studies, we chose alkene 7 as a symmetrical
alkene in solution.19 Metathesis reactions were performed
between alkenes 4a-d and alkene 7 (5.0 equiv) using
precatalyst 1b (5 mol %) in DCE at 24 °C for 22 h.
Following cleavage with TFA, alcohols 8a-d were isolated
(entries 1-4).20 All reaction yields were quantified based
on an external standard method (see Supporting Information).
Indeed, reaction yields were strongly influenced by the
carbon chain length; ether 4a (n ) 1) afforded alcohol 8a in
12% yield (entry 1), while ether 4d (n ) 4) gave alcohol 8d
in nearly quantitative yield. The low yield of 8a is not due
to the steric hindrance imposed by the trityl group because
a control cross-coupling between allyl trityl ether and 7 (5
equiv) catalyzed by 1b (5 mol %) afforded the corresponding
metathesis product in 61% yield. Also, no intrabead ho-
modimerization was observed for each carbon chain length.
We found that catalyst 1b consistently gave higher yields
than catalyst 1a (entries 1-4; brackets), which is reminiscent
of a report by the Schreiber group.21 Thus, we concluded
that 1b was superior to 1a in solid-phase olefin cross-
metathesis.
of trityl, the chlorine atoms should only affect cleavage and
have no effect on the olefin’s reactivity. This alcohol was
loaded onto aminomethyl polystyrene resin via a standard
amide forming method, and the resulting compound was
converted to trityl chloride 10 by the action of acetyl chloride.
This trityl chloride was reacted with alkenyl alcohols to form
trityl ethers 11a-11c (n ) 1-3). To our delight, metathesis
of 11a with 7 (5.0 equiv) using 1b followed by cleavage
(5% TFA in CH2Cl2) provided the desired product 8a in 62%
yield. Similar yields were observed from 11b and 11c with
the linker (55 and 57% yield). These data indicate that with
an additional linker between the trityl moiety and polymer,
more consistent yields can be obtained (cf. Table 1, entries
1-3).
We next investigated more substituted alcohols on solid
support. With trityl ethers 12, 15, and 18 without the linker
and trityl ethers 13, 16, and 19 with the linker (Scheme 3),
Scheme 3. Cross-Metathesis with Substituted Alcohols
To determine the generality of this proximity effect we
also loaded each alkenyl alcohol onto alkylsilyl resin22 and
Merrifield resin to generate compounds 5a-d and 6a-d,
respectively. Metathesis reactions were performed in a similar
manner as described above, and products 8a-d were isolated
after cleavage.20 These experiments revealed a similar
proximity effect; silyl ethers 5a-d produced the correspond-
ing alcohols 8a, 8b, 8c, and 8d in 37% (entry 5), 52% (entry
6), 80% (entry 7), and 83% yield (entry 8), respectively.
Benzyl ethers 6a-d produced alcohols 8a, 8b, 8c, and 8d
in 37% (entry 9), 42% (entry 10), 50% (entry 11), and 70%
(entry 12), respectively. Again, intrabead homodimerization
did not occur. These solid-phase experiments showed that
increasing the distance between the reacting olefin and the
resin improved the efficiency of olefin cross-metathesis.
While these studies provided insight, the addition of
carbons in the substrate and product is not always acceptable
in organic synthesis. Therefore, on the basis of the proximity
effect and the necessity for a traceless linker, we turned our
attention to the commercially available trityl alcohol 9
(Scheme 2). Although 9 contains a chlorotrityl moiety instead
Scheme 2. Cross-Metathesis with Linker
metathesis reactions were carried out using 7 (5 equiv) and
1b (5 mol %). In general, raising the temperature from 24
to 40 °C increased isolated yields by approximately 2 fold,
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Org. Lett., Vol. 9, No. 25, 2007
5237

thus the yields at 40 °C are shown here. With the substituted
homoallylic ethers 12 and 13, the reaction was again more
efficient with the linker (25% vs 47% yield). With the
substituted allylic ether 15 without the linker, the reaction
essentially did not proceed. In contrast, the allylic ether 16
with the linker underwent olefin metathesis with 7 to form
17 in 41% yield. This coupling could be improved to 53%
yield when the reaction mixture was heated to 60 °C. In the
case of type III olefins,23 18 and 19, the reaction was also
more efficient with the linker (<5% vs 20%). Similar to 16
the coupling was further improved to 38% when the reaction
mixture was heated to 60 °C. With these more substituted
allylic and homoallylic alcohols, the linker effect is promi-
nent.
Having established the olefin cross-metathesis technology
on solid support, we revisited our initial problem depicted
in Scheme 1. The epoxyalcohol was loaded onto linker resin
10 to generate trityl ether 21. Metathesis of 21 with quinine
(5 equiv) was performed using 1b and Ti(OiPr)4 at 40 °C
for 24 h. NMR analysis of the crude material cleaved from
the resin revealed that the quinine derivative 3 was formed
in 60% yield (Scheme 4). In the absence of Ti(OiPr)4, the
be applied to the synthesis of morphed drugs/natural products
with new properties.
In summary, olefin cross-metathesis in solid phase was
strongly influenced by the proximity between the olefin of
the substrate and polymer. On the basis of this insight, a
linker was used to increase the distance between the polymer
and the reacting olefins, which enabled cross-metathesis to
be successfully performed. This method could be applied to
both the primary and secondary alkenyl alcohols on the resin
and quinine in solution. The linker on solid-support should
now enable olefin cross-metathesis of a wide range of
alkenes.
Acknowledgment. A.L.G. is grateful for the NSF REU
program and the Novartis Graduate Fellowship. Reagent 1b
is a generous gift from Boehringer Ingelheim. We thank Ms.
Jihyun An (University of Pittsburgh) for preliminary experi-
ments. We thank Mr. Damodaran Krishnan and Dr. John
Williams (University of Pittsburgh) for assisting with NMR
and mass spectroscopic (NIH Grant 1S10RR017977-01)
analyses, respectively. This work was in part supported by
the Department of Defense (Grant W81XWH-06-2-0027).
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 4. Cross-Metathesis with Solid-Supported Epoxide
OL702415X
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via high vacuum to yield pure metathesis products.
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reaction again did not proceed validating our initial claim
of catalyst inactivation by the epoxide. These results clearly
demonstrate the merit of linker 9 in performing metathesis
reactions on solid support. Moreover, the quinine example
illustrates that the solid-phase olefin cross-metathesis could
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Org. Lett., Vol. 9, No. 25, 2007