Oxidative cyclorelease from soluble polymeric supports

Article abstract of DOI:10.1021/jo0480951

Single electron oxidation is shown to be a viable method for effecting concomitant cyclization and cleavage (cyclorelease) of a series of polymer bound homobenzylic ethers. Soluble oligonorbornene polymers are stable toward redox chemistry and are isolable through precipitation with methanol, making them excellent supports for this process. These oxidative conditions are also shown to cleave secondary and tertiary alcohols and ethers in a new traceless approach to polymer-supported aldehyde and ketone synthesis.

Full text of DOI:10.1021/jo0480951

Oxidative Cyclorelease from Soluble Polymeric Supports
Hua Liu, Shuangyi Wan, and Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
florean@pitt.edu
Received October 27, 2004
Single electron oxidation is shown to be a viable method for effecting concomitant cyclization and
cleavage (cyclorelease) of a series of polymer bound homobenzylic ethers. Soluble oligonorbornene
polymers are stable toward redox chemistry and are isolable through precipitation with methanol,
making them excellent supports for this process. These oxidative conditions are also shown to cleave
secondary and tertiary alcohols and ethers in a new traceless approach to polymer-supported
aldehyde and ketone synthesis.
Introduction
Constructing molecules on polymer supports has proven
to be useful for minimizing separation-derived waste
production, processing intermediates that are difficult to
handle, and generally expediting chemical synthesis.1
Although notable exceptions have been reported2 this
approach is not routinely used to prepare nonoligomeric
organic molecules due to limitations in the scope of
synthesis on insoluble polymers. For example, the kinet-
ics of reactions that are performed on a solid polymeric
support can be significantly different from the analogous
reactions run in solution as a result of limited substrate
accessiblity to reagents in certain solvents.3 Product
purification can also be difficult if all steps along a
sequence do not proceed with high efficiency. The former
issue has been addressed through the development of
soluble polymer supports4 that can be isolated from low
molecular weight reagents and solvents by precipitation
upon solvent change (“liquid-phase synthesis”)5 or by
nanofiltration.6 Alternative monomeric approaches that
FIGURE 1. Generalized cyclorelease from a polymeric sup-
port.
use a “tagging” strategy to isolate products have also been
explored,7 with fluorous tags showing particular promise
in multistep syntheses.8 Cyclorelease strategies9 (Figure
1) have been developed to address the latter issue.
Cyclorelease couples intramolecular bond formation with
product cleavage from the polymer. Thus only substrates
in which the requisite functional groups for the cycliza-
tion event have been successfully installed will be
released from the polymer, thereby providing an editing
mechanism that facilitates separation at the end of the
sequence. Herein we report that substrates for electron
transfer initiated cyclization (ETIC) reactions10 can be
synthesized on soluble polymeric supports, and that
(1) (a) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (b)
Fru¨chetel, J. S.; Jung, G. Angew. Chem., Int. Ed. 1996, 35, 17. (c) Gold,
L.; Polisky, B.; Uhlenbach, O.; Yarus, M. Annu. Rev. Biochem. 1995,
64, 763. (d) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.
A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233.
(6) Majumdar, D.; Zhu, T.; Boons, G.-J. Org. Lett. 2003, 5, 3591.
(7) (a) Yoshida, J.-i.; Itami, K. Chem. Rev. 2002, 102, 3693. (b) Flynn,
D. L. Med. Res. Rev. 1999, 19, 408.
(8) Curran, D. P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1174.
(9) For notable examples, see: (a) Beebe, X.; Schore, N. E.; Kurth,
M. J. J. Am. Chem. Soc. 1992, 114, 10061. (b) Piscopio, A. D.; Miller,
J. F.; Koch, K. Tetrahedron Lett. 1997, 38, 7143. (c) Nicolaou, K. C.;
Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis,
D.; Yang, Z.; Li, T.; Giannokakou, P.; Hamel, E. Nature 1997, 387,
268.
(10) (a) Kumar, V. S.; Floreancig, P. E. J. Am. Chem. Soc. 2001,
123, 3842. (b) Seiders, J. R., II; Wang, L.; Floreancig, P. E. J. Am.
Chem. Soc. 2003, 125, 2406. (c) Aubele, D. L.; Rech, J. C.; Floreancig,
P. E. Adv. Synth. Catal. 2004, 346, 359.
(2) For reviews, see: (a) Nicolaou, K. C.; Pfefferkorn, J. A. Biopoly-
mers 2001, 60, 171. (b) Watson, C. Angew. Chem., Int. Ed. 1999, 38,
1903.
(3) Cilli, E. M.; Oliveira, E.; Marchetto, R.; Nakaie, C. R. J. Org.
Chem. 1996, 61, 8992 and references therein.
(4) (a) Boyle, N. A.; Janda, K. D. Curr. Opin. Chem. Biol. 2002, 6,
339. (b) Wentworth, P., Jr.; Janda, K. D. Chem. Commun. 1999, 1917.
(c) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 469.
(5) Mutter, M.; Hagenmaier, H.; Bayer, E. Angew. Chem., Int. Ed.
Engl. 1971, 10, 811.
10.1021/jo0480951 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/18/2005
3814
J. Org. Chem. 2005, 70, 3814-3818

Oxidative Cyclorelease from Soluble Polymeric Supports
FIGURE 2. Oxidative cleavage reactions of homobenzylic
ethers.
cyclorelease reactions occur efficiently upon single elec-
tron oxidation to provide products of high purity. Ad-
ditionally we show that single electron oxidation is an
excellent trigger for traceless liberation11 of aldehydes
and ketones from polymeric supports even in the absence
of an internal nucleophile.
FIGURE 3. ROMP approach to oligonorbornenes.
mer prove to be susceptible to oxidation, olefin hydroge-
nation removes all redox active groups in the support.15
(5) Molecular weight can be controlled rationally by
adjusting metathesis catalyst loading or employing a
different catalyst16 in order to alter the solubility proper-
ties of the polymer to suit the needs of a particular class
of substrate. Based on structure-reactivity studies con-
ducted in our labs relating the effects of arene substitu-
tion to the propensity of intermediate radical cations to
fragment,10b,17 we chose to attach the polymer to the
substrates through an ether linkage at the para position
of the arene.
Upon single electron oxidation homobenzylic ethers
undergo mesolytic cleavage reactions to form benzyl
radicals and oxocarbenium ions.12 This process is revers-
ible and, in the absence of a rapid ensuing reaction, the
radical cation can be regenerated and reduced by solvent
with no net reaction being observed. Appending a nu-
cleophile to the homobenzylic ether in a manner that
allows for a rapid addition into the intermediate oxocar-
benium ion, however, makes the oxidative cleavage
irreversible and provides cyclic products. This protocol
is well-suited for cyclorelease applications since rapid and
irreversible carbon-carbon bond cleavage is observed
only in the presence of an appropriate nucleophile.
Capping the homobenzylic oxygen with an electrofugal
group that will depart from the oxocarbenium ion rapidly
to form an aldehyde or ketone represents an alternative
method for driving the radical-ion pair toward a stable
product. This approach, while not subject to the editing
mechanism of cyclorelease, is a unique method for
unmasking carbonyl groups during polymer supported
syntheses.
Results and Discussion
A representative synthesis of a polymer-supported
substrate and the subsequent cyclorelease are shown in
Scheme 1. Hydroxymethyl norbornene (3), which can be
purchased or prepared in multigram quantities through
an easy two-step sequence,18 was converted to iodide 4
in three steps. As a demonstration of concept homoben-
zylic ether 519 was appended to the norbornene monomer
to provide 6. Oligomerization of 6 proceeded smoothly in
the presence of 5 mol % of the second generation Grubbs
metathesis catalyst (2)20 to yield, after capping with ethyl
vinyl ether, polymer 7 with a predicted molecular weight
distribution centered at appromimately 32 000 (60-
mer).21 Upon precipitation with methanol and drying the
polymer was isolated in 79% yield. Subjecting the polymer-
bound substrate to our standard photoinitiated aerobic
ETIC conditions (hν, Pyrex filtration, 2.5 mol % of
N-methylquinolinium hexafluorophosphate (NMQPF6),
O2, NaOAc, Na2S2O3, 1,2-dichloroethane, toluene)22 fol-
lowed by filtering the reaction mixture over a short plug
of silica gel provided the desired tetrahydrofuran 8 in
72% yield contaminated with only minor amounts of
aromatic impurities. This yield is comparable to the yield
observed for the oxidative cyclization of the corresponding
monomeric substrate (84%).10b
The oligonorbornene scaffolding,13 prepared from ring-
opening metathesis polymerization (ROMP) of an ap-
propriately substituted norbornene monomer, was se-
lected as the support for this study in consideration of
several desirable attributes. (1) The polymers are soluble
in most organic solvents but precipitate in high yield
upon methanol addition.14 (2) Loading levels in these
systems are quite high relative to other soluble polymers
such as poly(ethylene glycol). (3) The polymers can be
characterized by standard spectroscopic techniques
throughout the course of a synthetic sequence. (4) Oxida-
tive decomposition of the support is not expected to be a
problem under cyclorelease conditions. Should the poly-
(11) Comely, A. C.; Gibson, S. E. Angew. Chem., Int. Ed. 2001, 40,
1012.
(12) (a) Arnold, D. R.; Lamont, L. J. Can. J. Chem. 1989, 67, 2119.
(b) Perrott, A. L.; Arnold, D. R. Can. J. Chem. 1992, 70, 272. (c) Arnold,
D. R.; Du, X.; Chen, J. Can. J. Chem. 1995, 73, 307. (d) Perrott, A. L.;
de Lisjer, H. J. P.; Arnold, D. R. Can. J. Chem. 1997, 75, 384. (e)
Baciocchi, E.; Bietti, M.; Putignani, L.; Steenken, S. J. Am. Chem. Soc.
1996, 118, 5952. (f) Baciocchi, E.; Bietti, M.; Lanzalunga, O. Acc. Chem.
Res. 2000, 33, 243. (g) Chen, L.; Farahat, M. S.; Gan, H.; Farid, S.;
Whitten, D. G. J. Am. Chem. Soc. 1995, 117, 6398. (h) Freccero, M.;
Pratt, A.; Albini, A.; Long, C. J. Am. Chem. Soc. 1998, 120, 284.
(13) For initial applications of this scaffolding to multistep synthesis,
see: (a) Ball, C. P.; Barrett, A. G. M.; Poitout, L. F.; Smith, M. C.;
Thorn, Z. E. Chem. Commun. 1998, 2453. (b) Harned, A. M.; Mukher-
jee, S.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2003, 5, 15.
(14) Barrett, A. G. M.; Hopkins, B. T.; Ko¨bberling, J. Chem. Rev.
2002, 102, 3301.
(15) Arnauld, T.; Barrett, A. G. M.; Hopkins, B. T. Tetrahedron Lett.
2002, 43, 1081.
(16) Harned, A. M.; Hanson, P. R. Org. Lett. 2002, 4, 1007.
(17) Wang, L.; Seiders, J. R., II; Floreancig, P. E. J. Am. Chem. Soc.
2004, 126, 12596.
(18) Moore, J. D.; Harned, A. M.; Henle, J.; Flynn, D. L.; Hanson,
P. R. Org. Lett. 2002, 4, 1847.
(19) The synthesis of this compound is detailed in the Supporting
Information.
(20) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(21) Moore, J. D.; Byrne, R. J.; Vedantham, P.; Flynn, D. L.; Hanson,
P. R. Org. Lett. 2003, 5, 4241.
(22) Kumar, V. S.; Aubele, D. L.; Floreancig, P. E. Org. Lett. 2001,
3, 4123.
J. Org. Chem, Vol. 70, No. 10, 2005 3815

Liu et al.
SCHEME 1. Cyclorelease through Carbon Oxygen Bond Formationa
a Reagents and conditions: (a) NaH, DMF, then allyl bromide, quant. (b) (Sia)2BH, THF, -10 °C, then NaOOH, 87%. (c) MsCl, Et3N,
CH2Cl2, 0 °C, then NaI, actone, 89%. (d) K2CO3, 5, DMF, 76%. (e) 2 (5 mol %), CH2Cl2, then ethyl vinyl ether, MeOH precipitation, 79%.
(f) NMQPF6, hν, O2, NaOAc, DCE, PhMe, 72%.
SCHEME 2. Cyclorelease through Carbon-Carbon Bond Formationa
a Reagents and conditions: (a) I2, Ph3P, imidazole, CH2Cl2, 99%. (b) Lithium acetylide, DMSO, 81%. (c) HOAc, [Ru(p-cymene)Cl2]2,
Fur3P, Na2CO3, PhMe, 28%. (d) 1, CH2Cl2, then ethyl vinyl ether, MeOH precipitation, 57%. (e) CAN, NaHCO3, DCE, CH3CN, 85%.
Having demonstrated the viability of this method to
effect cyclorelease with carbon-oxygen bond formation
we turned our attention toward cyclorelease through
carbon-carbon bond formation. Norbornene-tagged cy-
clization substrate 9 was prepared in three steps from 6
(Scheme 2). To minimize the possibility of destroying the
enol acetate, 9 was subjected to polymerization using the
first generation Grubbs metathesis catalyst (1)23,24 (2 mol
%) to provide polymer 10 in 57% yield with an expected
average molecular weight of 18 000 (30-mer). Cyclore-
lease of 10 using ceric ammonium nitrate (CAN) rather
than NMQPF6 provided alkoxycyclohexanone 11 in 85%
yield, again in excellent purity (Figure 4) and with
efficiency that rivals that of the monomeric variant of
the reaction (91%).10b
three step sequence used to convert 6 to 9 was applied
to polymer-supported substrate 7 (Scheme 3) to provide
cyclization precursor 10 in 52% yield over four steps. This
level of recovery indicates that further optimization in
polymer length is still necessary for this substrate.
Cyclorelease with CAN provided 11 in 79% yield. The
slight drop in yield for this process relative to the
cyclorelease in which the polymer was prepared directly
from 9 most likely results from sub-quantitative reaction
yields during the sequence.
Successful examples of carbon-carbon and carbon-
oxygen bond formation and photoinitiated and ground-
state oxidative cleavage reactions led us to pursue
multistep protocols on the polymeric support. Alcohol 6
was again subjected to ROMP conditions, though for this
sequence the polymers precipitated more readily when
4 mol % of catalyst 2 was used to give an average
molecular weight of approximately 16 000 (25-mer). The
(23) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
(24) For a discussion of the selectivity profiles for catalysts 1 and
2, see: Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
FIGURE 4. 1H NMR spectrum of 11 following filtration.
3816 J. Org. Chem., Vol. 70, No. 10, 2005

Oxidative Cyclorelease from Soluble Polymeric Supports
SCHEME 3. Polymer Supported Substrate Synthesis and Cycloreleasea
a Reagents and conditions: (a) I2, Ph3P, imidazole, CH2Cl2, 94%. (b) Lithium acetylide, DMSO. (c) HOAc, [Ru(p-cymene)Cl2]2, Fur3P,
Na2CO3, PhMe, 52% from 7. (d) CAN, NaHCO3, DCE, CH3CN, 78%.
SCHEME 4. Diastereoselective Cycloreleasea
SCHEME 5. Oxidative Traceless Cleavage of
Aldehydes and Ketonesa
a Reagents and conditions: (a) 1 (5 mol %), CH2Cl2, MeOH
precipitation, 95%. (b) Tributylstannylallene, Ti(Oi-Pr)4/TiCl4,
CH2Cl2, -78 °C, 82% recovery. (c) HOAc, [Ru(p-cymene)Cl2]2,
Fur3P, Na2CO3, PhMe, 88% recovery. (d) TBSCl, imidazole,
CH2Cl2, 80% recovery. (e) CAN, NaHCO3, DCE, CH3CN, 41%.
a Reagents and conditions: (a) hν, NMQPF6, O2, NaOAc,
Na2S2O3, DCE, PhMe, 17 (78%), 19 (89%).
through a straightforward sequence. The THP ether was
selected as the electrofugal group based on our success
in using the tetrahydropyranyl cation as a proton sur-
rogate in several cyclization reactions.10 Subjecting 16
to our aerobic photochemical oxidation conditions indeed
resulted in the formation of aldehyde 17 in 78% yield.
Protection of the hydroxyl group was subsequently shown
to be unnecessary, with polymeric tertiary alcohol 18
being cleaved to form ketone 19 in 89% isolated yield.
The robust nature of the benzylic carbon-carbon bond
in these systems, coupled with the highly selective
mechanism for carbonyl release should be attractive in
combinatorial synthesis and in other areas such as
surface modification17 where selective carbonyl group
introduction could be quite useful.
Encouraged by our initial success in this study, we
turned our attention to expanding the types of reactions
that can be performed on the polymer-bound substrate
and to increasing the molecular complexity of the prod-
ucts through conducting diastereoselective cyclorelease
reactions. We prepared monomer 12 following a sequence
that was developed in our recent studies17 in stereose-
lective syntheses of 2,6-disubstituted tetrahydropyrones
and subjected it to ROMP conditions with 5 mol % of 1
to provide polymer 13 with an expected average molec-
ular weight of 9200 (20-mer). Exposing 13 to a three-
step sequence of TiCl4/Ti(Oi-Pr)4-mediated acetal opening
with allenyl tributylstannane, ruthenium catalyzed acetic
acid addition, and hydroxyl silylation yielded enol acetate
polymer 14 with good mass recovery at each step (Scheme
4). Cyclorelease of 14 with CAN provided 15 as a single
stereoisomer in 41% yield, again demonstrating that
these reactions can be used to provide products that
require minimal separation following sequences that
contain difficult steps that do not proceed in nearly
quantitative yield.
Summary and Conclusions
We have shown that ETIC reactions are well-suited
for cyclorelease chemistry. The method accommodates
carbon-oxygen and carbon-carbon bond forming reac-
tions, and can be effected by photoinitiated or ground-
state electron transfer. The soluble oligonorbornene
scaffolding proved to be stable toward single electron
oxidation and functioned well in multistep sequences due
to facile isolation by precipitation with MeOH. Cycliza-
Our demonstration of oxidative cyclorelease reactions
led us to consider other modes for cleaving molecules from
polymer supports by single electron oxidation. In the
absence of an appended nucleophile, the alternate path-
way for oxocarbenium ion decomposition of electrofuge
departure to form a carbonyl group25 creates a pathway
for an oxidative, traceless release of ketones and alde-
hydes.26 To test this hypothesis we prepared polymer 16
(26) For recent reports of aldehyde and ketone cleavage from
polymer supports, see: (a) Lepore, S. D.; Wiley, M. R. Org. Lett. 2003,
5, 7. (b) Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999,
121, 9907. (c) Huwe, C. M.; Kunzer, H. Tetrahedron Lett. 1999, 40,
683. (d) Murphy, A. M.; Dagnino, R.; Vallar, P. L.; Trippe, A. J.;
Sherman, S. L.; Lumpkin, R. H.; Tamura, S. Y.; Webb, T. R. J. Am.
Chem. Soc. 1992, 114, 3156.
(27) Redox processes have been shown to be useful for modifying
surfaces for biochemical studies. Yeo, W.-S.; Yousaf, M. N.; Mrksich,
M. J. Am. Chem. Soc. 2003, 125, 14994.
(25) For a recent example, see: Ying, B.-P.; Trogden, B. G.; Kohl-
man, D. T.; Liang, S. X.; Xu, Y.-C. Org. Lett. 2004, 6, 1523.
J. Org. Chem, Vol. 70, No. 10, 2005 3817

Liu et al.
tion products are isolated in high purity because carbon-
carbon bond cleavage is efficient only in the presence of
an appropriately placed nucleophile. Substrates in which
the nucleophile is not properly installed do not cleave
from the support and are easily removed from solution.
We have also shown that polymer-supported homoben-
zylic ethers and alcohols can undergo oxidative cleavage
in a new method for traceless aldehyde and ketone
synthesis. The high chemoselectivity demonstrated by
these methods should prove to be useful for applications
in combinatorial and spatially directed synthesis.
Acknowledgment. This work was supported by
generous funding from the National Science Foundation
and the Research Corporation (Research Innovation
Award).
Supporting Information Available: Synthetic schemes
for all cyclization substrates; experimental procedures and
characterization for all cylorelease reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0480951
3818 J. Org. Chem., Vol. 70, No. 10, 2005