Monomer-on-monomer (MoM) Mitsunobu reaction: Facile purification utilizing surface-initiated sequestration

Article abstract of DOI:10.1021/ol1022382

A monomer-on-monomer (MoM) Mitsunobu reaction utilizing norbornenyl-tagged (Nb-tagged) reagents is reported, whereby purification was rapidly achieved by employing ring-opening metathesis polymerization, which was initiated by any of three methods utilizi

Full text of DOI:10.1021/ol1022382

ORGANIC
LETTERS
2011
Vol. 13, No. 1
8-10
Monomer-on-Monomer (MoM) Mitsunobu
Reaction: Facile Purification Utilizing
Surface-Initiated Sequestration
Pradip K. Maity,† Alan Rolfe,† Thiwanka B. Samarakoon,† Saqib Faisal,†
Ryan D. Kurtz,† Toby R. Long,† Alexander Scha¨tz,‡ Daniel L. Flynn,†
Robert N. Grass,| Wendelin J. Stark,| Oliver Reiser,*,‡ and Paul R. Hanson*,†
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe, Lawrence,
Kansas 66045, United States and The UniVersity of Kansas Center for Chemical
Methodologies and Library DeVelopment (KU-CMLD), 2034 Becker DriVe, Delbert M.
Shankel Structural Biology Center, Lawrence, Kansas 66047, United States, Institute
for Organic Chemistry, UniVersity of Regensburg, UniVersita¨tsstr. 31, D-93053
Regensburg, Germany, Deciphera Pharmaceuticals LLC, 1505 Wakarusa DriVe,
Lawrence, Kansas 66047, and Institute for Chemical and Bioengineering, Department
of Chemistry and Applied Biosciences, ETH Zurich, Wolfang-Pauli-Strasse 10,
CH-8093 Zurich, Switzerland
phanson@ku.edu
Received September 18, 2010
ABSTRACT
A monomer-on-monomer (MoM) Mitsunobu reaction utilizing norbornenyl-tagged (Nb-tagged) reagents is reported, whereby purification was
rapidly achieved by employing ring-opening metathesis polymerization, which was initiated by any of three methods utilizing Grubbs catalyst:
(i) free catalyst in solution, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.
The Mitsunobu reaction and its variants are powerful tools
for the synthesis of biologically active molecules and natural
products in drug design.1 The Mitsunobu reaction is a mild
but rapid method for the formation of C-C, C-S, C-N,
and C-O bonds, including the capacity to invert the
stereochemistry of stereogenic carbinol-bearing centers.2
Formally a four-component “redox” condensation between
an unactivated alcohol and an acidic pro-nucleophile, the
Mitsunobu reaction, is promoted under relatively mild
conditions by a combination of a tertiary phosphine and an
azodicarboxylate, usually triphenylphosphine (PPh3) and
diethyl or diisopropyl ester (DEAD or DIAD). Despite these
attributes, the corresponding purification is a tedious and
time-consuming process that is not desirable for parallel and
high-throughput chemistry, and several recent advances have
been developed.3 Even with these recent innovations,
† University of Kansas.
‡ University of Regensburg.
† Deciphera Pharmaceuticals LLC.
| ETH Zurich.
(1) (a) Abero, M. A.; Lin, N.-H.; Garvey, D. S.; Gunn, D. E.; Hettinger,
A.-M.; Wasicak, J. T.; Pavlik, P. A.; Martin, Y. C.; Donnelly-Roberts, D.
l.; Sullivan, J. P.; Williams, M.; Arneric, S. P.; Holladay, M. W. J. Med.
Chem. 1996, 39, 817–825. (b) Park, A.-Y.; Moon Hyung, R.; Kim Kyung,
R.; Chun Moon, W.; Jeong Lak, S. Org. Biomol. Chem. 2006, 22, 4065–
4067. (c) Azzouz, R.; Fruit, C.; Bischoff, l.; Marsais, F. J. Org. Chem.
2008, 73, 1154–1157. (d) Zapf, C. W.; Del Valle, J. R.; Goodman, M.
Bioorg. Med. Chem. Lett. 2005, 15, 4033–4036.
(2) For comprehensive reviews, see: (a) Mitsunobu, O. Synthesis 1981,
1–28. (b) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127–164.
10.1021/ol1022382  2011 American Chemical Society
Published on Web 12/01/2010

continued development of facilitated chromatography-free
Mitsunobu protocols for parallel synthesis is warranted.
Ring-opening metathesis polymerization (ROMP)-derived,
high-load oligomeric reagents and scavengers have been
utilized in many chromatography-free transformations, suited
for parallel synthesis.4,5 Previously we reported the applica-
tion of a polymer-on-polymer (PoP) Mitsunobu reaction
employing both ROMP-derived oligomeric triphenylphos-
phine and oligomeric azodicarboxylate.6 This multipolymer
platform was successfully utilized to transform a variety of
small molecules via an efficient Mitsunobu reaction. Facile
purification was achieved via precipitation and filtration of
now insoluble polymeric reagents and spent oligomers to
yield the desired products in high purity. We herein report
a new variant termed a monomer-on-monomer (MoM)7
Mitsunobu reaction that utilizes norbornenyl-tagged (Nb-
tagged) reagents that are rapidly sequestered post reaction
using ring-opening metathesis polymerization that is initiated
by any of three methods utilizing Grubbs catalyst cat-B:8
(i) free catalyst in solution, (ii) surface-initiated catalyst-
armed silica, or (iii) surface-initiated catalyst-armed Co/C
magnetic nanoparticles (Np’s) (Figure 1).
Figure 1. Norbornenyl-tagged reagents and Co/C Np’s for MoM
Mitsunobu Reactions.
monomeric reagents. This is an important feature that enables
reactions to be performed without the need of excess
reagents, reaction times (heterogeneous kinetics), or harsher
conditions to name a few classic properties when utilizing
immobilized reagents. With the norbornenyl-tagged PPh3
(Nb-TPP) and DEAD (Nb-BEAD)6a readily accessed, we
investigated their application in the Mitsunobu reaction
utilizing a variety of benzoic acids and benzyl alcohols (Table
1, entry 1-6). Utilizing 1.3 equiv of both reagents, the
In comparison to solid-phase immobilized reagents, the
utilization of norbornenyl-tagged (Nb) reagents allows for
reactions to be carried out in solution phase with small
Table 1. Mitsunobu Esterification Utilizing Nb-TPP and
Nb-DEAD
(3) (a) Dembinski, R. Eur. J. Org. Chem. 2004, 2763–2772. (b)
Reynolds, A. J.; Kassiou, M. Curr. Org. Chem 2009, 13, 1610–1632, and
references therein. (c) Chu, Q.; Henry, C.; Curran, D. P. Org. Lett. 2008,
10, 2453–2456. (d) Lan, P.; Porco, Jr, J. A.; South, M. S.; Parlow, J. J.
J. Com. Chem 2003, 5, 660–669. (e) Starkey, G. W.; Parlow, J. J.; Flynn,
D. L. Bioorg. Med. Chem. Let 1998, 8, 2385–2390. (f) Danapani, S.;
Newsome, J. J.; Curran, D. P. Tetrahedron Lett. 2004, 45, 6653–6656. (g)
But, T. Y. S.; Toy, P. H. J. Am. Chem. Soc. 2006, 128, 9636–9637. (h)
Taft, B. R.; Swift, E. C.; Lipshutz, B. H. Synthesis 2009, 2, 322–334.
(4) For reviews concerning ROMP reagents, see: (a) Barrett, A. G. M.;
Hopkins, B. T.; Ko¨bberling, J. Chem. ReV. 2002, 102, 3301–3324. (b) Flynn,
D. L.; Hanson, P. R.; Berk, S. C.; Makara, G. M. Curr. Opin. Drug
DiscoVery DeV. 2002, 5, 571–579. (c) Harned, A. M.; Probst, D. A.; Hanson,
P. R. The Use of Olefin Metathesis in Combinatorial Chemistry: Supported
and Chromatography-Free Syntheses. In Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; pp 361-402. (d)
Harned, A. M.; Zhang, M.; Vedantham, P.; Mukherjee, S.; Herpel, R. H.;
Flynn, D. L.; Hanson, P. R. Aldrichimica Acta 2005, 38, 3–16.
entry
R1
R2-OH
2-MeBnOH
yield (%) purity (%)
1
4-NO2
4-NO2
4-NO2
2,4-Cl
4-NO2
4-NO2
2-Me
3,4-Cl
4-NO2
2,6-Cl
75
77
78
79
84
81
81
91
74
71
73
76
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
2
3,5-OMeBnOH
3-Me-2-butene-1-ol
2-MeBnOH
3
4
5
4-ClBnOH
6
4-BrBnOH
7
3-NMe2BnOH
3-OMeBnOH
8
(5) (a) Long, T.; Maity, P. K.; Samarakoon, T. B.; Hanson, P. R. Org.
Lett. 2010, 12, 2904–2907. (b) Rolfe, A.; Probst, D.; Volp, K.; Omar, I.;
Flynn, D.; Hanson, P. R. J. Org. Chem. 2008, 73, 8785–8790. (c) Stoianova,
D. S.; Yao, L.; Rolfe, A.; Samarakoon, T.; Hanson, P. R. Tetrahedron Lett.
2008, 49, 4553–4555. (d) Barrett, A. G. M.; Hopkins, B. T.; Love, A. C.;
Tedeschi, L. Org. Lett. 2004, 6, 835–837. (e) Arstad, E.; Barrett, A. G. M.;
Tedeschi, L. Tetrahedron Lett. 2003, 44, 2703–2707. (f) Mukherjee, S.;
Poon, K. W. C.; Flynn, D. L.; Hanson, P. R. Tetrahedron Lett. 2003, 44,
7187–7190.
9
(R)-MeCH(OH) CO2Et
(R)-MeCH(OH)CO2Et
10
11
12
3-NMe2 (R)-MeCH(OH) CO2Et
4-Cl
(R)-MeCH(OH) CO2Et
a Crude purity determined by 1H NMR following precipitation of
polymers with EtOAc and filtration though silica SPE.
(6) (a) Harned, A. M.; Song He, H. S.; Toy, P. H.; Flynn, D. L.; Hanson,
P. R. Org. Lett. 2005, 127, 52–53. (b) Of notable importance is the seminal
advances made by Barrett and co-workers demonstrating the concept of
reagent annihilation (norbornenyl-tagged DEAD); see: (c) Barrett, A. G. M.;
Roberts, R. S.; Schro¨der, J. Org. Lett. 2000, 2, 2999–3002. For additional
examples of in situ scavenging, see: (d) Moore, J. D.; Harned, A. M.; Henle,
J.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2002, 4, 1847–1849.
desired esters were synthesized in good yield and purity
without the need for standard chromatography.
Key to this efficient purification was the phase switching
of the Nb-tagged monomeric reagents/spent reagents by the
utilization of ROM polymerization. This process transforms
the Nb-monomeric reagents into a soluble oligomeric
polymer, possessing a differential solubility profile to the
desired products. Precipitation of the spent oligomer in Et2O
or MeOH, followed by filtration via a silica SPE, yields the
desired products in high crude purity. This purification
protocol can be observed via TLC analysis, whereby a
multispot crude reaction is purified to a single product spot
utilizing the polymerization sequestration protocol. Building
(7) MoM is an acronym for reactions that utilize two monomeric species
(“monomer-on-monomer”) to carry out a transformation, in which upon
completion these monomers are sequestered via polymerization. This
acronym correlates to our previous use of ”polymer-on-polymer” (PoP),
for reactions employing the simultaneous use of two polymeric species that
react together in a transformation; see ref 6a.
(8) Cat-B: (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953–956. It should be noted that the Grubbs first generation
catalyst (PCy3)2(Cl)2RudCHPh [Cat-A] is deactivated in the presence of
Ph3PdO. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100–110. (c) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs,
R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039–2041.
Org. Lett., Vol. 13, No. 1, 2011
9

on these results, the MoM protocol was utilized efficiently
for the esterification and stereoinversion of chiral, nonracemic
secondary alcohols (Table 1, entries 9-12).
Table 2. MoM Mitsunobu Reaction Utilizing Silica and Co/C
Nanoparticle Sequestration
Despite success in this protocol, precipitation of each reaction
containing catalyst was deemed not ideal for a parallel high-
throughput approach. Therefore, investigations were directed
toward sequestration of the functionalized Nb-monomers by
polymerizing off a catalyst-armed immobilized surface. Se-
questration in this manner would further optimize the MoM
protocol by removing the need for precipitation and ultimately
result in an overall more cost-efficient and environment-friendly
protocol. To this effect, the use of silica9 or carbon-coated cobalt
(Co/C)10 nanoparticles bearing a norbornene moiety was
envisioned for the sequestration of excess/spent Nb-tagged
reagents via surface-initiated ROM polymerization.11,12 Mag-
netic nanoparticles are increasingly being utilized as supports
for immobilized catalysts in chromatography-free protocols,13
whereas Nb-tagged silica particles have been utilized to
synthesize silica surface grafted polymer supports.9,11 Key
to this approach was the arming of the nanoparticle surface
(1 equiv) with cat-B8 (0.6-0.8 equiv) for 30 min before the
addition of the crude reaction mixture.14
entry
R1
R2
yield (%)
crude purity (%)a
1b
2b
3b
4b
5b
6c
7c
8c
4-NO2
4-NO2
4-NO2
4-NO2
2-Me
4-NO2
4-NO2
4-NO2
4-Cl
2-Me
3,4-Cl
2-MeBn
3,5-OMeBn
4-BrBn
3-NMe2Bn
3,5-NMe2Bn
4-ClBn
3,5-OMeBn
4-BrBn
84
88
82
83
87
84
88
82
83
87
93
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
c
9
3-NMe2Bn
3-NMe2Bn
3,5-OMeBn
10c
11c
a Crude purity determined by 1H NMR following precipitation of
polymers with EtOAc and filtration though silica SPE. b Crude reactions
sequestered with catalyst-activated Si-Nb-tagged Np’s. c Crude reactions
sequestered with catalyst-activated Nb-tagged Co/C- Np’s.
With the corresponding Nb-tagged silica and Nb-tagged
Co/C in hand, the employment of the MoM Mitsunobu
reaction utilizing catalyst-armed Si particles (Table 2, entries
1-5) and Co/C Np’s (Table 2, entries 6-11) was success-
fully achieved yielding the desired products in high crude
purity. Purification when utilizing Si-armed particles was
minimized to a simple filtration of the crude reaction via a
Celite SPE. The utilization of Co/C magnetic Np’s required
simple application of an external magnet to the reaction
vessel and decantation of the crude mixture (Figure 2).
In conclusion, we have demonstrated the utilization of Nb-
tagged PPh3 and Nb-tagged BEAD reagents in a new MoM
Mitsunobu reaction. Purification of the excess and spent
monomeric reagents was initially achieved via a polymeri-
zation-precipitation-filtration protocol utilizing Grubbs cat-
Figure 2. (a) Sequestration utilizing catalyst-activated Nb-tagged
Co/C; (b) spent magnetic oligomer; and (c) Nb-tagged Si particles.
B. Purification was further optimized and streamlined for
parallel application utilizing catalyst-armed immobilized
surfaces to polymerize any Nb-tagged species via simple
filtration of the Nb-tagged Si particles or magnetization-
decantation when utilizing Nb-tagged Co/C magnetic Np’s.
(9) (a) Buchmeiser, M. R.; Sinner, F.; Mupa, M.; Wurst, K. Macro-
molecules 2000, 33, 32–39. (b) Krause, J. O.; Lubbad, S.; Nuyken, O.;
Buchmeiser, M. R. AdV. Synth. Catal. 2003, 345, 996–1004. (c) Kim, N. Y.;
Jeon, N. L.; Choi, I. S.; Takami, S.; Harada, Y.; Finnie, K. R.; Girolami,
G. S.; Nuzzo, R. G.; Whitesides, G. S.; Laibinis, P. E. Macromolecules
2000, 33, 2793–2795.
(10) (a) Grass, R. N.; Athanassiou, E. K.; Stark, W. J. Angew. Chem.
2007, 119, 4996. (b) Scha¨tz, A.; Grass, R. N.; Stark, W. J.; Reiser, O.
Chem.sEur. J. 2008, 14, 8262–8266. (c) Scha¨tz, A.; Grass, R. N.; Kainz,
Q.; Stark, W. J.; Reiser, O. Chem. Mater. 2010, 22, 305–310. (d) Wittmann,
S.; Scha¨tz, A.; Grass, R. N.; Stark, W. J.; Reiser, O. Angew. Chem., Int.
Ed. Engl. 2010, 49, 1867–1870.
Acknowledgment. This work was supported by the
National Institute of General Medical Science (Center in
Chemical Methodologies and Library Development at the
University of Kansas, KU-CMLD, NIH P50 GM069663 and
NIH-STTR R41 GM076765) with additional funds from the
State of Kansas, the International Doktorandenkolleg NANO-
CAT (Elitenetzwerk Bayern), the Deutsche Forschungsge-
meinschaft (Re 948/8-1, “GLOBUCAT”), and the EU-
Atlantis program CPTUSA-2006-4560. We thank Materia
Inc. for providing metathesis catalyst.
(11) (a) Mayr, M.; Mayr, B.; Buchmeiser, M. R. Angew. Chem., Int.
Ed. 2001, 40, 3839–3842. (b) Weck, M.; Jackiw, J. J.; Rossi, R. R.; Weiss,
P. R.; Grubbs, R. H. J. Am. Chem. Soc. 1999, 121, 4088–4089. (c) Scha¨tz,
A.; Long, T. R.; Grass, R. N.; Stark, W. J.; Hanson, P. R.; Reiser, O. AdV.
Func. Mater. 2010, published online ahead of print; DOI:, 10.1002/
adfm.201000959
.
(12) For examples of ROM polymerization off of polymeric beads, see:
(a) Fuchter, M. J.; Hoffman, B. M.; Barrett, A. G. M. J. Org. Chem. 2006,
71, 724–729. (b) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S. Org. Lett.
1999, 1, 1083–1086
.
(13) (a) Abu-Reziq, R.; Wang, D.; Post, M. L. J. Am. Chem. Soc. 2006,
128, 5279. (b) Lee, D.; Lee, J.; Lee, H.; Jim, S.; Hyeon, T.; Kim, B. M.
AdV. Syn. Catal. 2006, 348, 41–46. (c) Dalaigh, C. A.; Corr, S. A.; Gun’ko,
Y.; Connon, S. J. Angew. Chem. 2007, 119, 4407–4410.
(14) The order of addition of reagents in the sequestration protocol is
critical to minimize polymerization occurring as a result of free catalyst in
solution.
Supporting Information Available: Experimental details
and spectral characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL1022382
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Org. Lett., Vol. 13, No. 1, 2011