Heterobivalent library expansion by "living radical" processes: Thiocarbonyl addition/elimination, and nitroxide-based reactions with fluorous deconvolution

Article abstract of DOI:10.1021/ja0756321

Degenerate radical addition fragmentation and nitroxide fragmentation reactions are applied to the expansion of heterobivalent libraries without contamination from homobivalent species. Deconvolution by means of a fluorous tagging process is described. Co

Full text of DOI:10.1021/ja0756321

Published on Web 09/19/2007
Heterobivalent Library Expansion by “Living Radical” Processes:
Thiocarbonyl Addition/Elimination, and Nitroxide-Based Reactions with
Fluorous Deconvolution
David Crich,*,† Daniel Grant, and Albert A. Bowers
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Ilinois 60607-7061
Received July 27, 2007; E-mail: Dcrich@chem.wayne.edu
“Living radical” (LR) reactions (Scheme 1) involve the regenera-
tion of masked radicals without loss by simple processes such as
heating. The reversible fragmentation of hydroxylamine C-O
bonds, giving a persistent nitroxide radical and a carbon-based
radical, is a LR based on the persistent radical effect (PRE)1 that
is applied extensively in living radical polymerization (LRP) of
alkenes2 but infrequently in synthesis.3 The “degenerate” addition
of radicals to dithiocarboxyl esters with expulsion of a second
radical [reversible addition-fragmentation chain transfer (RAFT)]
is an alternative approach to LR chemistry that is used in synthesis4
and LRP.5
Scheme 1. Living Radical Processes in (a) PRE and (b) RAFT
Figure 1. Twenty-five-member RAFT library with initiators in red.
We show that LR is suitable for the combinatorial expansion of
small heterobivalent libraries.6 At the simplest level, a pair of
molecules is squared to a matrix of four related ones (Scheme 2)
by reversible fragmentation of the A-X-R and B-X-R′ groups.
In this chemistry the use of PRE, or the dithioester RAFT reaction,
prevents the formation of homobivalent dimers, R-X-R′, A-X-
A, and B-X-B, which is unavoidable with most other methods
of heterobivalent library expansion.7,8 We also describe the use of
fluorous tagging as a means of deconvolution.
Scheme 2. Squaring of Two-Component Libraries
Figure 2. Mixed RAFT library with initiators in red.
To prove the principle a 1:1 mixture of dithiocarbamates 1 and
peptide coupling methods gave a series of 4-acylamino TEMPOs,
which were then benzylated on oxygen in the presence of copper
triflate9 to give a set of hydroxylamines (TEMPOL benzyl ethers).
Two of these, 38 and 39, were heated to reflux in equal proportions
in BuOH for 24 h, after which four compounds, 38-41, were
isolated chromatographically in yields of 86, 88, 80, and 82%,
2 was heated to 80 °C in benzene in the presence of 2.5 mol % of
AIBN, following which a separable mixture of the four hetero-
bivalent dimers 1-4 (Figure 1) was obtained cleanly. An initial
five-member library was then similarly expanded to a 25-member
library (Figure 1). Examination of the 13C NMR spectrum of this
library revealed >20 signals from δ 195-201 (CdS). A combina-
tion of GC-MS and ESI-MS enabled the identification of all 25
members of the anticipated library.
t
respectively, indicating almost complete equilibration.
Dithiobenzoates were also amenable to library expansion as
demonstrated by the formation of a set of four compounds 26-29
from 26 and 27. A more diverse library was obtained when an
equimolar mixture of two dithiocarbamates and two dithiobenzoates
underwent clean expansion to a 16-member mixed library, as
verified mass spectrometrically (Figure 2).
Derivatization of 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-NH2-TEMPO) by reaction with acyl chlorides or by standard
Protection of 2,2-dimethyl-2-nitroethanol as its TBDMS ether
followed by reduction with zinc and NH4Cl and subsequent
condensation with benzaldehyde gave nitrone 42, which could be
† Current address: Chemistry Department, Wayne State University, 5101 Cass
Avenue, Detroit, Michigan 48202.
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10.1021/ja0756321 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
treated with either phenyl or tert-butyl Grignard to provide two
nitroxides, 43 and 44. Reductive benzylation in the presence of
copper powder then afforded two further alkoxylamines, which were
individually tagged to give 45 and 46. After 24 h at reflux in
dichloroethane an equimolar mixture of 45 and 46 was transformed
into a library of 45-48, which could be isolated in yields of 96,
95, 92, and 95%, respectively, thereby establishing the validity of
the PRE-based hetereobivalent library expansion for a second class
of hydroxylamines.
heterobivalent expansion, each member of the complete nine
compound library would have a different fluorine atom count.
Heterobivalent library expansion of these compounds proceeded
smoothly in tBuOH at reflux overnight, and nine compounds were
resolved by analytical fluorous HPLC (Figure 4). Preparative HPLC
over fluorous silica gel was difficult, presumably owing to the
complication of the differing polarities of the various compounds.
However, separation was achieved with reasonable efficiency by
cutting the library into three fractions of differing polarity on normal
silica gel and then subjecting each fraction to fluorous HPLC.11
While the temperatures required for heterobivalent library
expansion by these methods may preclude their use in a dynamic
combinatorial sense for discovery of inhibitors of many enzymes,12
these systems may prove ideal for targeting thermophilic bacte-
ria.13,14
Acknowledgment. A.A.B. thanks the University of Illinois at
Chicago for a Moriarty Scholarship.
Supporting Information Available: Experimental details and
characterization. This material is available free of charge via the Internet
at http://pubs.acs.org.
A library of five N-acyl TEMPOL ethers was then successfully
expanded to a 25-member library in which each component could
be readily identified in the ESI-mass spectrum (Figure 3).
References
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Figure 3. Twenty-five-member PRE library with initiators in red.
(10) (a) Curran, D. P.; Zhang, Q.; Richard, C.; Lu, H.; Gudipati, V.; Wilcox,
C. S. J. Am. Chem. Soc. 2006, 128, 9561-9573. (b) Manku, S.; Curran,
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(11) In an operational setting involving screening of an heterobivalent library
separation should not be necessary. For example, if a 25-member library
derived by expansion of five compounds shows activity, it should suffice
to prepare five 16-member libraries each derived by omitting one of the
original five components. Assuming one active compound, a maximum
of two of the five-member libraries will be inactive from which the identity
of a hit will be readily ascertained.
(12) Note, however, the use of RAFT to functionalize a protein at room
temperature with initiation by γ-irradiation. Liu, J.; Bulmus, V.; Herlam-
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Figure 4. Nine-member fluorous library with initiators in red (number of
F atoms in parentheses).
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possible, as demonstrated by an elegant radical-mediated racemization of
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Nechab, M.; Azzi, N.; Vanthuyne, M.; Bertrand, M.; Gastaldi, S.; Gil, G.
J. Org. Chem. 2007, 72, 6918-6923.
Finally, we investigated the possibility of library deconvolution
by a fluorous tagging approach related to the fluorous-mixture
synthesis technique.10 A three-member N-functionalized TEMPOL
ether library was designed in which both the benzyl ether and
TEMPOL moieties carried distinct fluorous tags such that, after
(14) In addition it should be recognized that radicals are widespread intermedi-
ates in enzymic processes. Stubbe, J.; van der Donk, W. A. Chem. ReV.
1998, 98, 705-762.
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