6
,8
acids. Simple and general access to tailored R-hydroxy
acids and to the subsequent functionalized cyclic copolym-
erization reagents, however, remains a synthetic challenge.
To address this problem, we developed a procedure to gain
rapid access to R-hydroxy acid derivatives using a one-pot,
Passerini-type condensation reaction.
Table 1. Isolated Yields of N-Acylindoles from the
Passerini-Type Condensation Reaction
a
9
10
The Passerini and Ugi reactions are multicomponent
condensations that employ isocyanides to generate carboxa-
mides and bis-amides, respectively. Recently, Kobayashi and
11
12
co-workers reported that a convertible isocyanide (1) can
be successfully used in Passerini and Ugi condensations to
convert the typically stable carboxamide products to readily
cleavable N-acylindole intermediates. We, therefore, explored
the possibility of using this convertible isocyanide in a
Passerini-type condensation reaction to develop a general
method for generating R-hydroxy N-acylindoles containing
a variety of side chain functionality (Scheme 1). We
Scheme 1
.
Proposed General Condensation of Aldehydes with a
a
Convertible Isonitrile
a
CSA ) camphorsulfonic acid.
transformed in situ to an N-acylindole in the presence of a
catalytic amount of camphorsulfonic acid (CSA), presumably
12
in a similar manner as described previously. To investigate
the general utility of these condensation conditions, we tested
several aldehydes for the ability to generate side chain func-
tionalized N-acylindoles (Table 1). The results indicate that we
can introduce a range of chemical properties in good yield using
this method; that is, functionality with azide-reactive (2b),
alkyne-reactive (2c and 2d), hydrophilic (2d), or sterically bulky
(2e) properties. We chose to incorporate side chains from
aldehydes 2b-2e in the condensation reaction in order to
provide chemical handles for postpolymerization modification
or to introduce other potentially useful chemical or physical
properties into the polymer. Functional groups provided by
aldehydes 2b-d, for instance, would lead to PLA-based
copolymers that could be modified by utilizing a Cu(I)-catalyzed
a
The resulting N-acylindoles may be further converted to side chain
functionalized hemilactides and incorporated into poly(R-hydroxy acid)
copolymers.
hypothesized that these functionalized R-hydroxy N-acylin-
doles could be readily hydrolyzed to the corresponding acids
and further converted to hemilactides for subsequent incor-
poration into PLA-based copolymers. A significant advantage
of this synthetic approach is its versatility, since this common
strategy can potentially generate a large and diverse set of
tailored polymers from simple, commercial or readily
prepared aldehydes.
We demonstrated that reaction of isocyanide (1), acetalde-
hyde, and water afforded the N-acylindole of lactic acid (2a)
in good yield (Table 1). In this procedure, the putative amide
produced from this Passerini-type condensation reaction was
13
azide-alkyne cylcoaddition (CuAAC) reaction. Compound
2d, in addition to providing a handle for CuAAC, may also
impart a degree of water solubility to a polymer that is otherwise
14
insoluble in aqueous solution. Aldehyde 2e may also afford
access to a PLA-based copolymer containing side chains with
15
amine handles upon deprotection of the phthalimide group.
(
(
(
8) Yin, M.; Baker, G. L. Macromolecules 1999, 32, 7711–7718
.
To illustrate another potential advantage of this Passerini-type
condensation for generating large scale quantities of N-acylin-
9) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126–129.
10) Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offerman, K. Angew.
Chem., Int. Ed. 1965, 4, 472–484.
(
11) (a) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9,
(13) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Tornoe, C. W.; Davis,
P.; Porreca, F.; Meldal, M. J. Pept. Sci. 2000, 6, 594–602. (c) Meldal, M.;
Tornoe, C. W. Chem. ReV. 2008, 108, 2952–3015.
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2
631–3634. (b) Isaacson, J.; Gilley, C. B.; Kobayashi, Y. J. Org. Chem.
007, 72, 3913–3916. (c) Buller, M. J.; Gilley, C. B.; Nguyen, B.;
Olshansky, L.; Fraga, B.; Kobayashi, Y. Synlett 2008, 2244–2248. (d) Gilley,
C. B.; Buller, M. J.; Kobayashi, Y. Synlett 2008, 2249–2252.
(14) Drieskens, M.; Peeters, R.; Mullens, J.; Franco, D.; Lemstra, P. J.;
Hristova-Bogaerds, D. G. J. Polym. Sci. B-Polym. Phys. 2009, 47, 2247–
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(12) Kobayashi, K.; Yoneda, K.; Mizumoto, T.; Umakoshi, H.; Morikawa,
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