Diastereofacial Solid Phase Synthesis and Self-Promoted Cleavage of a [2.2.1] Bicyclic Diversity Scaffold

Article abstract of DOI:10.1021/ol017264q

(matrix presented) We have previously described a diastereofacially selective 1,3-dipolar cycloaddition reaction of isomuenchnones with vinyl ethers. While adapting this methodology for solid phase synthesis, we discovered a chemoselective and self-promoted linker aminolysis that provides liberated product in high purity, at a significantly enhanced rate. Herein we described the implementation of a chiral auxiliary as a solid-phase linker, the detailed investigation of its unique aminolysis, and the utility of this cleavage within a chemical diversity format.

Full text of DOI:10.1021/ol017264q

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1419-1422
Diastereofacial Solid Phase Synthesis
and Self-Promoted Cleavage of a [2.2.1]
Bicyclic Diversity Scaffold
Sergey N. Savinov and David J. Austin*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06511
daVid.austin@yale.edu
Received December 19, 2001 (Revised Manuscript Received March 19, 2002)
ABSTRACT
We have previously described a diastereofacially selective 1,3-dipolar cycloaddition reaction of isomu1nchnones with vinyl ethers. While adapting
this methodology for solid phase synthesis, we discovered a chemoselective and self-promoted linker aminolysis that provides liberated
product in high purity, at a significantly enhanced rate. Herein we describe the implementation of a chiral auxiliary as a solid-phase linker, the
detailed investigation of its unique aminolysis, and the utility of this cleavage within a chemical diversity format.
In our previous Letter we described the development of a
chiral auxiliary for facial selectivity in a 1,3-dipolar cyclo-
addition reaction of isomu¨nchnones with vinyl ethers, for
the construction of [2.2.1] bicyclic molecules.1 Examples of
both the synthesis2 and use3 of these molecules as a scaffold
for chemical diversity have also been described. In this Letter,
we report the adaptation of this chiral auxiliary to the solid
phase synthesis of this diversity scaffold. In addition, we
describe a unique self-catalyzed and rate-accelerated amin-
olysis that undergoes a self-promoted, selective cleavage
from the resin, yielding a single product.
have prompted our interest in porting the 1,3-dipolar cyclo-
addition of isomu¨nchnones with vinyl ethers to the solid
phase. A rhodium-catalyzed isomu¨nchnone cycloaddition-
cycloreversion with alkyne dipolarophiles has recently been
reported, by us7 and others,8 to proceed quite efficiently on
solid phase. It remained to be evaluated, however, whether
the diastereo-2 and enantiofacial1 selectivity of the vinyl
ethers would also transfer to solid phase reaction conditions.
A solid phase asymmetric linker, structurally analogous
to the most successful solution phase auxiliary design,1 was
constructed starting with the benzhydrylamine (BHA) resin.9
The development of diversely functionalized probes for
the discovery and understanding of basic biological pathways
has exploded in the past few years.4 The synthetic generality
of cycloaddition chemistry, the facility of polymer-supported
synthesis for chemical diversity,5 and the adaptation of the
1,3-dipolar cycloaddition reaction to resin-based synthesis6
(5) (a) Czarnik, A. W.; Keene, J. D. Curr. Biol. 1998, 8, R705. (b) Lam,
K. S.; Lebl, M. Methods Mol. Biol. (Totowa, N.J.) 1998, 87, 1. (c) Spaller,
M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A. Curr. Opin. Chem. Biol.
1997, 1, 47. (d) Choong, I. C.; Ellman, J. A. Ann. Rep. Med. Chem. 1996,
31, 309.
(6) (a) Barrett, A. G. M.; Procopiou, P. A.; Voigtmann, U. Org. Lett.
2001, 3, 3165-8. (b) Washizuka, K.-I.; Nagai, K.; Minakata, S.; Ryu, I.;
Komatsu, M. Tetrahedron Lett. 2000, 41, 691-5. (c) Gong, Y.-D.; Najdi,
S.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 3081-6. (d)
Marx, M. A.; Grillot, A.-L.; Louer, C. T.; Beaver, K. A.; Bartlett, P. A. J.
Am. Chem. Soc. 1997, 119, 6153-67.
(7) (a) Whitehouse, D. L.; Nelson, K. H., Jr.; Savinov, S. N.; Lowe, R.
S.; Austin, D. J. Biorg. Med. Chem. 1998, 6, 1273-82. (b) Whitehouse, D.
L.; Savinov, S. N.; Austin, D. J. Tetrahedron Lett. 1997, 38, 7851-2.
(8) Gowravaram, M. R.; Gallop, M. A. Tetrahedron Lett. 1997, 38,
6973-6.
(1) Savinov, S. N.; Austin, D. J. Org. Lett. 2002, 4, 1415-18.
(2) Savinov, S. N.; Austin, D. J. Chem. Commun. 1999, 1813-14.
(3) (a) Liu, F.; Austin, D. J. Org. Lett. 2001, 3, 2273-6. (b) Savinov, S.
N.; Austin, D. J. Comb. Chem. High Thpt. Scr. 2001, 4, 593-7.
(4) (a) Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127-50. (b)
Denison, C.; Kodadek, T. Chem. Biol. 1998, 5, R129-45. (c) Clackson, T.
Curr. Opin. Chem. Biol. 1997, 1, 210-8.
10.1021/ol017264q CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/30/2002

Linking to the solid support via the para position of the
aromatic ring ensured little influence of the extra asymmetric
center on the facial selectivity, while preserving its conver-
gent assembly.1 Coupling of the BHA resin with both
enantiomers of R-hydroxyvaline furnished the immobilized
auxiliaries (S)-2 and (R)-2 (Scheme 1), as evident by a
Scheme 2. Induction of Facial Selectivity with Chiral Resins
Scheme 1. Synthesis of Chiral Linkers (S)- and (R)-4a
a (i) D- or L-hydroxyvaline, BOP, HOBt; (ii) DIC, DMAP; (iii)
MsN3, Et3N.
negative ninhydrin test and strong amide I band (νCdO
)
1654 cm-1) in the FTIR spectrum. These, in turn, were
functionalized with N-acylmalonamic acid 3 and subjected
to diazotransfer, providing diazoimide resins (S)-4 and (R)-
4. Characteristic diazo (νdiazo ) 2139 cm-1) stretch in the
FTIR spectra was employed to monitor the course of the
reaction.
Rh(II)-catalyzed nitrogen extrusion, followed by cyclo-
addition in the presence of vinyl ethers, completed the solid
phase assembly. The high solubility and high turnover ratio
(>3000)2 of the Rh2(pfbm)4 catalyst enabled a smooth
adaptation of the solution phase protocol to the solid phase
synthesis. After extensive washing of the resin, the detach-
ment of the bicyclic structures 5-11 (Scheme 2) was
accomplished as previously described (1 M methylamine in
methanol, 23 °C, sonication).1
filtration through a short silica gel plug was required to afford
analytically pure (>95% by HPLC and H NMR) bicyclic
substrates in 55-60% isolated yields after five synthetic
steps.10 As observed in our solution phase studies,1 secondary
amines, diethylamine and dibenzylamine, fail to liberate
substrate from the resin.
The rate and purity of the resin cleavage stimulated our
interest in investigating this unusual yet highly beneficial
behavior. As an initial experiment, a comparative kinetic
analysis was undertaken to ascertain and quantify the
observed rate enhancement for the auxiliary cleavage. Three
aminolysis substrates were envisioned, cycloadduct func-
tionalized auxiliary (S)-15, acetyl functionalized substrate (S)-
16, and methyl acetate itself. Benzyl-substituted auxiliary
(S)-13 (Scheme 3), designed to mimic the BHA solid phase
attachment, was synthesized from benzoxy benzylamine 12
and L-hydroxyvaline. Subsequent diazotransfer and Rh(II)
catalysis under standard conditions yielded cycloadduct (S)-
15 in good yield. Cleavage substrate (S)-16 was generated
from direct acylation of (S)-13.
1
The extent of diastereofacial selectivity with the resin-
supported asymmetric bias was found to be comparable with
our solution phase results.1 The induction of stereoselectivity
of the auxiliary can be best illustrated by the chiral
(-)-menthyl-based dipolarophile. The cycloaddition pro-
ceeded with a high degree of selectively in both the
“matched” (>95% de) and even the “mismatched” case (90%
de).
1
In every case, the H NMR and HPLC of the liberated
crude material indicated a remarkable purity of the aminoly-
sis-derived products with the desired bicyclic species being
the sole products of the multistep synthetic sequence.
Unidentified nonpolar impurities, which appeared to originate
from the polystyrene resin itself, were also present in the
crude mixtures in varied quantities. Hence, only a gradient
(10) The overall yield is based on the initial loading of BHA resin (0.75
mmol/g). The solid phase products were compared with analogous solution
phase substrates. The species liberated from the solid support matched well
with the solution phase synthesized heterocycles in all physical properties,
including optical rotation.
(9) Heavner, G. A.; Doyle, D. L.; Riexinger, D. Tetrahedron Lett. 1985,
26, 4583-6.
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Org. Lett., Vol. 4, No. 9, 2002

tional search with energetically accessible conformations of
the bicyclic species. Thus, a set of the most favored
arrangements was established, a great majority of which were
small permutations of a single hydrogen-bonded conforma-
tion (Figure 2). A unique recognition event is predicted to
Scheme 3. Synthesis of Substrates for Kinetic Analysisa
a (i) L-Hydroxyvaline, BOP, HOBt, 85%; (ii) DIC, DMAP; (iii)
MsN3, Et3N, 73%; (iv) Rh2(pfbm)4, ethyl vinyl ether, 83%; (v)
Ac2O, Et3N, 82%.
Substrates (S)-15 and (S)-16, along with methyl acetate, a
kinetic control, were subjected to aminolysis with methyl-
amine under pseudo-first-order conditions (25 equiv of
MeNH2, 23 °C) and the reaction course was monitored by
1H NMR, until near completion (Figure 1). Ester (S)-15 was
Figure 2. Computational model of nucleophilic attack.
occur between the primary amine and rigidly projected
hydrogen-bond acceptors (i.e., the ether and carbonyl oxy-
gens). These are positioned ideally for the formation of two
hydrogen bonds with the primary amine, effectively fixing
the nucleophile near the ester group.
An emerging model for this rate enhancement involves
an amine nucleophile, entropically constrained in the im-
mediate proximity of the electrophilic site, where it is
presented to the ester carbonyl in a Burgi-Duntz type
arrangement.13 Hence, the reactivity of the bound amine is
enhanced due to potential contributions from both proper
orientation of the reagents and extra electron density on the
amine provided by the polarization effect of the hydrogen-
bond acceptors.14
In addition to rate enhancement, this system displays
several characteristics that provide for chemoselective cleav-
age. First, since secondary and tertiary amines cannot form
a bis-hydrogen bonding interaction, the auxiliary ester is
immune to their attack (vide infra). Second, since the
recognition element is not present until the cycloaddition step,
none of the previous reaction byproducts that are carried
through on the resin will undergo cleavage. In the absence
of the complexation site, these esters would be guarded from
cleavage by the bulk of the chiral auxiliary, as demonstrated
in the kinetic study with (S)-16. This, in turn, ensures high
purity of the liberated material.
Figure 1. Kinetic analysis of cleavage substrates (S)-16, methyl
acetate, and (S)-15.
cleaved significantly faster than the other two substrates. In
fact, the rate was more than 2-fold greater for (S)-15
compared to methyl acetate. In contrast, no aminolysis was
observed for acetate (S)-16. These data suggest that the
bicyclic product itself was playing a role in its cleavage from
the auxiliary.
To ascertain the possibility and nature of a self-catalyzed
aminolysis, a molecular mechanics investigation of the
bicyclic scaffold and a primary amine was initiated using
the MacroModel software package.11 Using a Monte Carlo
conformational search routine,12 the amine was allowed to
sample various binding arrangements via rotational/transla-
Thus, a dual chemoselectivity is accomplished, whereby
only a specific class of nucleophiles can react with only one
type of electrophile, leaving potential byproducts attached
to the solid support and sparing less reactive electrophilic
(12) Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989,
111, 4379.
(11) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440.
(13) Bu¨rgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153.
(14) Ashton, P. R.; Calcagno, P.; Harris, K. D. M.; Philp, D. Org. Lett.
2000, 10, 1365.
Org. Lett., Vol. 4, No. 9, 2002
1421

and (iii) promoting the reaction via stereoelectronic and
inductive incentives.
Scheme 4. Selective Resin Cleavage with Substituted Amines
To demonstrate the potential of a simultaneous resin
cleavage and diversity elaboration, polymer-supported diazo-
imides (S)-4 and (R)-4 were subjected to the cyclization-
cycloaddition, followed by resin cleavage with a variety of
primary amines (Scheme 4). After incubation with an amine
scavenger (Amberlyst-15), the crude mixtures were filtered
through a plug of silica gel to provide compounds 17-26.
The functionalized primary amines liberated product at rates
comparable with methylamine. In fact, no relationship
between cleavage rate and nature of the amine could be
established, as R-branched, â-branched, and linear amines
showed very similar reactivities. No byproducts from the
1
substrate assembly were visible in the H NMR spectrum,
and no further chromatographic purification was required to
achieve this high level of purity.
As a result, a library of bicyclic substrates was generated
with primary amines serving as diversity elements. To
quantify the diastereofacial selectivity of the cycloaddition
step, (-)-cis-myrtanylamine was employed. In the case of
resin (S)-4, the anticipated compound 21 was the only
diastereomer observed in the 1H NMR spectrum, indi-
cating an exceptionally high (>95% de) level of diastereo-
selection. Similarly, the linker containing the opposite
asymmetric bias (R)-4 provided diastereomer 26 as the sole
product.
In conclusion, we have demonstrated the adaptability of
a 1,3-dipolar cycloaddition, utilizing a chiral auxiliary, to
the solid phase synthesis of a diversity scaffold. In addition,
we have discovered a novel, self-promoted, and chemo-
selective resin cleavage process. The synthesis and evaluation
of scaffold-based libraries is currently underway.
Acknowledgment. The authors thank Wolfgang Hinz and
Viet-Anh Nguyen for helpful discussion and the National
Institutes of Health (R01 GM59673) for financial support.
D.J.A. is the recipient of an Alfred P. Sloan Foundation
Fellowship.
functionalities. The cycloaddition, therefore, fulfills the
function of a “safety-catch” trigger.15 A unique linker strategy
emerges when considering the chemoselectivity and rate
enhancement of the cleavage, since the desired product can
only be cleaved under mild conditions after completion of
the cycloaddition step. Hence, the bicyclic structure acts
similarly to an enzyme by (i) specifically “recognizing” its
substrate, (ii) orienting it vis-a`-vis the reactive functionality,
Supporting Information Available: Experimental details
and characterization of compounds 5-26. This material is
available free of charge via the Internet at http://pubs.acs.org.
Note added after ASAP: There were errors in Schemes
1-4 in the version posted ASAP March 30, 2002; the
corrected version was posted April 9, 2002.
(15) (a) Backes, B. J.; Ellman, J. A. J. Org. Chem. 1999, 64, 2322-30.
(b) Backes, B. J.; Ellman, J. A. Curr. Opin. Chem. Biol. 1997, 1, 86-93.
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