Asymmetric azidation-cycloaddition with open-chain peptide-based catalysts. A sequential enantioselective route to triazoles

Article abstract of DOI:10.1021/ja0177814

A family of β-substituted histidine-containing peptides has been synthesized to probe the effect of noncovalent conformational rigidification on catalyst enantioselectivity. Unambiguous enhancement of enantioselectivity in the conjugate addition of azide

Full text of DOI:10.1021/ja0177814

Published on Web 02/13/2002
Asymmetric Azidation-Cycloaddition with Open-Chain Peptide-Based
Catalysts. A Sequential Enantioselective Route to Triazoles
David J. Guerin and Scott J. Miller*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467-3860
Received December 17, 2001
Scheme 1 a
Recent advances in both the peptide design field and the area of
high throughput catalyst screening have led to the discovery of small
molecule, peptide-based organocatalysts that enable new enantio-
selective processes.1 In this context, we recently disclosed a class
of peptides that catalyze the conjugate addition of azide ion to R,â-
unsaturated carbonyl compounds with moderate enantioselectivity
(45-85% ee, eq 1).2-4 The optimal catalyst (1) was found to adopt
a Conditions: (a) CH3MgBr, CuBrDMS, THF, -40 °C, (b) KHMDS,
THF, -50 °C; then trisyl azide, -78 °C; (c) NaOMe, MeOH/CH2Cl2, -10
°C; (d) H2, Pd/C, AcOH/MeOH; (e) BOC2O, CH2Cl2; (f) LiOH, THF/
MeOH/H2O.
Table 1. Catalyst Screen for â-azidation Employing Peptide
Catalysts (2)a
a â-turn-type structure, presumably favored by a L-Pro-D-tert-Leu
sequence.5 In addition, an amine base (e.g., the imidazole found in
N-alkyl-His residues) proved to be essential for catalyst activity.6
In searching for ways to improve catalyst enantioselectivity, we
were drawn to the strategy of conformational rigidification through
dihedral angle restriction.7,8 We therefore targeted â-substituted His
derivatives (e.g., 2) as catalyst candidates that could provide
selectivity and reactivity enhancement.9 Reported herein are
improved peptide-based azidation catalysts that take advantage of
this design element. Their application to the synthesis of optically
enriched triazoles and triazolines employing an azidation/cycload-
dition sequence is also reported.10
a All reactions conducted at 25 °C. See Supporting Information for details.
b Determined by 1H NMR (400 MHz). c Determined by chiral HPLC.
Reported ee values are the average of two runs. See Supporting Information
for details.
The synthesis of the required â-substituted His residues was
accomplished in analogy to reports by Hruby (Scheme 1).11
Urocanic acid derivative 5 was subjected to diastereoselective
conjugate addition employing MeMgBr in the presence of CuBr
to afford derivative 6 (4:1 dr).12 Asymmetric azidation according
to the Evans procedure proceeded with complete diastereocontrol
to afford R-azido imide 7 (72%).13 Conversion to the N-BOC-
protected amino acid was accomplished by employing a four-step
sequence to give 9b (59%). Analogous procedures were employed
to afford 9c-e, with other substituents in the â-position of the His
derivative. Conversion of the â-substituted His derivatives to the
derived azidation catalysts (1, 2b-e, epi-2c) followed standard
solution phase peptide synthesis procedures.14
with cyclohexyl-substituted acrylate 10b, with 11b being formed
with 85% ee. Notably, the â-substituted catalysts afforded products
with altered enantioselectivity under the same conditions (2.5 mol
% 2, 25 °C). In particular, methyl-bearing catalyst 2b afforded
improved ee values with both substrates. In the crotonate case, the
product was obtained with 78% ee (entry 2), and for the cyclohexyl-
substituted case, 11b was formed with 89% ee (entry 8). Catalysts
2c-e also afforded different levels of selectivity, supporting the
notion that the â-stereogenic center substantively influences the
transition state structures. For example, ethyl bearing catalyst 2c
led to the production of product 11a with 76% ee (entry 3); isobutyl-
substituted catalyst 2d afforded the same product with 64% ee (entry
4); isopropyl catalyst 2e afforded 11a with only 47% ee (entry 5).
The cyclohexyl-substituted acrylate provided a similar selectivity
Presented in Table 1 are the results of enantioselective conjugate
additions of azide with these catalysts. Entries 1 and 7 show the
results with the previously reported unsubstituted catalyst 1.
Moderate enantioselectivity was observed with crotonate derivative
10a (63% ee, 97% conversion); improved selectivity was observed
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10.1021/ja0177814 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for â-Azidation Employing Peptide
Catalysts (1 and 2b)a
for these substrates relative to those obtained with catalyst 1,
unsubstituted at the â-position.2
The improvements in enantioselectivity are noteworthy in part
because they are the result of substitution two carbons removed
from the basic imidazole nitrogen in an open chain compound.
Notably, catalyst 14 affords minimal enantioselectivity (<5% ee)
for these conjugate additions, underscoring the importance of the
secondary structure. An improvement in ee from 63% to 78% (i.e.,
the reactions of substrate 10a with catalyst 1 versus 2b at 25 °C,
respectively) corresponds to a ∆(∆∆Gq) ) 0.4 kcal/mol of transition
state energy differentiation. This quantity is clearly in the range
that could be due to subtle changes in conformational equilibria. It
1
is noteworthy that catalysts 1 and 2b-e afford H NMR spectra
that are consistent with this possibility. For example, the benzylic
protons within these catalysts exhibit chemical shift differences (∆δ)
that imply increasingly restricted rotation in that region:15 1, ∆δ )
0.08 ppm; 2b, ∆δ ) 0.10 ppm; 2c, ∆δ ) 0.20 ppm; 2d, ∆δ )
0.20 ppm; 2e, ∆δ ) 0.46 ppm. On the other hand, for catalyst
epi-2c, one of the least selective for the azidation, ∆δ ) 0.00 ppm
(singlet). These observations suggest that the â-substituted His-
containing peptides may indeed be rigidified with respect to their
unsubstituted counterparts.
a All reactions conducted according to the optimized conditions. See
Supporting Information for details. b After silica gel chromatography. Runs
at -10 °C are conversions (1H NMR, 400 MHz). c Determined by chiral
HPLC. Reported ee values are the average of two runs. See Supporting
Information for details.
profile. With catalyst 2c, 11b was obtained with 86% ee (entry 9);
catalyst 2d and 2e afforded the product with 77% ee and 70% ee,
respectively (entries 10 and 11). Finally, the epimeric catalyst epi-
2c was substantially less selective for both substrates relative to
2c: azide 11a was formed in only 45% ee under its influence (entry
6), while 11b was obtained in 68% ee under the same conditions
(entry 12). These results underscore the functional significance of
the â-position of the His residue. In addition, they reveal that
improved selectivities may be achieved with a methyl group in the
appropriate stereochemical configuration (cf. 2c and epi-2c).
However, a subtle remote steric effect is also at play: groups of
greater steric bulk than methyl result in catalysts that afford lower
selectivity (cf. 2b with 2c-e).
Chiral alkyl azides represent versatile synthons in organic
synthesis.16 We therefore set out to couple the asymmetric azidation
to a second transformation to increase the potential utility of the
reaction. We therefore attempted a sequential conjugate addition/
1,3-dipolar cycloaddition sequence involving a pendant alkyne to
access enantiomerically enriched triazoles (Scheme 2).17 Substrates
Scheme 2
With catalysts of improved selectivity in hand, we sought to
examine the scope of substrates that could undergo asymmetric
azidation in the presence of catalyst 2b (Table 2). Among the
parameters that we examined was temperature. Thus, for substrate
10a, enantioselectivity was enhanced with catalyst 2b (entry 1, 78%
ee; cf. 63% ee with 1), and was further improved to 86% ee when
the reaction was conducted at -10 °C (entry 2). Reactions are
slower at the lower temperature; nevertheless, comparable levels
of conversion can be achieved by carrying out the reaction for 48
h under these conditions (cf. 24 h at 25 °C). Whereas cyclohexyl-
substituted substrate 10b afforded 11b with 89% ee at 25 °C (entry
4), the product was obtained in 92% ee at -10 °C (entry 5).
Isopropyl-substituted acrylate 10c gave similar results: azide 11c
was obtained with 84% ee at 25 °C (entry 7), and with 90% ee
under the optimized conditions (entry 8). Piperdinyl-substituted
compound 10d afforded 11d with 80% ee at 25 °C (entry 10; cf.
71% ee with catalyst 1, entry 12), and 87% ee at the reduced
temperature (entry 11). Similarly, the less sterically demanding
acrylate 10e was converted to azide 11e with 77% ee at 25 °C
(entry 13; cf. 71% ee with catalyst 1, entry 15), but 85% ee at -10
°C. Finally, the more conventional oxazolidinone substrate 12 was
converted to azide 13 with 71% ee at 25 °C (entry 16; cf. 45% ee
with catalyst 1, entry 18), and with 78% ee at -10 °C (entry 17).
In general, these results represent improvements in enantioselectivity
of the type 15 were envisioned to undergo enantioselective azidation
to produce intermediates 16. Subsequent intra- or intermolecular
cycloaddition was projected to produce the corresponding triazoles
(17).
The synthesis of the key substrates was accomplished by standard
methods. Asymmetric azidations were then carried out with
improved peptide catalyst 2b under the optimized conditions. The
reaction mixtures were then filtered through silica plugs to remove
the catalyst; concentration, followed by redissolving in toluene and
heating (reflux or 130 °C; see Supporting Information for details)
efficiently converted the azides to the corresponding triazoles. The
results are summarized in Table 3. Noteworthy are that intramo-
lecular and intermolecular cycloadditions proceed efficiently.
Importantly, there was no erosion of substrate ee during the
cycloaddition step. For example, acetylene-substituted substrate 18
undergoes conjugate addition to afford the derived azide with 82%
ee. Filtration through a plug of silica gel, followed by heating to
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C O M M U N I C A T I O N S
Table 3. Enantioselective Azidation/Cycloaddition Sequence
the asymmetric azidations reported herein, this improvement enabled
the development of a two-step sequence for the production of
optically enriched triazoles relying on 1,3-dipolar cycloadditions
of the azidation products. Asymmetric transformations that set up
further complexity-generating transformations have been shown to
be of value in both target-oriented and diversity-oriented synthetic
contexts. Studies along these lines are underway in our laboratory.
Acknowledgment. This research is supported by the NIH (GM-
57595). We are also grateful to the NSF (CHE-9874963), DuPont,
Eli Lilly, Glaxo-SmithKline, and Merck for research support. D.J.G.
would like to thank the Organic Division of the American Chemical
Society and the Bristol-Myers Squibb Foundation for a graduate
fellowship. S.J.M. is a Fellow of the Alfred P. Sloan Foundation,
a Cottrell Scholar of Research Corporation, and a Camille Dreyfus
Teacher-Scholar.
Supporting Information Available: Experimental procedures and
product characterization for all new compounds synthesized (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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a Combined yield for two steps after silica gel chromatography. Ratio
in parentheses refers to ratio of regioisomers or diastereomers. b Determined
by chiral HPLC. See Supporting Information for details. Enantioselectivities
before and after the cycloaddition step were found to be (2% ee. c Heated
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130 °C for 48 h then affords optically enriched triazole 19 in 76%
overall (entry 1). Similarly, methyl-substituted substrate 20 is
converted to triazole 21 in good overall yield and ee (86% ee, 83%
isolated yield, entry 2). The sequence also works for cases where
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no erosion of ee. Cycloaddition with dimethylacetylenedicarboxylate
yields triazole 22 in 73% yield (92% ee, entry 3). Use of methyl
propiolate affords adduct 23 in 85% yield as a 4:1 mixture of
regioisomers (92% ee, entry 4). Cycloaddition with ethyl butynoate
yields adduct 24 in 78% overall yield as a 2:1 mixture of
regioisomers, again with no loss of ee (entry 5). Condensation with
bis(acetoxy)-2-butyne-diol produces triazole 25 in 77% overall yield
(92% ee, entry 6). Finally, cycloaddition with N-methylmaleimide
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