A peptide-based catalyst approach to regioselective functionalization of carbohydrates

Article abstract of DOI:10.1016/j.tet.2003.05.002

Two small peptide libraries (150 members and 36 members) have been subjected to screening experiments to evaluate their potential for regioselective (i.e. site-selective) acylation of carbohydrate monomers. Two substrates, one diol derived from N-acetyl glucosamine and one tetraol derived from glucose, have served as the test cases. In each case, the inherent regioselection of catalyzed acylation was defined as that derived from the reaction where N-methylimidazole (NMI) is used as the catalyst. With both substrates, peptides were found to perturb the inherent selectivities from those observed with NMI. From the libraries, the catalysts that provide the largest deviation from NMI were subjected to optimization studies. The work sets the groundwork for studies of expanded peptide libraries and development of structure-selectivity relationships to obtain catalysts that can selectively derivatize the unique sites in stereochemically complex polyols.

Full text of DOI:10.1016/j.tet.2003.05.002

Tetrahedron 59 (2003) 8869–8875
A peptide-based catalyst approach to regioselective
functionalization of carbohydrates
*
Keith S. Griswold and Scott J. Miller
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467-3860, USA
Received 28 February 2003; accepted 1 May 2003
Abstract—Two small peptide libraries (150 members and 36 members) have been subjected to screening experiments to evaluate their
potential for regioselective (i.e. site-selective) acylation of carbohydrate monomers. Two substrates, one diol derived from N-acetyl
glucosamine and one tetraol derived from glucose, have served as the test cases. In each case, the inherent regioselection of catalyzed
acylation was defined as that derived from the reaction where N-methylimidazole (NMI) is used as the catalyst. With both substrates, peptides
were found to perturb the inherent selectivities from those observed with NMI. From the libraries, the catalysts that provide the largest
deviation from NMI were subjected to optimization studies. The work sets the groundwork for studies of expanded peptide libraries and
development of structure-selectivity relationships to obtain catalysts that can selectively derivatize the unique sites in stereochemically
complex polyols.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
products that are unambiguously ‘natural-product-like’ in
8
their genesis.
The chiral pool continues to represent a tremendous store-
house of useful compounds that often serve as starting places
for complex molecule synthesis. Similarly, complex poly-
Recent studies in our laboratory have demonstrated that
small peptides containing modified histidine residues
(p-methyl histidine, 1) are effective catalysts for enantio-
selective acylation and phosphorylation reactions. Two of
the most encouraging cases are shown below. Octapeptide 2
1
functional natural products often represent important starting
points for the generation of natural product analogs in the
search for biologically active molecules with optimized
properties. While great strides have been made in the use of
the chiral pool for both purposes, there is little doubt that the
endeavor is complicated by a large dependence on protecting
group manipulations. One approach to the selective function-
alization of polyfunctional molecules continues to be the
9
catalyzes kinetic resolution of a range of secondary alcohols
1
0
with krel values up to .50 (Eq. (1)). Pentapeptide 3
catalyzes the desymmetrization of meso triol 4, affording
1
1
product 5 in 65% isolated yield, with .98% ee (Eq. (2)).
The fact that peptides in this family are able to convey
substantial stereochemical information in these catalytic
reactions, in combination with the fact that each was
discovered from screening experiments, stimulated us to
explore this family of chiral catalysts for its ability to carry
out regioselective reactions.
2
application of enzymes as regioselective catalysts. Indeed,
biotechnology continues to make important contributions to
this area. But, the specificity of enzymes has led to a situation
where enzyme-based methods do not provide a comprehen-
sive set of solutions. Other approaches have included the
3
innovative use of designed protecting-directing groups, and
4
also the exploitation of host–guest interactions. To date, the
application of small-molecule catalysts has been fairly limited
in scope, with most of the studies focused on the use of chiral
5
6
nucleophilic catalysts. In particular, both Yoshida and
7
Vasella have made important contributions in this area,
studying a set of catalysts for the selective functionalization of
a range of minimally protected carbohydrate monomers. The
development of a few approaches to efficient manipulation of
the chiral pool could have a substantial impact, both on
synthesis, and also the generation of libraries of natural
ð1Þ
Keywords: regioselectivity; N-methylimidazole (NMI); acylation.
*
Corresponding author. Tel.: þ1-617-552-3620; fax: þ1-617-552-2705;
e-mail: scott.miller.1@bc.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.05.002

8870
K. S. Griswold, S. J. Miller / Tetrahedron 59 (2003) 8869–8875
ð3Þ
ð2Þ
With the fundamental reactivity of substrate 6 defined under
a unique set of conditions, we sought to evaluate a small
peptide library to see if there were observable differences in
product distribution. We chose 150 peptides that had been
prepared in our earlier studies. All peptides were in the
family defined by structure 1, which included tetrapeptides
through octapeptides (the sequences may be found in the
Section 4.6). The catalysts were then studied under a
uniform set of reaction conditions (2 mol%, 1 equiv. Ac O,
2
258C, 15 h followed by MeOH quench); data are presented
in a histogram in Figure 1. The peptides indeed afford a
range of product distributions. Several things become clear
upon evaluation of the data. First, with all of the peptides,
deviations from the selectivity observed with NMI are
apparent. Second, the inherently higher reactivity of the
3-OH under the conditions is manifested with essentially all
of the catalysts. Indeed, many provide enhanced selectivity
for product 7 in comparison to NMI, a result that may reflect
an interaction between the acetamide of 6 and the H-bond
donors and acceptors of the catalysts. In contrast, very few
of the catalysts reverse the inherent selectivity of the
peptide, tilting the product ratio toward product 8. Perhaps
also of significance is that with the peptide-based catalysts,
very little of the diacetate 9 is typically produced (data not
shown). The two most noteworthy catalysts from the initial
screen are identified in Figure 1 with bold arrows. For the
catalyst labeled 10, there is a significant increase in
selectivity for the C3–OH product 7. For catalyst 3, the
2
. Results and discussion
Our experiments began with an investigation of the
1
acylation reactivity of glucosamine derivative 6 (Eq. (3)).
2
This substrate presents two regiotopic diols that are clearly
in different environments. Whereas the 3-hydroxyl is
flanked by the 2-acetamide and the 4-secondary hydroxyl,
the 4-OH is vicinal to a hydroxyl and two oxygen based
substituents. In terms of positional reactivity, when 6
undergoes acylation in the presence of NMI (20 mol%,
1
equiv. Et N, toluene, 258C), a complex reaction mixture is
3
produced (86% conversion). In order to document that the
observed product distributions are the product of kinetic
selection, isolated samples of each product were obtained,
and resubjected to the reaction conditions. In these
experiments, the isolated products were found to be stable,
and were recovered without modification.
Figure 1. 3D Bar graph showing regioselectivity for acylation of diol 6. Selectivity for product 7 is shown in grey. Selectivity for product 8 is shown in white.
Data for diacetate 9 is not shown. Two catalysts that provide highly disparate selectivity are identified with a red arrow. There are 15 catalysts in each stacked
row.

K. S. Griswold, S. J. Miller / Tetrahedron 59 (2003) 8869–8875
8871
selectivity starts to go the other way, with a near 1:1 7/8
ratio observed under the reaction conditions. These two
catalysts were then selected for further study.
extent under these conditions.
When each was purified and explored in toluene solution,
unambiguous deviations from NMI were documented
ð4Þ
(
Table 1). Catalyst 10, shown below (Table 1), results in
highly selective formation of product 7, affording a 97:3
ratio of products, and diacetate 9 is not observed. In
contrast, peptide 3 delivers a near 1:1 mixture (53:47) for
the C3–OH (7) and C4–OH (8) products. Although 3 does
not provide high selectivity for product 8, the fact that it
shifts the selectivity to the other side of the ratio afforded by
NMI suggests that this peptide-catalyst is overcoming the
inherent reactivity biases presented by the substrate. This
possibility bodes well for future studies of catalysts in this
family for this objective.
Evaluation of a small peptide library (36 members, Fig. 2)
once again showed that the peptides are indeed capable of
1
4
perturbing the inherent selectivities. Of particular note
was that in these experiments, the overall extent of
conversion was enhanced in comparison to NMI. In
addition, many of the catalysts reversed the inherent
selectivity of the reaction away from the primary hydroxyl
groups such that one of the secondary alcohols was
derivatized to a greater extent. Among the catalysts
examined, peptide 17 surfaced as the one that was most
distinct from NMI in terms of its selectivity profile.
Having observed peptides that could deliver product
distributions on either side of the ratio delivered by NMI,
we wished to establish if such a possibility were specific to
glucosamine derivatives like 6, or if it might be possible
with polyols that lacked amides. We thus elected to explore
When 17 was employed in the reaction under optimized
conditions, complete consumption of the tetraol to acetyl-
ated products was observed. Interestingly, 4-OAc product
15 was the dominant product, observed as 58% of the
reaction mixture. Primary acetate 16 was the next most
abundant component, present as 22% of the mixture.
Finally, the 2-OAc product 13 and the 3-OAc product 14
were present at 9 and 11% respectively. That peptide 17
shifts the inherent selectivity observed with NMI from the
primary hydroxyl group to one of the secondary sites is
particularly intriguing. This observation is one that will
1
3
tetraol 12 in the same type of screening study (Eq. (4)). Of
note, the product distribution delivered when NMI is used as
the catalyst is particularly modest. Under standard con-
ditions (1 equiv. Ac O, CHCl , NaOAc, 08C), overall
2
3
reactivity is quite low with only 14% total conversion
observed. Furthermore, of the acylated products, the
primary acetate 16 is the dominant product (64% of total
acetate), followed by 20% of acetate 14 and 16% of acetate
15 (relative to total acetylated product). Of particular note,
the 2-OAc product 13 is not observed to an appreciable
Table 1. ‘Hit’ catalysts for deviation for NMI derived from the initial peptide library
Catalyst
Total conversion
NMI
50
97
53
22
3
47
28
0
0
86
88
80
1
3
0
2
mol% catalyst, PhCH
3
, 258C, 15 h.

8872
K. S. Griswold, S. J. Miller / Tetrahedron 59 (2003) 8869–8875
manipulation of the chiral pool are among our current
objectives.
4. Experimental
4.1. General procedures
Proton NMR spectra were recorded on Varian 400 or 500
spectrometers. Proton chemical shifts were reported in ppm
(d) relative to internal tetramethylsilane (TMS, d, 0.0).
Spectral data is reported as follows: chemical shift
(
(
multiplicity [singlet (s), doublet (d), triplet (t), quartet
q), and multiplet (m)], coupling constants (J) [Hz],
integration). Carbon NMR spectra were recorded on a
Varian 400 MHz (100 MHz) spectrometer with complete
proton decoupling. Carbon chemical shifts are reported in
ppm (d) relative to the residual solvent signal (CDCl , d
3
77.16). NMR data were collected at 258C, unless otherwise
indicated. Infrared spectra were obtained on a Perkin–
Elmer Spectrum 1000 spectrometer. Analytical thin-layer
chromatography (TLC) was performed using Silica Gel 60
F254 pre-coated plates (0.25 mm thickness), TLC R values
f
Figure 2. Histogram showing product distribution for regioselectivity
observed for acylation of tetraol 12. Selectivity for product 13 is shown in
blue; selectivity for 14 in red; selectivity for 15 in green; selectivity for 16
in violet. Data for polyacetates not shown.
are reported and visualization was accomplished by
irradiation with a UV lamp and/or staining with cerium
ammonium molybdate (CAM) solutions. Flash column
chromatography was performed using Silica Gel 60A
(40 m) from Scientific Adsorbents Inc. High resolution
require additional studies to understand and exploit to a
more dramatic extent (Table 2).
mass spectra were obtained from Mass Spectrometry
Facilities of Boston College (Chestnut Hill, MA). The
method of ionization is given in parentheses. Elemental
analyses were obtained from Robertson Microlit
Laboratories Inc. (Madison, NJ).
3. Conclusions
Analytical and preparative HPLC were performed on a
Rainin 50–200 chromatograph equipped with a single
wavelength UV detector (214 nm).
Many challenges remain to achieve a systematic approach
to catalytic regioselective carbohydrate acylation. While it
is clear that the functionality and chirality endemic to small
peptides possess the ability to alter kinetic selectivity in
All reactions were carried out under a nitrogen atmosphere
employing oven and flame-dried glassware, unless
otherwise indicated. All solvents were distilled from
appropriate drying agents prior to use. Acetic anhydride
was distilled over P O prior to use and stored under a
reactions of polyols with Ac O, the rules which dictate the
2
perturbations are elusive at this time. One approach to the
problem is to apply an expanded diversity-based approach
in combination with the development of structure-
selectivity relationships to obtain a mechanistic under-
standing of the selectivity distributions. The development of
such a database of results, and its application to the efficient
2
5
nitrogen atmosphere.
Compound 6 was prepared in four steps from commercially
Table 2. ‘Hit’ catalysts for deviation from NMI derived from the peptide library
Catalysts
Total Conversion
NMI
0
9
20
11
16
58
64
22
14
100
17
2
3 2 2
mol % catalyst, PhCH /CH Cl , 08C, 15 h.

K. S. Griswold, S. J. Miller / Tetrahedron 59 (2003) 8869–8875
8873
available N-acetyl-D-glucosamine. (for procedure see
Ref. 12). N-Methyl imidazole (NMI) was distilled and
stored under an atmosphere of nitrogen prior to use.
4.3.4. Conditions for high throughput screen for selective
acetylation of 12. Initial library screening was accom-
plished under the conditions of Yoshida and co-workers
(Ref. 6): Ac O (1 equiv.), 5 mol% catalyst, NaOAc, CHCl
at 08C, 1 h.
2
3
4.2. Conditions for high throughput screen for selective
acetylation of 6
4.3.5. Analysis of product distribution. Product distri-
A stock solution of 6 in methylene chloride (50.0 mL,
butions were determined by integration of the acetate proton
signals arising from monoacetates 13, 14, 15 and 16.
Spectral data were compared to that reported by Yoshida
and co-workers (Ref. 6b). Product yields were determined
relative to acetic anhydride employing bromoform as an
internal standard.
0
.0286 mmol) was diluted with toluene (2.90 mL). A stock
solution of acetic anhydride in methylene chloride (50.0 mL,
.0286 mmol) was added, followed by the addition of a
stock solution of catalyst in methylene chloride (50.0 mL,
.572 mmol). After stirring for 15 h at 258C, the reaction
0
0
was quenched with 50.0 mL of methanol, allowed to stir for
an additional 5 min and then concentrated in vacuo. The
crude reaction mixtures were then subjected to NMR
analysis.
4.3.6. Optimized conditions for the selective acetylation
of 12. A stock solution of 12 in methylene chloride (400 mL,
0.0171 mmol) was added to 2.00 mL of toluene followed by
the addition of a stock solution of acetic anhydride in
methylene chloride (50.0 mL, 0.0122 mmol). A stock
solution of catalyst (20.0 mL, 0.244 mmol) was added to
the reaction. Reactions run at 08C were cooled in an ice bath
for 20 min prior to the addition of catalyst. After stirring for
15 h at 25 or 08C, the reaction was quenched with methanol
(50.0 mL), allowed to stir for an additional 5 min and then
concentrated in vacuo. The crude reaction mixtures were
then subjected to NMR analysis.
4
.3. Assay of product distribution
1
Product distribution was determined by integration of H
NMR signals arising from the C3 proton of compound 7
and the C4 proton of compound 8. Identification of
regioisomers was determined by 2D NMR experiments in
which proton assignments were made relative to the
anomeric proton of compounds 7 and 8. Conversions
relative to diol 6 were calculated employing bromoform
as an internal standard.
4.4. Preparation of 12
1
4
4
1
.3.1. Data for monoacetate 7. H NMR (CDCl3,
00 MHz) d 5.80 (d, J¼9.15 Hz, 1H), 5.04 (t, J¼9.15 Hz,
H), 4.39 (d, J¼8.42 Hz, 1H), 3.99–3.84 (m, 3H), 3.74 (dt,
Glucose derivative 12 was prepared in three steps from
commercially available 3,4,6-tri-O-benzyl D-glucal. Syn-
thesis of 12 began with formation of a 1,2-anhydro glycosyl
donor from tri-O-benzyl D-glucal employing the procedure
of Danishefsky (Ref. 13). Glycosylation employing 1-
octanol as the glycosyl acceptor followed by hydrogenolysis
of the benzyl groups affords 12 (Scheme 1).
J¼9.15, 2.56 Hz, 1H), 3.52–3.41 (m, 5H), 2.11 (s, 3H), 1.96
1
3
(
(
s, 3H), 0.90 (s, 9H), 0.10 (d, J¼2.93 Hz, 6H); C NMR
CDCl , 100 MHz) d 171.9, 170.2, 101.9, 75.6, 74.2, 71.7,
3
64.9, 56.5, 53.8, 26.0, 23.6, 21.3, 18.5, 25.1, 25.2; IR (film,
1
cm ) 3313, 3093, 2923, 2854, 1746, 1651; TLC R 0.47
2
f
(
10% MeOH/CH Cl ). Exact mass calcd for [C H N
2 2 17 34
O Si] requires m/z 392.2105. Found 392.2106 (ESþ).
7
1
4
4
1
3
(
(
.3.2. Data for monoacetate 8. H NMR (CDCl3,
00 MHz) d 5.80 (d, J¼4.03 Hz, 1H), 4.84 (t, J¼9.52 Hz,
H), 4.48 (d, J¼8.06 Hz, 1H), 3.89 (t, J¼9.52 Hz, 1H),
.74–3.67 (m, 2H), 3.51–3.43 (m, 5H), 2.11 (s, 3H), 2.05
Scheme 1.
1
3
s, 3H), 0.89 (s, 9H), 0.059 (d, J¼1.83 Hz, 6H); C NMR
4.4.1. Synthesis of 12a. To a suspension of 1,2-anhydro-
glucal substrate (1.04 g, 2.40 mmol) and 4 A˚ molecular
sieves (0.100 g, pellets) in anhydrous CH Cl (10.0 mL)
CDCl , 100 MHz) d 172.2, 170.4, 100.8, 75.3, 73.5, 72.2,
3
6
(
2.9, 58.9, 56.7, 34.8, 26.1, 23.8, 21.3, 18.6, 24.9, 25.1; IR
2
2
film, cm2 ) 3295, 3100, 2923, 2923, 2955, 2854, 1746,
1
was added 1-octanol (190 mL, 1.20 mmol). p-Toluene-
sulfonic acid (5.0 mg, 0.024 mmol) was then introduced
into the reaction. The reaction was allowed to stir at room
temperature for 15 h. The reaction was then concentrated in
vacuo and purified by silica gel chromatography eluting
with a 5–10% EtOAc/hexane gradient to afford each
individual anomer. (66% isolated yield, 30/70 a/b desired
anomer-b).
1658; TLC R 0.35 (10% MeOH/CH Cl ). Exact mass calcd
for [C H N O Si] requires m/z 392.2105. Found 392.2086
f
2
2
1
7
34
7
(
ESþ).
1
4
.3.3. Data for diacetate 9. H NMR (CDCl , 400 MHz) d
3
5
.42 (d, J¼8.79 Hz, 1H), 5.20 (t, J¼10.07, 1H), 5.00 (t,
J¼9.70 Hz, 1H), 4.49 (d, J¼8.42 Hz, 1H), 3.93–3.86 (m,
1
2
6
1
1
1
H), 3.75–3.67 (m, 2H), 3.55–3.49 (m, 5H), 2.03 (s, 3H),
.02 (s, 3H), 1.95 (s, 3H), 0.88 (s, 9H), 0.056 (d, J¼3.66 Hz,
1
Data for 12a. H NMR (CDCl , 400 MHz) d 7.39–7.16 (m,
3
1
3
H); C NMR (CDCl , 100 MHz) d 171.1, 170.0, 169.3,
3
15H), 4.94 (d, J¼11.4 Hz, 1H), 4.83 (d, J¼11.0 Hz, 2H),
4.62 (d, J¼12.1 Hz, 1H), 4.56–4.52 (m, 2H), 4.24 (d,
J¼7.30 Hz, 1H), 3.94–3.89 (m, 1H), 3.75 (dd, J¼10.8,
1.92 Hz, 1H), 3.69 (dd, J¼10.6, 4.76 Hz, 1H), 3.61–3.46
(m, 5H), 2.31 (d, J¼2.2 Hz, 1H), 1.63 (m, 2H), 1.31 (m,
01.6, 74.9, 73.1, 69.3, 62.8, 56.6, 54.6, 26.1, 23.7, 21.0,
1
2
8.6, 25.0; IR (film, cm ) 3269, 3093, 2930, 2854, 1753,
658, 1570; TLC R 0.53 (10% MeOH/CH Cl ). Exact mass
f
2
2
calcd for [C H NO NaSi] requires m/z 456.2030. Found
1
4
9
35
8
1
3
56.2037 (ESþ).
10H), 0.88 (t, J¼6.78 Hz, 3H); C NMR (CDCl ,
3

8874
K. S. Griswold, S. J. Miller / Tetrahedron 59 (2003) 8869–8875
1
1
7
2
2
00 MHz) d 138.5, 138.0, 137.9, 128.3, 128.2, 128.2,
27.8, 127.7, 127.6, 127.5, 127.4, 102.6, 84.5, 77.6, 75.1,
5.0, 75.0, 74.7, 73.5, 70.1, 68.9, 31.9, 29.7, 29.5,
(br s, 1H), 6.79 (s, 1H), 5.61 (br s, 1H) 4.83–4.78 (m, 1H),
4.48–4.28 (m, 4H), 3.70 (s, 3H), 3.66 (br s, 1H), 3.57 (s,
3H), 3.18–2.89 (m, 5H), 2.33–1.87 (m, 9H), 1.71–0.88 (m,
21
21
9.3, 26.1, 22.7, 14.2; IR (film, cm ) 3428, 3066, 3028,
926, 2855; TLC R 0.32 (20% EtOAc/hexane). Anal.
29H); IR (film, cm ) 3269, 3074, 2974, 2923, 2848, 2357,
2332, 1709, 1627; TLC R 0.32 (10% MeOH/CH Cl ).
f
f
2
2
calcd for C H O : C, 74.70; H, 8.24. Found C, 74.60; H,
3
Exact mass calcd for [C H N O Na] requires m/z
43 65 7 10
5
46
6
8
.24.
862.4691. Found 862.4705. Analytical HPLC, purity of
peptide 10 was assayed using a reverse phase RP-18 X Terra
(Waters) column. Conditions: isocratic elution with 60%
methanol in water, at a flow rate of 0.3 mL/min. Retention
time¼7.8 min.
4
1
.4.2. Synthesis of 12. A solution of 12a (0.605 g,
.14 mmol) in HPLC grade MeOH (15.0 mL) was purged
with nitrogen for 2 min and then placed under house
vacuum for 1 min. Following three repetitions of this
purging cycle was the addition of 10% Pd/carbon (0.240 g,
Peptide 3. Spectral and chromatography data are available
in Ref. 11.
0
.228 mmol). The reaction vessel was placed under an
atmosphere of hydrogen (balloon) and stirred at room
temperature. Reaction progress was monitored by TLC
1
Peptide 17. H NMR (CDCl , 400 MHz) d 8.79 (br d,
3
(
20% EtOAc/hexane). Upon consumption of starting
material, the suspension was purged with nitrogen for
0 min and then filtered through celite. The resultant
J¼5.06 Hz, 1H), 7.49 (s, 1H), 7.39–7.09 (m, 10H), 6.93 (s,
1H), 6.74 (s, 1H), 6.71 (s, 1H), 5.30 (br d, J¼6.59 Hz, 1H),
5.12–4.98 (m, 8H), 4.78 (q, J¼6.59 Hz, 1H), 4.68–4.47 (m,
3H), 4.31–4.27 (m, 1H), 3.64 (s, 3H), 3.55 (s, 3H), 3.17–
1
solution was concentrated in vacuo to yield a white solid
1
21
determined to be .98% pure by H NMR. (.90% isolated
yield).
2.89 (m, 6H), 1.70–0.85 (m, 25H); IR (film, cm ) 3288,
2923, 2848, 1740, 1658, 1501; TLC R 0.24 (10% MeOH/
f
CH Cl ). Exact mass calcd for [C H N O Na] requires
47 63 9 8
2
2
1
Data for 12. H NMR (CDCl , 400 MHz) d 4.30 (d,
3
m/z 904.4697. Found 904.4722; Analytical HPLC, purity of
peptide 17 was assayed using a reverse phase RP-18 X Terra
(Waters) column. Conditions: isocratic elution with 60%
methanol in water, at a flow rate of 0.3 mL/min. Retention
time¼6.2 min.
J¼7.33 Hz, 1H), 3.85 (m, 2H), 3.62–3.28 (m, 4H), 1.62 (m,
1
3
2
H), 1.28 (m, 12H), 0.88 (t, J¼6.77 Hz, 3H); C NMR
(
6
3
CDCl , 100 MHz) d 102.9, 76.4, 75.7, 73.4, 70.6, 69.5,
3
1.5, 2.1, 29.9, 29.8, 29.6, 26.2, 22.9, 14.4; IR (film, cm2
366, 2921, 1466, 1039; TLC R 0.17 (10% MeOH/
1
)
f
CH Cl ). Exact mass calcd for [C H O Na] requires m/z
2
2
14 28 6
3
15.1784. Found 315.1769 (ESþ).
Acknowledgements
4
.5. Peptide synthesis
We wish to thank Drs Elizabeth R. Jarvo and Thomas
E. Horstmann for their contributions to this work. This
research is supported by the National Institutes of Health
The peptide libraries screened for the selective acetylation
of 6 and 12 contained peptides synthesized on solid support
using commercially available Wang resin preloaded with
either FMOC-Phe or FMOC-Ala. Couplings were per-
formed using 5 equiv. amino acid derivative, 5 equiv.
HBTU, and 10 equiv. Hunig’s base in DMF for 3 h.
FMOC-deprotections were performed using 20% piperdine
in DMF for 20 min (to minimize diketopiperazine for-
mations, dipeptides were deprotected using 50% piperdine
in DMF for 5 min). Peptides were cleaved from solid
(GM68649). We are also grateful to the Merck Chemistry
Council and Pfizer Global Research for research support.
SJM is a Fellow of the Alfred P. Sloan Foundation, and a
Camille Dreyfus Teacher-Scholar.
References
support using a mixture of MeOH:Et N:DMF (9:1:1) for 4d.
3
1. Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. Rev.
1995, 95, 1677–1716.
Initial screening was carried out on crude material (desired
sequence identified by mass spectrometry). Selected pep-
tides were resynthesized on solid support in a similar
fashion and subjected to preparative HPLC using a reverse
phase RP-18 X Terra (Waters) column, eluting with
methanol/water at a flow rate of 6 mL/min. The purity
was checked by analytical HPLC under similar conditions,
2. Riva, S. Curr. Opin. Chem. Biol. 2001, 5, 106–111. Danieli,
B.; Riva, S. Pure Appl. Chem. 1994, 66, 2215–2218. Gotor, V.
Org. Process Res. Dev. 2002, 6, 420–426.
3. Moitessier, N.; Chapleur, Y. Tetrahedron Lett. 2003, 44,
1731–1735.
4. L u¨ ning, U.; Peterson, S.; Schyja, W.; Hacker, W.; Marquardt,
T.; Wagner, K.; Bolte, M. Eur. J. Org. Chem. 1998,
1077–1084.
1
and the peptides were characterized by H NMR and high
resolution mass spectrometry.
5
. For a review on small molecule-catalyzed asymmetric
acylation reactions, see: (a) Spivey, A. C.; Maddaford, A.;
Redgrave, A. J. Org. Prep. Proced. Int. 2000, 32, 333–3365.
For additional lead references, see: (b) Vedejs, E.;
Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813–5814.
Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420. Spivey,
A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65,
3154–3159. Sano, T.; Miyata, H.; Oriyama, T. Enantiomer
2000, 5, 119–123.
4
.6. Peptide library members
A list of peptide library members and their performance
under the conditions of the high throughput screen is
available upon request from the authors.
1
4
.6.1. Data for ‘hit’ peptides. Peptide 10. H NMR
(
CDCl , 400 MHz) d 7.37 (s, 1H), 7.30–7.12 (m, 6H), 6.94
3

K. S. Griswold, S. J. Miller / Tetrahedron 59 (2003) 8869–8875
8875
6
. Kurahashi, T.; Mizutani, T.; Yoshida, J. Tetrahedron 2002, 58,
669–8677. Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem.
Soc., Perkin Trans. 1 1999, 465–474.
11. (a) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. J. Am.
Chem. Soc. 2002, 124, 11653–11656. (b) Sculimbrene, B. R.;
Morgan, A. J.; Miller, S. J. J. Chem. Commun. 2003,
1781–1785.
8
7
. Hu, G.; Vasella, A. Helv. Chim. Acta 2002, 85, 4369–4391.
. Abel, U.; Koch, C.; Speitling, M.; Hansske, F. G. Curr. Opin.
Chem. Biol. 2002, 6, 453–458.
8
12. RajanBabu, T. V.; Ayers, T. A.; Halliday, G. A.; You, K. K.;
Calabrese, J. C. J. Org. Chem. 1997, 62, 6012–6028.
9
. Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann,
T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629–1630.
1
3. Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
11, 6661–6666.
1
1
0. Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
496–6502. Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.;
Bonitatebus, P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999,
21, 11638–11643.
1
4. The 36 library members were chosen at random from the
6
catalysts employed in the screen of substrate 6.
1