Dynamic polythioesters via ring-opening polymerization of 1,4-thiazine-2,5-diones

Article abstract of DOI:10.1039/b903612a

We describe the preparation and characterization of polythioesters composed of alternating α-amino acid and α-thioglycolic acid residues that undergo dynamic constitutional exchange under mild conditions. The polymers are assembled via reversible ring-ope

Full text of DOI:10.1039/b903612a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Dynamic polythioesters via ring-opening polymerization of
1,4-thiazine-2,5-diones†
Yasuyuki Ura,‡ Mohammad Al-Sayah,§ Javier Montenegro, John M. Beierle, Luke J. Leman and
M. Reza Ghadiri*
Received 20th February 2009, Accepted 29th April 2009
First published as an Advance Article on the web 8th June 2009
DOI: 10.1039/b903612a
We describe the preparation and characterization of polythioesters composed of alternating a-amino
acid and a-thioglycolic acid residues that undergo dynamic constitutional exchange under mild
conditions. The polymers are assembled via reversible ring-opening polymerizations of
1,4-thiazine-2,5-diones and related monomers in solution-phase conditions that do not require the use
of transition metal catalysts. Because 1,4-thiazine-2,5-diones can be derived in part from a-amino acids,
a variety of side chain functionalized monomers in optically pure forms could readily be accessed. In
addition, the resulting polythioesters have the potential for intra- and inter-chain hydrogen bonding,
which is known to impart materials properties to other previously studied polyamides. The studies
reported here could be useful in advancing a new class of biodegradable polymers and furthermore
suggest that dynamic constitutional exchange could be exploited to modify many known synthetic and
natural polythioesters.
Introduction
Results and discussion
Most conventional polymers can be classified as constitutionally
exchange-inert by virtue of their practically irreversible covalent
bond connections. In contrast, although constitutionally dynamic
polymers hold considerable promise in offering unique functional
and materials attributes, polymers assembled via covalent bond
connections that are reversible under ambient conditions have
surprisingly received little attention until recently.1,2
To study the potentially dynamic properties of thioester-based
polymers, we first required an efficient method to prepare such
materials. We were somewhat surprised to find that the 1,4-
thiazine-2,5-dione had not been used in polythioester synthe-
sis despite its structural similarity to widely used monomers
such as lactide,9,10 glycolide,10 and 1,4-morpholine-2,5-diones
(Scheme 1),11–13 and despite previous examples of polythioester
preparation through catalyzed ring-opening polymerizations of
five-, six-, or seven-membered thiolactones.5 We reasoned that
the nucleophilic attack by a thiol initiator onto a 1,4-thiazine-
2,5-dione monomer would yield the corresponding ring-opened
a-thiol-terminated dipeptide thioester that could participate in
subsequent ring-opening reactions to propagate polymer growth
(Scheme 2).
Thioesters are known to undergo rapid, reversible transthioes-
terification reactions under mild conditions in the presence of
thiols, and the utility of transthioesterification as a reversible
covalent linkage has previously been established by the construc-
tion of dynamic combinatorial thioester libraries3 and native
chemical ligation.4 Even so, to the best of our knowledge the
potential for constitutional exchange in polythioesters5 has only
been previously explored in the context of short cyclic oligomers
(n = 3–4).6 Polythioesters have recently been designated as
biomaterials based on the discovery of poly(3-mercaptoalkanoate)
biosynthesis in wild-type and engineered bacteria,7 providing a
new avenue for polythioester preparation and making a better
understanding of the properties of such polymers more desirable.
In contrast to polythioesters, polyesters and polyamides have
already been shown to undergo dynamic interchange, although
relatively extreme conditions (250–300 ◦C, usually with transition
metal catalysts) are necessary to observe exchange reactions at
useful rates for these polymers.8
Scheme 1 Structure of the 1,4-thiazine-2,5-dione and other commonly
used monomers for ring-opening polymerization.
Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
CA 92037, USA. E-mail: ghadiri@scripps.edu; Fax: (+1) 858-784-2798;
Tel: (+1) 858-784-2700
† Electronic supplementary information (ESI) available: Schemes S1–S3,
Figures S1, S2. See DOI: 10.1039/b903612a
‡ Present address: Nara Women’s University, Nara, Japan.
§ Present address: American University of Sharjah, UAE.
Scheme 2 Proposed dynamic ring-opening polymerization.
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Table 1 Monomer conversions, polymer yields, and observed Mn’s for polymerizations under various conditionsa
Entry
Monomer
Thiol equiv.b
Time (h)
Conv. (%)
Yield (%)
Mn (Da)c
Mw (Da)c
PDI (Mw/Mn)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
0.1
0.1
0.1
0.1
0.1
0.01
1.0
0.1 (BnSH)
20
15
20
20
20
20
20
20
20
0.5
4
80
81
92
80
88
53
81
81
80
55
66
39
75, 80
83, 82
77, 77
77
67
84
77
81
35
79
67
70
28
49
13
61
80
72
9800
8800
Insol.
9000
9700
7300
6800
9400
10100
7500
10200
3800
12700
15500
8200
16100
16600
Insol.
16000
13300
13300
11200
15300
16800
12100
17800
5700
1.6
1.9
Insol.
1.8
1.4
1.8
1.6
1.6
1.7
1.6
1.7
1.5
2.4
2.0
1.9
2
3
4
5
1
1
1
1
0.1 (pentylSH)
1
0.1
0.1
0.1
0.1
0.1
0.1
1
6
18
15
15
21
1 (1 eq), 3 (1 eq)
1 (3 eq), 3 (1 eq)
1 (1 eq), 2 (1 eq)
30600
30300
15300
a See ESI for full experimental details.† Conversion refers to monomer conversion as determined by HPLC. Yield refers to isolated yield of polymer
precipitates. N.D. = not detected. b Unless otherwise noted, HSCH2CO2Me was used as the thiol initiator. c Determined using size exclusion
chromatography calibrated with polystyrene standards.
We therefore prepared monomers 1–8 derived from standard
amino acids to evaluate their suitability for polymerization. Sub-
strates 1–3 and 5 were prepared by coupling thioglycolic acid to an
N-protected, activated amino acid, removing the amine protecting
group, and then cyclizing under dilute conditions to form the 1,4-
thiazine-2,5-dione (Scheme 3). Monomers 7 and 8 were likewise
prepared by replacing thioglycolic acid with thiopropionic acid
and a standard amino acid with N-methylglycine, respectively
(Scheme S2†). Monomers 4 and 6 were prepared by a slightly
different procedure involving conversion of an amino acid into
the corresponding amino thioacid, followed by reaction of the
thioacid with an unsubstituted or substituted bromoacetic acid
derivative, respectively, to generate the substrate for cyclization
(Scheme S1†).
Incubation of monomers 1–5 (~200 mM, room temperature,
no catalyst, 10 eq (iPr)2NEt) with methyl thioglycolate (0.1 eq)
as an initiator yielded precipitates that started to appear generally
within a few hours. Analysis of these precipitates by gel permeation
chromatography (GPC) indicated polymers having uncorrected
polystyrene-calibrated number average molecular masses (Mn)
around 9000 Da (Table 1).14 In the case of monomer 3, the
resulting polymer was insoluble in the GPC solvent (DMF),
preventing Mn characterization. In contrast, copolymerizations of
monomer 3 with 1 (Table 1, entries 13–14) provided good yields of
soluble polymers having Mn values up to 15 500 Da. Polythioester
polydispersity was somewhat higher for the copolymerizations
(Table 1, entries 13–15) than for reactions initiated with a single
monomer.
Polymer yields and Mn values were similar for three different
thiol initiators (Table 1, entries 1, 8–9). The optimal concentration
of thiol initiator was about 0.1 equivalents. Reduced yields were
obtained for reaction periods shorter than ~15 h, although Mn
values remained similar to those of the longer reactions (Table 1,
entries 10–11). A survey of reaction solvents other than CH2Cl2
using monomer 2 indicated that no polymerization occurred in
more polar solvents such as DMF, NMP, or 1,4-dioxane, while
polymerization proceeded moderately in acetonitrile. Buffered
water was examined as a solvent using side chain-deprotected
derivatives of monomers 4 or 5 (see Schemes S1 and S3 for
synthesis†); no polymerization was observed.
Scheme 3 Synthesis of monomers 1–3, 5. Reagents and conditions:
(a) HSCH2CO2H (1.1 eq), (iPr)2NEt (2.1 eq), CH2Cl2, 0 ◦C to rt, 18 h;
(b) TFA (50 eq), Et3SiH (5.0 eq), CH2Cl2, rt, 4 h; (c) 1 N HCl; (d) EDC·HCl
(1.2 eq), HOBt·H2O (1.2 eq), (iPr)2NEt (2.2 eq), CH2Cl2, 40 mM, 0 ◦C to
rt, 3 h.
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Compared to substrates 1–5, monomer 6 polymerized poorly
(Table 1) and appeared by HPLC to epimerize during the reaction
(presumably at the methine carbon adjacent to sulfur). These
findings are consistent with reports for analogous 1,4-morpholine-
2,5-diones.11 Monomers 7 and 8 both failed to polymerize under
our experimental conditions. Considering that alleviation of
ring strain provides the driving force for ROP, this result for
the seven-membered monomer 7 was surprising. Although the
simple seven-membered ring thiocaprolactone was reported to
polymerize more efficiently than the analogous six-membered
compound,15 ring-opening polymerization of seven-membered
analogs of the morpholinedione or thiazinedione monomers have
never been reported. Furthermore, a seven-membered diester
compound more similar to monomer 7 than thiocaprolactone was
reported not to homopolymerize.16 It is therefore possible that
the conformational or hydrogen-bonding properties of monomer
7 and similar species drive the monomer/polymer equilibrium
to disfavor polymerization. N-Methylated derivatives13,17 of
1,4-morpholine-2,5-diones have been reported not to homopoly-
merize efficiently, consistent with the failure of monomer 8.
To confirm the reversibility of the polythioesters, we treated
a sample of poly-2 (prepared as in Table 1, entry 2) with a
large excess of base and thiol (>10 eq each) in DMF. After
five minutes, HPLC analysis indicated the polymer was cleanly
depolymerized to yield cyclic monomer 2 and the ring-opened
monomeric derivative in a ~2:1 ratio, respectively (Figure S1†).
To establish the feasibility of dynamic constitutional exchange,
homopolymers of 1 and 3 (prepared as in Table 1, entries 11 and
3) were dissolved in a ~1:1 ratio and analyzed using MALDI-TOF
mass spectrometry. As expected, we observed the presence of only
homopolymeric species (Fig. 1). After incubating the mixture for
17 h with base and thiol (~0.3 eq each), however, MS analysis
indicated the presence of additional heteropolymeric products
that matched those formed in an independent copolymerization
of monomers 1 and 3 (prepared as in Table 1, entry 13). These
findings are consistent with a dynamic process in which subunits
were reversibly exchanged between the original homopolymers to
generate hetero-copolymers.
Conclusions
1,4-Thiazine-2,5-diones should be suitable for copolymerizations
with lactide, glycolide, and other substrates for ring-opening poly-
merization, making possible the synthesis of other novel materials.
Furthermore, the dynamic aspect of the polymers demonstrated
here is likely a common feature of many polythioesters, and
therefore could be exploited to alter the properties of other
synthetic or bio-engineered polythioesters.
Experimental
Polymerization reactions
Typical reaction procedure: monomer 1 (5.7 mg, 22.6 mmol)
was dissolved in CH2Cl2 (63 mL) containing 10 mM acetanilide
(an internal concentration standard) in an eppendorf vial. A
1.0 mL aliquot of this solution was removed and quenched in
1% TFA/ACN (200 mL); this aliquot was analyzed by HPLC
as a time zero point for determining the initial concentration of
monomer compared to the internal standard. (iPr)2NEt (37.4 mL,
226 mmol) and HSCH2CO2Me (11.3 mL of a 200 mM stock
solution in CH2Cl2, 2.3 mmol) were added to the solution to initiate
the polymerization reaction. The vial was sealed and the solution
stirred at room temperature for ~20 h. After this time, 1.0 mL of the
suspension was removed and dissolved in 1% TFA/ACN (200 mL)
for HPLC determination of the amount of monomer remaining
relative to the internal standard. Et2O (400 mL) was added to the
reaction suspension and the mixture was vortexed. The mixture
was centrifuged and supernatant decanted. The white polymer
precipitates were washed several times using Et2O (400 mL) and
dried. After weighing the dried precipitate (4.4 mg, 77%), 0.6 mg of
the precipitate was dissolved in 300 mL of the GPC solvent (DMF
containing 100 mM LiBr) to give a 0.2% solution that was used
for GPC analysis. Polymerization of monomer 8 was carried out at
100 mM due to poor monomer solubility. Copolymerizations were
conducted as described above by dissolving the two monomers in
the CH2Cl2/acetanilide solution. Polymer precipitates were stored
at -20 ◦C.
Attempted aqueous polymerizations
Reactions using side chain-deprotected derivatives of monomers
4 and 5 (compounds 13 and 14, respectively, see Schemes S1
and S3†) were attempted using buffered water as solvent. Two
conditions were examined: buffer 1 (50 mM PIPES buffer, 10 mM
tris-carboxyethyl phosphine [TCEP] as reducing agent, pH 6.5)
or buffer 2 (50 mM HEPES buffer, 10 mM TCEP, pH 8.0).
Reactant concentrations and reaction times were similar to those
described above. Polymers did not form, although slow monomer
consumption as a result of hydrolysis was observed (15% of
compound 14 hydrolyzed in 24 h at pH 6.5).
Fig. 1 (a) Schematic illustration of dynamic constitutional exchange in
polythioesters. (b) Homopolymers of substrates 1 and 3 were dissolved in
a stoichiometric ratio in hexafluoroisopropanol. MALDI-TOF analysis
of the mixture before (left) and after (center) a 17 h incubation with
(iPr)2NEt and HSCH2CO2Me indicated the development of product peaks
corresponding to heteropolymers. Comparative analysis of an independent
copolymerization of 1 and 3 (right) gave a similar peak distribution as the
product polymer generated via dynamic exchange.
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Depolymerization reaction
same solvents (10 mL/min) with a Phenomenex Jupiter Proteo
column (250 ¥ 21.2 mm).
A portion (~0.1 mg) of the precipitate obtained from the poly-
merization of 2 (obtained as in Table 1, entry 2) was dissolved
in DMF (15 mL). A 1.0 mL aliquot of this solution was removed
and quenched in 1% TFA/ACN (200 mL) for HPLC analysis. An
excess of (iPr)2NEt (8.0 mL, neat) and methyl thioglycolate (0.4 mL,
neat) were added and the solution was left at rt for 5 min, after
which time another aliquot was removed for HPLC analysis. The
difference in HPLC spectra before and after the reaction clearly
show that a depolymerization of the oligomers occurred to give
the ~2:1 mixture of monomer 2 and the ring-opened monomeric
derivative (Figure S1†).
Preparation and characterization of new compounds
Preparation of compounds 10a–d. (Scheme 1). Representative
synthetic procedure for Boc-Phe-SCH2CO2H (10b): to a dry
CH2Cl2 solution (20 mL) of Boc-Phe-OSu (9b) (1.55 g, 4.28 mmol,
from Novabiochem or Bachem), thioglycolic acid (0.34 mL,
4.88 mmol) and (iPr)2NEt (1.60 mL, 9.16 mmol) were added
at 0 ◦C. The mixture was stirred at rt overnight. The solvent
was removed under vacuum. The residue was taken up in
EtOAc (30 mL) and washed with 0.5 M citric acid (10 mL ¥
2) and brine. The organic layer was dried over Na2SO4, and
subsequent removal of the solvent gave a white solid. To the solid,
dicyclohexylamine (0.85 mL, 4.28 mmol) and hexane were added
and triturated. The obtained white precipitate was collected and
washed with hexane. The precipitate was suspended in EtOAc
and the dicyclohexylamine was extracted with 0.5 M citric acid
(10 mL ¥ 3). The organic layer was washed with brine and dried
over Na2SO4. Filtration and removal of solvent under vacuum
gave 10b as a white solid (1.34 g, 3.96 mmol, 92%). Compounds
10a, 10c, and 10d were prepared in a similar manner.
Dynamic polymer exchange
Portions of the precipitate obtained from the polymerization of
1 (0.8 mg) (obtained as in Table 1, entry 11) and of 3 (0.7 mg)
(obtained as in Table 1, entry 3) were mixed and dissolved
in hexafluoroisopropanol (60 mL). To 20 mL of this solution,
(iPr)2NEt (3.0 mL) and HSCH2CO2Me (3.0 mL of a 200 mM stock
solution in hexafluoroisopropanol) were added. The reaction was
stirred at rt for 17 h, after which time Et2O (400 mL) was added
to precipitate the polymers. The mixture was centrifuged, the
supernatant decanted, and the solids were washed several times
with Et2O. The obtained solid was analyzed using MALDI-TOF
spectrometry.
Compound 10a. 1H NMR (400 MHz, CDCl3): d 7.37–7.28 (m,
5H), 5.54 (d, J = 8.7 Hz, 1H), 4.53–4.50 (m, 1H), 4.50 (s, 2H), 3.99
(dd, J = 2.9, 9.7 Hz, 1H), 3.79 (d, J = 16.2 Hz, 1H), 3.66 (d, J =
16.9 Hz, 1H), 3.66 (dd, J = 3.6, 9.6 Hz, 1H), 1.47 (s, 9H). ESI-MS
(m/z) 370.1327 [M + H]+ (MWcalcd = 370.1319).
Compound 10b. 1H NMR (400 MHz, DMSO-d6): d 12.77 (br s,
1H), 7.74 (d, J = 8.4 Hz, 1H), 7.29–7.18 (m, 5H), 4.28 (ddd, J =
4.0, 8.4, 11.0 Hz, 1H), 3.65 (s, 2H), 3.07 (dd, J = 4.1, 13.9 Hz,
1H), 2.77 (dd, J = 11.1, 13.9 Hz, 1H), 1.32 (s, 9H). ESI-MS (m/z)
340.1209 [M + H]+ (MWcalcd = 340.1213).
MALDI-TOF MS conditions
For routine analysis of the polymers, a portion of the obtained
precipitates was suspended in a solution saturated with a-cyano-
3-hydroxycinnamic acid (in 1:1 H2O/ACN containing 0.1% TFA)
and sonicated for a period of 3 minutes. For analysis, 1.0 mL of the
suspension was spotted on a MALDI plate and was analyzed in
the positive mode. In some cases, the obtained precipitates and
3-aminoquinoline (usually 1:100 ratio by weight) were ground
together using a mortar and pestle, and the obtained powder was
pressed to make a thin disc. A piece of the disc was mounted on
MALDI plate with double-sided tape and was analyzed in the
positive mode.18
Compound 10c. 1H NMR (400 MHz, DMSO-d6): d 12.71 (br s,
1H), 7.67 (d, J = 7.9 Hz, 1H), 4.10–4.04 (m, 1H), 3.60 (s, 2H),
1.68–1.43 (m, 3H), 1.41 (s, 9H), 0.87 (d, J = 6.6 Hz, 3H), 0.82 (d,
J = 6.6 Hz, 3H). ESI-MS (m/z) 306.1362 [M + H]+ (MWcalcd
=
306.1370).
Compound 10d. 1H NMR (400 MHz, DMSO-d6): d 12.74 (br s,
1H), 9.15 (br s, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.43–7.29 (m, 10H),
5.25 (d, J = 12.5 Hz, 1H), 5.21 (d, J = 12.5 Hz, 1H), 5.05 (s, 2H),
4.06–4.02 (m, 1H), 3.94-3.64 (m, 2H), 3.59 (s, 2H), 1.69-1.41 (m,
4H), 1.39 (s, 9H). ESI-MS (m/z) 617.2266 [M + H]+ (MWcalcd
617.2276).
GPC conditions and calibration
Polymer Mn and Mw values were determined by means of
gel permeation chromatography using a Hitachi D-7000 HPLC
system monitoring UV absorbance at 265 nm. DMF (HPLC
grade) containing 0.1 M LiBr was used as the eluent at a flow rate
of 0.6 mL min-1. A Waters Styragel HR 4E column (7.8 ¥ 300 mm)
=
Preparation of monomers 1–3, 5. (Scheme 1). Representative
synthetic procedure for 2: to a dry CH2Cl2 solution (50 mL)
of 10b (1.20 g, 3.54 mmol), Et3SiH (2.83 mL, 17.7 mmol) and
TFA (13.1 mL) were added at 0 ◦C. The reaction mixture was
stirred at rt for 3–4 h. Volatile materials were removed under
vacuum, and the residue was azeotroped with toluene (¥ 3) to give
a white solid. For compounds 10a, 10c, and 10d, the obtained
TFA salts were converted to hydrochloride salts by treatment
with 1 N HCl followed by removal of the solvent under vacuum.
To a CH2Cl2 suspension (80 mL) of the deprotected compound
(1.10◦g, 3.25 mmol), (iPr)2NEt (1.18 mL, 7.15 mmol) was added
at 0 C. HOBt·H2O (0.60 g, 3.91 mmol) and EDC·HCl (0.75 g,
3.91 mmol) were then added to the reaction mixture at 0 ◦C,
◦
heated to 40 C was used. Molecular weights were calculated on
the basis of polystyrene standards without further correction.
HPLC conditions
Analytical reverse-phase HPLC was performed at 257 nm using
Phenomenex Jupiter Proteo or Zorbax 300-SB C-18 columns
connected to a Hitachi D-7000 HPLC system. Solvent system
(1.5 mL/min): binary gradients of solvent A (99% H2O, 0.9%
acetonitrile, 0.1% TFA) and solvent B (90% acetonitrile, 9.9%
H2O, 0.07% TFA). Preparative HPLC was carried out using the
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and the mixture was warmed up to rt. After stirring for 3–4 h,
the reaction mixture was washed with aqueous KHSO4 (5%).
CH2Cl2 was used to extract the aqueous layer (¥ 2). The combined
organic layers were washed with water and brine, and dried over
Na2SO4. Filtration and removal of solvent under vacuum gave a
colorless oil, which solidified upon cooling in a refrigerator. Silica
gel column chromatography (hexane:EtOAc = 1:1 to 1:3) gave 2
(550 mg, 2.49 mmol, 70%) as a white solid. Compounds 1, 3, and
5 were prepared in a similar manner.
evaporated under vacuum to leave an oily residue. The product
was purified by column chromatography on silica using a gradient
eluent of EtOAc/hexane starting with a 1:9 and reaching a 1:1
1
ratio to give 12 (1.5 g, 3.2 mmol, 46%). H NMR (400 MHz,
CDCl3) d (ppm): 7.35 (m, 5H), 5.23 (d, 1 H), 5.13 (s, 2H), 4.52 (m,
1H), 3.60 (dd, 2H), 2.49 (m, 2H), 2.24 (m, 1H), 2.01 (m, 1H), 1.45
(s, 9H), 1.43 (s, 9H). SSI-LCMS: (m/z) 489.7 [M + Na]+; 506.5
[M + K]+ (MWcalcd = 490.2 [M + Na]+; 506.2 [M + K]+).
Preparation of monomer 4. (Scheme S1†). Triethylsilane
(1.2 mL, 7.5 mmol) was added to a solution of 12 (1.4 g, 3 mmol)
in CH2Cl2 (6.2 mL) under argon. TFA (2.89 mL, 39 mmol) was
then added. The reaction was monitored by HPLC and LCMS
and required 24 hrs to reach 95% completion. The solvent was
removed under vacuum and the residue was dissolved in water
and lyophilized to give a solid (1.2 g, 2.6 mmol, 87%). Without
any further purification, a solution of the deprotected product
(1.0 g, 2.2 mmol) and (iPr)2NEt (0.8 mL, 4.7 mmol) in CH2Cl2
(120 mL) was added dropwise to a CH2Cl2 (130 mL) solution
of PyBop (1.5 g, 2.8 mmol) over a period of 2 h. The reaction
was then followed by LCMS and TLC (silica, EtOAc/hexane 1:1)
and was complete after 1 additional hr. The organic solution was
washed with water (2 ¥ 50 mL) and brine (1 ¥ 50 mL), dried
(Na2SO4), and evaporated under vacuum to leave an oily residue.
The product was purified by column chromatography on silica
using EtOAc/pentane (1:1) to afford an oily residue that solidified
upon sitting (400 mg, 1.4 mmol, 64%). 1H NMR (400 MHz,
CDCl3) d (ppm): 7.36 (m, 5H), 7.17 (bs, 1H), 5.14 (s, 2H), 4.10
(m, 1H), 3.84 (d, J = 15.2 Hz, 1H), 3.53 (dd, J = 1.6, 15.2 Hz
1H), 2.61 (t, J = 6.8 Hz, 2H), 2.35 (m 1H), 2.10 (m, 1H). ESI-MS
(m/z) 294.0796 [M + H]+ (MWcalcd = 294.0795).
Preparation of 13. (Scheme S1†). HF (10 mL) was introduced
to a mixture of monomer 4 (118 mg, 0.4 mmol) and anisole (88 mL,
0.8 mmol) at -78 ◦C. The solution was then warmed to 0 ◦C and the
reaction stirred for 1 h. The excess HF was removed by flowing N2.
The solid was dissolved in Et2O (5 mL) and extracted with water
(5 ¥ 10 mL). The combined aqueous extracts were concentrated
under reduced pressure and lyophilized to yield a white solid
identified as compound 13 (70 mg, 0.34 mmol, 90%). The solid
was purified by preparative HPLC. In column chromatography
(SiO2, CH2Cl2:MeOH 95/5) the material decomposed. 1H NMR
(CD3OD): d 1.94 (td, 1H, J = 7.3, 14.7 Hz,), 2.20 (dtd, 1H, J = 7.3,
13.4, 14.7 Hz,), 2.48 (t, 2H, J = 7.3 Hz), 3.56 (d, 1H, J = 15.0 Hz),
4.05 (d, 1H, J = 15.0 Hz), 4.23 (dd, 1H, J = 5.45, 7.87 Hz). ESI-MS
(m/z) 204.0323 [M + H]+ (MWcalcd = 204.0330).
Compound 1. 1H NMR (400 MHz, CDCl3): d 7.39–7.30 (m,
5H), 6.22 (br s, 1H), 4.58 (d, J = 11.7 Hz, 1H), 4.54 (d, J =
11.7 Hz, 1H), 4.25 (ddd, J = 2.6, 4.1, 6.7 Hz, 1H), 3.87 (dd, J =
4.1, 10.1 Hz, 1H), 3.81 (dd, J = 6.8, 10.2 Hz, 1H), 3.81 (d, J =
15.1 Hz, 1H), 3.64 (dd, J = 1.6, 15.1 Hz, 1H). ESI-MS (m/z)
252.0682 [M + H]+ (MWcalcd = 252.0689).
Compound 2. 1H NMR (500 MHz, CDCl3): d 7.36–7.20 (m,
5H), 6.20 (brs, 1H), 4.27 (ddd, J = 3.0, 4.5, 9.0 Hz, 1H), 3.75
(d, J = 15.2 Hz, 1H), 3.38 (dd, J = 4.6, 14.4 Hz, 1H), 3.35 (dd,
J = 1.0, 15.6 Hz, 1H), 2.90 (dd, J = 9.1, 14.6 Hz, 1H). 13C NMR
(125 MHz, CDCl3): d 198.60, 167.42, 134.90, 129.21 (2C), 129.19
(2C), 127.73, 63.62, 36.05, 31.44. ESI-MS (m/z) 222.0584 [M + H]+
(MWcalcd = 222.0583).
Compound 3. 1H NMR (400 MHz, CDCl3): d 6.32 (br s, 1H),
4.03 (ddd, J = 3.7, 4.7, 9.3 Hz, 1H), 3.84 (d, J = 15.1 Hz, 1H),
3.60 (dd, J = 1.5, 15.1 Hz, 1H), 1.89 (ddd, J = 4.8, 9.1, 14.0 Hz,
1H), 1.82–1.72 (m, 1H), 1.55 (ddd, J = 5.1, 9.2, 14.2 Hz, 1H),
1.00 (d, J = 6.5 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H). ESI-MS (m/z)
188.0739 [M + H]+ (MWcalcd = 188.0740).
Compound 5. 1H NMR (500 MHz, DMSO-d6): d 9.15 (br s,
2H), 8.29 (s, 1H), 7.44–7.30 (m, 10H), 5.25 (s, 2H), 5.05 (s, 2H),
4.22 (ddd, J = 3.2, 4.8, 7.8 Hz, 1H), 4.01 (d, J = 14.7 Hz, 1H),
3.95–3.83 (m, 2H), 3.48 (dd, J = 1.5, 14.7 Hz, 1H), 1.77–1.51 (m,
4H). ESI-MS (m/z) 499.1656 [M + H]+ (MWcalcd = 499.1646).
Preparation of 11. (Scheme S1†). Isobutyl chloroformate
(1.35 mL, 10.4 mmol) was added to a solution of Boc-Glu(OBz)-
OH (3.37 g, 10 mmol) and (iPr)2NEt (1.65 mL, 10 mmol) in
anhydrous THF (30 mL) cooled at -20 ◦C under argon. The
mixture was allowed to stir for 20 min at -20 ◦C, after which
time a white suspension was formed. A solution of NaSH (0.67 g,
12 mmol) in DMF (5 mL) was then added and the yellow
solution was stirred at 0 ◦C for 4 h, after which time the TLC
(silica, EtOAc/hexane/HOAc 3:7:0.5) showed completion of the
reaction. The solution was then acidified to pH = 3 with 1 N HCl
and the aqueous layer was extracted with EtOAc (3 ¥ 20 mL).
The combined organic layers were washed with water (1 ¥ 20 mL),
dried (Na2SO4), and evaporated under vacuum to afford the oily
product 11. The product was used without further purification.
Preparation of 14. (Scheme S3†). HF (10 mL) was introduced
to a mixture of monomer 5 (200 mg, 0.4 mmol) and anisole (88 mL,
0.8 mmol) at -78 ◦C. The solution was then warmed to 0 ◦C and
the reaction stirred for 1 h. The excess HF was removed by flowing
N2. The solid was dissolved in Et2O (10 mL) and extracted with
0.1 M HCl (3 ¥ 10 mL). The aqueous phase was washed with Et2O
(2 ¥ 15 mL), concentrated under vacuum, and lyophilized to afford
a white solid identified as 14 (91 mg, 0.39 mmol, 98%). 1H NMR
(CD3OD) d 1.68–2.14 (m, 6H), 3.67 (d, 1H, J = 15.0 Hz,), 4.19
(d, 1H, J = 15.0 Hz), 4.3–4.38 (m, 1H). ESI-MS (m/z) 231.0909
[M + H]+ (MWcalcd = 231.0910).
Preparation of 12. (Scheme S1†). t-Butyl bromoacetate (2.0 g,
10 mmol) was added to a stirred solution of crude 11 (2.5 g,
7.0 mmol) in MTBE (50 mL) at 0 ◦C followed by the addition
of Cs2CO3 (2.0 g). The cooling bath was then removed and the
mixture was stirred at rt. The reaction was followed by TLC
(silica, EtOAc/hexane/HOAc 1:1:0.1) and was complete within
2 h. EtOAc (30 mL) and water (30 mL) were added to the reaction
mixture and then the organic layer was separated, washed with
water (2 ¥ 15 mL) and brine (1 ¥ 15 mL), dried (Na2SO4), and
Preparation of 17. (Scheme S1†). Compounds 1519 and 1620
were prepared as reported previously. To a MTBE solution (5 mL)
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of 15 (286 mg, 1.0 mmol) and 16 (233 mg, 1.0 mmol), K2CO3
(141 mg, 1.0 mmol) was added in one portion at 0 ◦C. After
stirring at rt for 7 h (the reaction was followed by HPLC), the
reaction mixture was quenched with 3 mL of 1 N HCl, and was
extracted with EtOAc (¥ 2). The combined organic layers were
dried over Na2SO4. After filtration and removal of solvent under
vacuum, the residue was purified by preparative HPLC, to yield 17
as a white solid (207 mg, 0.48 mmol, 48%). 1H NMR (400 MHz,
CDCl3): d 7.30–7.08 (m, 11H), 4.65 (q, J = 7.1 Hz, 1H), 4.41
(t, J = 7.3 Hz, 1H), 3.36–3.24 (m, 2H), 3.10–2.97 (m, 2H), 1.39
(s, 9H).
Preparation of monomer 7. (Scheme S2†). To a dry CH2Cl2
solution (11 mL) of 18 (500 mg, 1.41 mmol), Et3SiH (1.13 mL,
7.05 mmol) and TFA (5.24 mL, 70.5 mmol) were added at 0 ◦C. The
reaction mixture was stirred at rt for 3 h. Volatile materials were
removed under vacuum, and the residue was azeotroped with
CHCl3 (¥ 3) and rotovapped to dryness. To a CH2Cl2 solution
(12 mL) of the obtained compound (105 mg, 0.29 mmol), DCC
(77 mg, 0.37 mmol) was added at 0 ◦C, and the mixture was stirred
at rt for 2 h. The white precipitates that appeared were filtered off,
and the filtrate was washed with H2O and brine and then dried over
Na2SO4. After filtration and removal of solvent under vacuum, the
residue was purified by silica gel column chromatography (hexane:
EtOAc = 20:1 to 1:2). The obtained white solid contained a small
amount of by-products which were removed by preparative HPLC
to give monomer 7 (25 mg, 0.11 mmol, 38%) as a white solid. 1H
NMR (400 MHz, CDCl3): d 7.35–7.28 (m, 3H), 7.13–7.11 (m,
2H), 6.71 (d, J = 8.1 Hz, 1H), 4.98 (dt, J = 8.5, 6.1 Hz, 1H), 3.27–
3.13 (m, 4H), 2.69 (t, J = 7.0 Hz, 2H). ESI-MS (m/z) 236.0732
[M + H]+ (MWcalcd = 236.0740).
Preparation of monomer 6. (Scheme S1†). To a dry CH2Cl2
solution (6 mL) of 17 (192 mg, 0.45 mmol), Et3SiH (0.36 mL,
2.26 mmol) and TFA (1.68 mL, 22.6 mmol) were added at 0 ◦C. The
reaction mixture was stirred at rt for 3 h. Volatile materials were
removed under vacuum, and the residue was azeotroped with
CHCl3 (¥ 3) to give a white solid. To a CH2Cl2 suspension (5 mL)
of this solid (85 mg, 0.20 mmol), (iPr)2NEt (74 mL, 0.45 mmol)
was added at 0 ◦C, and the mixture stirred at 0 ◦C for 20 min.
HOBt·H2O (35 mg, 0.23 mmol) and EDC·HCl (44 mg, 0.23 mmol)
were then added, and the mixture stirred at 0 ◦C for 6 h. Aqueous
KHSO4 (5%) and CH2Cl2 were added and separated. The aqueous
layer was further extracted with CH2Cl2 (¥ 2). The combined
organic layers were washed with water and brine and dried over
Na2SO4. After filtration and removal of solvent under vacuum, the
residue was purified by silica gel column chromatography (hexane:
EtOAc = 10:1 to 2:1) to give monomer 6 (30 mg, 0.1 mmol, 50%).
1H NMR (300 MHz, CDCl3): d 7.37–7.08 (m, 10H), 5.63 (br s,
1H), 3.89 (dd, J = 4.6, 8.3 Hz, 1H), 3.58 (ddd, J = 3.0, 4.1,
9.6 Hz, 1H), 3.38 (dd, J = 4.6, 14.2 Hz, 1H), 3.23 (dd, J = 4.4,
14.0 Hz, 1H), 3.15 (dd, J = 8.3, 14.3 Hz, 1H), 2.80 (dd, J =
Preparation of 19. (Scheme S2†). To a CH2Cl2 solution
(20 mL) of Boc-Sar-OH (3.80 g, 20.0 mmol), Et3N (3.15 mL,
22.6 mmol) and ClCO2Et (2.10 mL, 22.0 mmol) were added
dropwise at 0 ◦C. During addition of ClCO2Et, white precipitates
appeared. The reaction mixture was allowed to warm to rt and
was stirred for 30 min. A mixture of HSCH2CO2H (1.40 mL,
20.2 mmol) and Et3N (3.15 mL, 22.6 mmol) were added dropwise
to the above mixture at 0 ◦C, then the reaction mixture was warmed
to rt and stirred overnight. The mixture was filtered, and the
filtrate was dried over Na2SO4. After filtration and removal of
solvent under vacuum, the residue was purified by silica gel column
chromatography (hexane: CH2Cl2:AcOH = 15:3:1 to 6:3:1) to
9.6, 14.3 Hz, 1H). ESI-MS 312.1051 (m/z) [M + H]+ (MWcalcd
312.1053).
=
1
give 19 (2.99 g, 11.4 mmol, 57%) as a colorless oil. H NMR
(400 MHz, CDCl3): d 4.06 (s, 2H), 3.73 (s, 2H), 2.99 (s, 3H),
1.43 (s, 9H).
Preparation of 18. (Scheme S2†). To a dry CH2Cl2 solu-
tion (35 mL) of Boc-Phe-OSu 9b (3.00 g, 8.28 mmol), 3-
mercaptopropionic acid (0.82 mL, 9.44 mmol) and (iPr)2NEt
(3.09 mL, 18.7 mmol) were added at 0 ◦C. The mixture was stirred
at rt for 14 h. After removal of solvent under vacuum, EtOAc
(30 mL) was added and the solution was washed with 0.5 M citric
acid (10 mL ¥ 2) and brine (10 mL ¥ 1). The organic layer was
dried over Na2SO4. After filtration and removal of solvent, Et2O
and DCHA (1.48 mL, 7.45 mmol) were added to the residue, and
the solvent was removed. The obtained white solid was triturated
with pentane, and was collected by suction filtration. The solid was
recrystallized from hexane/benzene. Insoluble solid was removed
by filtration while the mixture was hot. The filtrate was cooled to
Preparation of monomer 8. (Scheme S2†). To a dry CH2Cl2
solution (100 mL) of 19 (2.43 g, 9.23 mmol), Et3SiH (7.38 mL,
46.2 mmol) and TFA (34 mL, 461.5 mmol) were added at 0 ◦C. The
reaction mixture was stirred at rt for 4 h. Volatile materials were
removed under vacuum, and the residue was azeotroped with
toluene (¥ 2). 1 N HCl (50 mL) was added, and the solvent
was removed to give a sticky oil, which gradually solidified upon
cooling at -15 ◦C to give white solid. To a CH2Cl2 suspension
(170 mL) of this solid (1.34 g, 6.71 mmol) and PyBroP (4.71 g,
10.1 mmol), (iPr)2NEt (3.50 mL, 21.2 mmol) was added at 0 ◦C,
and the mixture was stirred at rt for 11 h. At the initial stage of the
reaction, sonication was applied to dissolve the undissolved white
solid. AcOH (1.15 mL, 20.1 mmol) was added, and the reaction
mixture was then treated with 5% KHSO4 and was extracted with
CH2Cl2. The aqueous layer was further extracted with CH2Cl2
(¥ 2). The combined organic layers were washed with water and
brine, and dried over Na2SO4. After filtration and removal of
solvent under vacuum, the residue was purified by silica gel column
chromatography (hexane: EtOAc = 1:1 to 1:4) to give monomer 8
(613 mg, 4.22 mmol, 63%) as a white solid. 1H NMR (500 MHz,
CDCl3): d 4.13 (s, 2H), 3.71 (s, 2H), 3.08 (s, 3H). ESI-MS (m/z)
168.0094 [M + Na]+ (MWcalcd = 168.0090).
◦
rt, then to 0 C. The white solid that appeared was collected by
suction filtration, and was washed with pentane. The solid was
suspended in EtOAc, and DCHA was extracted with citric acid
(0.5 M, 10 mL ¥ 3). The organic layer was washed with brine, and
was dried over Na2SO4. Filtration and drying under vacuum gave
18 as a white solid (2.55 g, 7.22 mmol, 87%). 1H NMR (400 MHz,
DMSO-d6): d 12.38 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.29–7.18
(m, 5H), 4.26-4.20 (m, 1H), 3.04 (dd, J = 4.3, 13.9 Hz, 1H), 2.95
(t, J = 6.9 Hz, 2H), 2.77 (dd, J = 10.9, 13.8 Hz, 1H), 2.49–2.47 (m,
2H), 1.32 (s, 9H). ESI-MS (m/z) 354.1358 [M + H]+ (MWcalcd
354.1370).
=
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Acknowledgements
We are grateful to the Office of Naval Research (N00014-06-1-
0272) for financial support. J.M.B. is a NASA Earth and Space
Science Program (NNX07AR35H) Predoctoral fellow.
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The Royal Society of Chemistry 2009
©