Enhanced stereoselectivity of a Cu(II) complex chiral auxiliary in the synthesis of Fmoc-L-γ-carboxyglutamic acid

Article abstract of DOI:10.1021/jo101940k

L-γ-Carboxyglutamic acid (Gla) is an uncommon amino acid that binds avidly to mineral surfaces and metal ions. Herein, we report the synthesis of N-R-Fmoc-L-γ-carboxyglutamic acid γ, γ0-tert-butyl ester (Fmoc-Gla(OtBu)2-OH), a suitably protected analogue for Fmoc-based solid-phase peptide synthesis. The residue was synthesized using a novel chiral Cu(II) complex, whose structurebased design was inspired by the blue copper protein rusticyanin. The five-coordinate complex is formed by Shiff base formation between glycine and the novel ligand (S)-2-(N-(2-methylthio)benzylprolyl) aminobenzophenone in the presence of copper. Michael addition of di-tert-butyl methylenemalonate to the R-carbon of the glycine portion of the complex occurs in a diastereoselective fashion. The resulting (S,S)-complex diastereomer can be easily purified by chromatography. Metal complex decomposition followed by Fmoc protection affords the enantiomerically pure amino acid. With the use of this novel chiral complex, the asymmetric synthesis of Fmoc-Gla(OtBu)2-OH was completed in nine steps from thiosalicylic acid in 14.5% overall yield.

Full text of DOI:10.1021/jo101940k

FEATURED ARTICLE
pubs.acs.org/joc
Enhanced Stereoselectivity of a Cu(II) Complex Chiral Auxiliary in
the Synthesis of Fmoc-L-γ-carboxyglutamic Acid
Daniel J. Smith,†,‡ Glenn P. A. Yap,‡ James A. Kelley,† and Joel P. Schneider*,†
†Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland 21702,
United States
‡Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S Supporting Information
b
ABSTRACT:
L-γ-Carboxyglutamic acid (Gla) is an uncommon amino acid that binds avidly to mineral surfaces and metal ions. Herein, we report
the synthesis of N-R-Fmoc-L-γ-carboxyglutamic acid γ,γ0-tert-butyl ester (Fmoc-Gla(OtBu)2-OH), a suitably protected analogue
for Fmoc-based solid-phase peptide synthesis. The residue was synthesized using a novel chiral Cu(II) complex, whose structure-
based design was inspired by the blue copper protein rusticyanin. The five-coordinate complex is formed by Shiff base formation
between glycine and the novel ligand (S)-2-(N-(2-methylthio)benzylprolyl)aminobenzophenone in the presence of copper.
Michael addition of di-tert-butyl methylenemalonate to the R-carbon of the glycine portion of the complex occurs in a
diastereoselective fashion. The resulting (S,S)-complex diastereomer can be easily purified by chromatography. Metal complex
decomposition followed by Fmoc protection affords the enantiomerically pure amino acid. With the use of this novel chiral complex,
the asymmetric synthesis of Fmoc-Gla(OtBu)2-OH was completed in nine steps from thiosalicylic acid in 14.5% overall yield.
’ INTRODUCTION
L-γ-Carboxyglutamic acid (Gla) occurs in natural proteins as a
result of post-translational modification of glutamic acid residues
and serves both functional and structural roles.1 For example, in
the blood coagulation protein prothrombin, a host of Gla residues
in the N-terminal domain of the protein bind calcium ions with
high affinity resulting in a conformational change that enables
phospholipid binding and ultimate coagulant activity.2,3 The
Figure 1. Fmoc-protected L-γ-carboxyglutamic acid.
mineral-binding, Gla-containing domains of these proteins have
served as motivation to develop synthetic approaches to this resi-
been mimicked by integration of the Gla residue into synthetic
peptides.4,5 For example, we, as well as Murphy and co-workers,
due that are amenable to academic laboratories. Asymmetric
routes9,10 have greatly improved the yields of the amino acid in
have shown that peptides containing Gla residues can undergo
comparison to past racemic syntheses;11-13 however, reducing
calcium-mediated binding to surfaces such as hydroxyapatite
with high avidity4,6,7 and can possibly be used as tools to better
the number of steps required to access the fully protected Gla
understand apatite remodeling.8 This uncommon amino acid is
typically incorporated into peptides synthetically, rather than
analogue (S)-1 necessary for Fmoc-based SPPS still poses a
challenge, Figure 1.
enzymatically, using solid-phase peptide synthesis (SPPS). Syn-
theses are quite costly due to the commercial expense of the
suitably protected analogue of the Gla amino acid. This has
Received: October 7, 2010
Published: February 03, 2011
r
2011 American Chemical Society
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FEATURED ARTICLE
Figure 2. General route for preparation of enantiomerically pure Fmoc-amino acids starting from a chiral nucleophilic glycine equivalent.
Table 1. Solvent and Base Effect on the Addition of 14 to
BPB-Ni-Gly
Figure 3. (a) Novel thioether-containing chiral ligand (S)-7c. (b)
Structure of the chiral BPB metal complex containing an ortho-
entry
base
DBUc
DBUc
solvent
DMF
time (min) yielda (%) eeb (%)
substituted benzyl group. (c) Highlighted residues bound to Cu(II) in
the protein rusticyanin (PDB: 1RCY); note the axial methionine
ligation.
1
2
3
4
5
6
10
10
60
60
60
60
70
75
48
41
25
42
80
82
71
58
70
51
MeCN
d
NEt3
1:1 MeCN:DMF
One common approach for asymmetric amino acid synthesis
is the use of chiral nucleophilic glycine equivalents. This method
allows vast structural diversity at the amino acid side chain. Addi-
tion reactions to the Ni(II) complex of the Schiff base of glycine and
(S)-BPB (Figure 2) generally give rise to product mixtures with a high
excess of the diastereomer containing the (S)-amino acid.14-16
Isolation of the major diastereomer through chromatography, fol-
lowed by decomposition of the metal complex, results in enantio-
merically pure amino acid and recovery (>80%) of the chiral ligand.
These chiral templates have been used to gain access to a variety
of glutamic acid17-21 and proline22,23 derivatives in a highly
stereoselective fashion through Michael additions of activated
olefins to the glycine enolate. An attractive benefit of using the
BPB complexes for Michael additions is the mild conditions under
which the reactions can be performed. Early transformations using
excesses of sodium methoxide or triethylamine as a base provided
moderate yields and diastereoselectivities.17,22 More recently devel-
oped conditions employing catalytic amounts (15 mol %) of DBU
as a base could provide near-quantitative yields of a single product
diastereomer within minutes at ambient temperature.24-28 However,
as will be shown, the previously reported four-coordinate, square
planar Ni complex16 in Figure 2 proved to be ineffective for the
synthesis of (S)-1. Using previously reported and optimized reaction
conditions afforded a mixture of diastereomers that could not be
separated by conventional normal-phase chromatography. Thus, both
poor selectivity and poor chromatographic resolution resulted in the
inefficient preparation of (S)-1 using this common chiral auxiliary.
Inspired by the axial binding interactions between methionine
and copper in blue copper proteins, we set out to improve upon
the results of others29 by designing a novel chiral complex that
contains an additional axial thioether ligand, which can better
shield the top face of the coordination plane toward an incoming
electrophile. This proported five-coordinate, square-pyramidal
d
NH(iPr)2 1:1 MeCN:DMF
d
NEt(iPr)2 1:1 MeCN:DMF
KOHe
DCM
a Combined yield of major (S,S) and minor (S,R) diastereomers.
b Enantiomeric excess of the (S)-amino acid based on Marfey’s assay
of the amino acid after decomposition of the metal complex
diastereomers. 0.15 equiv of base. d 3.0 equiv of base. 10 equiv
c
e
of base.
complex could effectively increase the ratio of diastereomers
formed in the Michael addition reaction and, in addition, allow
better resolution and subsequent separation of diastereomers.
Herein, we synthesize the novel thioether-containing ligand (S)-
7c (Figure 3a) and demonstrate the increased diastereoselec-
tivity of the corresponding Cu(II)-containing glycine Schiff base
(S)-9c (Figure 3b) using di-tert-butyl methylenemalonate as a
Michael acceptor in our synthesis of γ-carboxyglutamic acid.
’ RESULTS AND DISCUSSION
Our need for a more selective chiral glycine equivalent was
realized during the optimization of reaction conditions for the
Michael addition reaction employing the known Ni(II) complex
of the Schiff base of glycine and (S)-2-(N-benzylprolyl)amino-
benzophenone (BPB)30,31 shown in Table 1. Initially, Michael
additions of the glycinate (BPB-Ni-Gly) to di-tert-butyl methy-
lenemalonate 1432 were optimized around conditions described
in the literature.21,22,33 The selectivity of the addition reaction
was assessed by decomposing the resulting metal complex to free
the amino acid, whose enantiomeric excess was measured using
Marfey’s reagent (Table 1, note b). The diastereomeric ratio of
the products favoring the (S,S) configuration was consistent with
reports discussed earlier. A slightly higher yield was obtained by
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Table 2. Michael Additions to Ni(II) Complexes (S)-8a-c and Cu(II) Complexes (S)-9a,c
entry
complex
product
metal (M)
R
yielda (%)
eeb (%)
1
2
3
4
5
6c
(S)-8a
(S)-9a
(S)-8b
(S)-8c
(S)-9c
(S)-9c
(S,S)-10a
(S,S)-11a
(S,S)-10b
(S,S)-10c
(S,S)-11c
(S,S)-11c
Ni
Cu
Ni
Ni
Cu
Cu
H
75
64
94
81
70
67
82
49
85
90
93
>99
H
Cl
SMe
SMe
SMe
a Combined yield of major (S,S) and minor (S,R) diastereomers. b Enantiomeric excess of the (S)-amino acid based on Marfey’s assay of the amino
acid after decomposition of the metal complex diastereomers. c Isolated yield of (S,S)-11c from product mixture (entry 5).
exchanging DMF with CH3CN as the reaction solvent (Table 1,
entries 1 and 2). In addition, the reaction proceeded more slowly
when DBU was exchanged for other amine and alkaline bases,
and resulted in lower yields and selectivity (Table 1, entries
3-6). To our dismay, regardless of the reaction conditions, the
product diastereomers were inseparable by chromatography on
silica gel using typical solvent systems.14,34 Owing to the fact that
this method of amino acid synthesis relies on the stereodiscri-
minating ability of the complex35 in the reaction and separation
of products to obtain a high excess of enantiomerically pure
amino acid, we began to examine methods to improve both of
these features en route to the synthesis of Gla residue (S)-1.
Efforts by others have been made to improve the stereose-
lectivity of addition reactions through substitutions on the N-
benzyl portion of the chiral complex.36,37 Saghiyan and co-workers
reported that 3,4-dimethyl-, 3,4-dichloro-, and 2-chloro-substi-
tuted benzyl analogues of the Ni(II) complex gave better
selectivity due to increased shielding of the coordination plane.29
Crystal structure analysis of the unsubstituted complex re-
vealed that the benzyl group (Table 2, R = H, M = Ni) centers its
aromatic ring directly above the metal in the coordination
plane.38 In comparison, when a chloro group is placed in the
ortho position of the benzyl ring (Table 2, R = Cl, M = Ni), the
aromatic ring moves off the metal atom and the Cl is positioned
directly above the nickel.39 Moreover, the sum of the Van der
Waals radii of the Cl and Ni atoms is greater than the Ni-Cl
atomic distance of 3.149 Å, implying a distinct axial interaction
between the nickel and the chlorine.39 This interaction was pos-
tulated to shield the top face of the complex toward an
approaching electrophile, thus increasing the selectivity of the
Michael addition. This crystallographic observation suggested to
us that other bonafide axial ligand-metal interactions could be
designed that enhance diastereoselectivity. Such axial interactions
can be found in some blue copper proteins such as rustacyanin
(Figure 3c), 1where sulfur coordination (from methionine) to a
central Cu atom occurs above the coordination plane formed
from a set of trigonal side-chain ligands at a Cu-S atomic
distance of 2.885 Å.40 We investigated the possibility of mimick-
ing this naturally occurring complex by replacing the 2-chloro
substituent on BPB with a methylthio-substituent and swapping
the nickel with copper (Table 2, R = SMe, M = Cu) to form a
purported five-coordinate pyramidal complex. The axial sulfur
donor should enhance the effective shielding of the coordination
plane and increase the stereodiscriminating ability of the com-
plex, and as a result, increase selectivity.
We began by preparing both the Ni(II) and Cu(II) complexes
containing methylsulfide and chloro ortho-substituted benzyl
groups to assess the ligating potential of the thioether and gauge
the importance of swapping the nickel with copper. Based on the
known propensity of thioethers to coordinate very weakly41 or
not at all42 axially to Ni(II), we did not expect the thioether to
coordinate to the Ni center, making it necessary to swap this
metal with Cu. Lastly, the unsubstituted benzyl complexes were
prepared to complete the comparative study.
Complexes of the Schiff base of glycine and 2-benzyl-sub-
stituted ligands based on (S)-2-(N-Benzylprolyl)-aminobenzo-
phenone (BPB) were synthesized according to Scheme 1 starting
from the aryl chloride. N-Benzylation of (S)-proline provided
compounds (S)-6a-c, which were amidated with 2-aminoben-
zophenone to give chiral ligands (S)-7a-c. Metal complexes (S)-
8a-c, (S)-9a, and (S)-9c were prepared using the corresponding
ligands, metal salts, and glycine to form the Schiff base complex.
Starting compound 5c was prepared by alkylating,43,44 reduc-
ing,45,46 and chlorinating47 thiosalicylic acid (Scheme 2).
Evaluation of the chiral metal complexes was performed
(Table 2) using the optimal conditions that were established
earlier (Table 1, entry 2). As expected, the Cu(II)-containing
complex (S)-9a is less diastereoselective than the analogous
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Scheme 1a
a Key: (a) (S)-Proline, NaOMe, MeOH, 45 °C, 16 h; (b) N-MeIm, MsCl, 2-aminobenzophenone, DCM, 48 °C 16 h; (c) glycine, Ni(NO3)2 6H2O, NaOMe,
3
MeOH, 55 °C, 90 min; (d) glycine, CuSO4 5H2O, KOH, MeOH, rt, 1 h.
3
Scheme 2a
a Key: (a) iodomethane, K2CO3, acetone, rt, 2 h; (b) LiAlH4, THF, rt, 3 h;
(c) concd HCl, toluene, rt, 90 min.
Ni(II) containing complex (S)-8a because of the weaker ligand-
metal coordination and distortion of the coordination plane in
the Cu(II) complex versus the Ni(II) complex.34 Improved
selectivity and yield was observed using the 2-Cl-benzyl-sub-
stituted Ni(II) complex (S)-8b, providing separable diastereo-
mers in a combined yield of 94%. Further improvement in
selectivity occurred using the 2-methylthio-benzyl-substituted
Ni(II) complex (S)-8c, albeit in lower yield than (S)-8b. This is
somewhat surprising, since we did not expect the thioether to
coordinate to the nickel. In fact, the crystal structure of (S)-8c in
Figure 4 shows that this is indeed the case. Here, the benzylic
moiety assumes a conformation that directs the thioether away
from the metal center; however, we cannot rule out any Ni-
thioether interaction that may be occurring in solution. At this
time, the reason for the slight increase in diastereoselectivity is
not yet known.
Finally, the Cu(II) complex (S)-9c outperformed all others in
terms of selectivity, resulting in an 11% increase in ee compared
to the known Ni complex (S)-8a. Unlike the inseparable mixture
of diastereomers resulting from the Michael addition to (S)-8a,
the mixture of diastereomers from the reaction of (S)-9c were
easily separated by chromatography (ΔRf = 0.1, 3:1 hexanes/
acetone) to allow isolation of the desired isomer (S,S)-11c in
high stereochemical purity (Table 2, entry 6).
Figure 4. Crystal structure of Ni(II) complex (S)-8c showing the
noncoordinated thioether. Second symmetry unique molecule and
hydrogen atoms omitted for clarity. Atoms refined anisotropically but
depicted with arbitrary radii. Crystal data: C28H27N3NiO3S, monoclinic,
P21, a = 10.428(5) Å, b = 8.062(4) Å, c = 29.581 Å, β = 96.108(8)°, V =
2473(2) Å3, Z = 4, Dcalc = 1.462 g/cm3, 32913 reflections collected,
12271 unique, Rint = 0.0825, 651 parameters, Rf = 0.0674, wR2 = 0.1302,
Flack parameter = -0.028(14), CCDC 795141.
band at 658 nm (Δε = 24). These features in the range of
300-450 nm and at 658 nm are consistent with sulfur-copper
charge transfer bands and a copper d-d transition, respectively,
and are consistent with assignments made for other compounds
reported in the literature.49
In addition, axial coordination of the thioether may also be
responsible for the difference in the color of the solid com-
pounds, changing from a brown color for (S)-9a to a green color
for (S)-9c. Comparing the selectivity of complexes (S)-9a and
(S)-9c, the ratio of diastereomeric products increases from 3:1 to
>27:1, respectively. We attribute this large difference to a more
effective shielding of the coordination plane via the addition of
intramolecular axial ligand coordination to the metal.
With high diastereoselectivity and facile separation methods in
hand, the synthesis of (S)-1 was finished by optimizing metal
complex decomposition and Fmoc-protection conditions. Typi-
cally, isolation of the amino acid from the metal complex is
accomplished by decomposing the compound in a heated
mixture of methanol and aqueous HCl.14 However, for the Gla
Although we were unable to obtain a crystal structure of (S)-
9c, UV spectroscopic data (see Supporting Information), taken
together with the increase in diastereoselectivity, supports axial
coordination of the methyl sulfide similar to the coordination in
complexes described by Belle and co-workers.48 A UV difference
spectrum was generated using the complexes (S)-9c and (S)-9a
in CH3CN and shows maxima at 309 (Δε = -211) and 422 nm
(Δε = 135), a shoulder at 335 nm (Δε = -761), and a broad
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Scheme 3a
a Key: (i) 1.5 M aq HCl, THF, rt, 7 h; (ii) EDTA, Fmoc-OSu, NaHCO3, 1:1 MeCN/H2O, 0 °C to rt, 24 h.
residue, milder conditions were sought to ensure that the acid-
labile tert-butyl esters would remain intact. It was found that
stirring any of the complexes ((S,S)-10a-c or (S,S)-11a,c) in
THF with a minimal amount of dilute aqueous HCl decomposed
the complex and preserved the t-butyl protecting groups. Con-
centrating the reaction mixture allowed for recovery of the
ligands (S)-7a-c by filtration or phase separation. To complete
the synthesis of (S)-1, (S,S)-11c was decomposed, Scheme 3.
The filtrate was neutralized after ligand isolation and the soluble
amino acid directly Fmoc-protected. From (S,S)-11c, the yield of
(S)-1 was 68% over two steps.
purified on silica gel using an automated flash chromatography system
employing a gradient of acetone in hexanes; product elutes at ∼20%
acetone to yield 357 mg of (S)-1 (0.68 mmol, 68% over two steps) as a
waxy solid: [R]20 = -8.6 (c 0.29, MeOH) [lit.50 [R]20 = -8.6
D
D
(c 0.173, MeOH)]; 1H NMR (400 MHz, CDCl3) δ = 7.77 (m, 2H, ArH-4
and ArH-40), 7.63 (m, 2H, ArH-1 and ArH-10), 7.41 (m, 2H, ArH-3 and
ArH-30), 7.33 (m, 2H, ArH-2 and ArH-20), 5.61 (NH), 4.42 (m, 2H,
CHCH2O), 4.33 (m, 1H, CHCH2O), 4.24 (m, 1H, R-H), 3.38 (m, 1H,
γ-H), 2.49 (m, 1H, β-H), 2.21 (m, 1H, β0-H), 1.48 (s, 18H, C(CH3)3);
13C NMR (100 MHz, CDCl3): δ = 173.7 (C-1), 168.5 (C-5), 168.2
(C-50), 156.2 (C-8), 144.0 (C-11), 143.9 (C-110), 141.3 (C-12 and
C120) 127.7 (C-14 and C-140), 127.1 (C-13 and C-130), 125.3 (C-15),
125.2 (C-150), 120.0 (C-16 and C-160), 82.0 (C-6 and C-60), 67.1 (C-9),
52.6 (C-2), 50.9 (C-4), 47.2 (C-10), 31.2 (C-3), 27.9 (C-7 and C-70);
ESI-MS calcd for C29H34NO8Na (M þ Naþ) 548.2, found 548.2.
2-(Methylthio)benzoic Acid (3c). Thiosalicylic acid (1.54 g, 10
mmol) was dissolved in acetone (81 mL), and K2CO3 (4.14 g, 30 mmol)
was added. Iodomethane (685 μL, 11 mmol) was added dropwise and
the mixture stirred for 1 h at room temperature, after which time solvent
was removed in vacuo and the residue dissolved in water (40 mL) and
cooled to 0 °C. With stirring, the pH of the solution was adjusted to ∼1
with 2 M HCl. The precipitated solid was filtered, washed with cold
H2O, and allowed to air-dry overnight to afford 1.61 g of the acid 3c (9.6
mmol, 96%) as a white solid: mp 168-170 °C (lit.51 mp 169 °C); 1H
NMR (400 MHz, CD3OD) δ = 7.94 (dd, 1H, J = 7.8, 1.5 Hz, ArH-4),
7.46 (ddd, 1H, J = 8.1, 7.3, 1.6 Hz, ArH-2), 7.32 (d, 1H, J = 8.1 Hz, ArH-
1), 7.13 (m, 1H, ArH-3), 2.38 (s, 3H, SCH3); 13C NMR (100 MHz,
CD3OD) δ = 168.3 (C-7), 143.3 (C-1), 132.1 (C-5), 131.1 (C-3), 127.0
(C-2), 124.1 (C-6), 122.9 (C-4), 14.0 (C-8); ESI-MS calcd for C8H8O2S
(MH-) 167.0, found 167.0.
’ CONCLUSION
We have successfully completed a facile chiral synthesis of
Fmoc-Gla(OtBu)2-OH in nine steps from thiosalicylic acid in
14.5% overall yield. We have designed the novel chiral ligand (S)-
7c, whose glycine Schiff base metal complexes show increased
diastereoselectivity in the Michael addition reaction of di-tert-
butyl methylenemalonate over previously reported ligands. Most
notably, the Cu(II) complex (S)-9c allowed us to complete a
highly stereoselective route to (S)-1 in three-steps with facile
separation of diastereomers. The increase in selectivity is most
likely due to an intramolecular axial coordination of a thioether to
the Cu(II) center of a BPB system, a design inspired by the blue
copper protein rusticyanin.
’ EXPERIMENTAL SECTION
Synthesis of (S)-1 from Metal Complexes 10a-c or 11a,
c. In a typical procedure, 1.5 M HCl (3.33 mL, 5 mmol) was added to a
solution of the Ni(II) or Cu(II) complex of γ-carboxyglutamic acid
(1 mmol) dissolved in THF (13 mL). The reaction was stirred for 7 h or
until no more metal complex was present (TLC) and was then
concentrated under vacuum to 1/6 the original volume. In the case of
10a or 11a, the precipitated ligand was removed from the aqueous
portion by filtration and was washed with H2O (2 ꢀ 1 mL). For 10b-c
and 11c, the biphasic mixture was transferred to a separatory funnel and
allowed to separate. The dense oily residue was removed, and the
aqueous portion was diluted with 2 mL of H2O. In both cases, the
aqueous portion was transferred to a clean flask, and solid NaHCO3
(336 mg, 4 mmol) was carefully added with stirring to neutralize the
2-(Methylthio)benzyl Alcohol (4c). Acid 3c (16.64 g, 99 mmol)
was dissolved in THF (225 mL) and added dropwise via addition fun-
nel to a slurry of LiAlH4 (7.14 g, 178 mmol) in THF (275 mL) under an
Ar atmosphere. The mixture was stirred at room temperature for 3 h,
after which time 1 M HCl (370 mL) was carefully added. The aqueous
mixture was extracted 3 ꢀ 250 mL with ether. Combined organics were
washed 2 ꢀ 100 mL with 1 M NaOH and 1 ꢀ 100 mL H2O, dried with
MgSO4, and concentrated to give 13.7 g of the alcohol 4c (89.1 mmol,
90%) as an oil: 1H NMR (400 MHz, CDCl3) δ = 7.42 (d, 1H, J = 7.2 Hz,
ArH-4), 7.30-7.23 (m, 2H, ArH-2 and ArH-1), 7.18 (ddd, 1H, J = 7.5,
5.9, 2.8 Hz, ArH-3), 4.74 (s, 2H, CH2OH), 2.48 (s, 3H, SCH3); 13C
NMR (100 MHz, CDCl3) δ = 139.1 (C-2), 136.4 (C-1), 128.0 (C-5),
127.6 (C-3), 126.2 (C-6), 125.3 (C-4), 62.9 (C-7), 15.9 (C-8); APCI-
MS 4c (C8H10OS) readily ionized to a benzylic cation through loss of
OH; calcd for C8H9S (Mþ) 137.0, found 137.0.
solution, followed by Na2EDTA H2O (372 mg, 1 mmol), and was
3
stirred for 5 min. Additional solid NaHCO3 (336 mg, 4 mmol) was
added, followed by a solution of Fmoc-OSu (337 mg, 1 mmol) in
CH3CN (5 mL). The reaction was stirred for 24 h under Ar, concen-
trated in vacuo to 1/2 its original volume, adjusted to pH 3 with 10%
citric acid, and extracted with EtOAc (3 ꢀ 15 mL). Combined organic
extracts were washed with brine, dried with MgSO4, concentrated, and
2-(Methylthio)benzyl Chloride (5c). Alcohol 4c (1.23 g,
8 mmol) was dissolved in toluene (2.85 mL) and cooled to 0 °C. Con-
centrated HCl (1.73 mL, 20.8 mmol) was added dropwise at 0 °C, and
the biphasic mixture was vigorously stirred to form an emulsion. Stirring
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FEATURED ARTICLE
was continuedfor 2 h at room temperature. The biphasic mixture was then
diluted with 6.4 mL of toluene, transferred to a separatory funnel, and
allowed to separate, and the aqueous portion was removed. The organic
portion was washed with 3 mL of H2O and stirred with solid NaHCO3
(0.223 g, 2.66 mmol) for 15 min. The toluene solution was decanted and
concentrated in vacuo to give 1.23 g of the chloride 5c (7.2 mmol, 90%)
(C-5), 30.8 (C-3), 24.0 (C-4), 15.5 (C-22); APCI-MS calcd for
C26H26N2O2S (MHþ) 431.2, found 431.1.
Ni(II) Complex of Schiff Base of (S)-MeS-BPB and Glycine
(MeS-BPB-Ni-Gly) (8c). In a round-bottomed flask fitted with an
addition funnel were added glycine (803 mg, 10.7 mmol) and Ni-
(NO3)2 6H2O (1.87 g, 6.42 mmol) to a solution of benzophenone 7c
3
1
(2.3 g, 5.35 mmol) in MeOH (16.5 mL) and the mixture heated to
55 °C. A 2.5 M solution of NaOMe (4.42 g, 81.85 mmol) in MeOH
was added dropwise via the addition funnel at 55 °C, after which time
the flask was fitted with a reflux condenser and stirred for 90 min. The
reaction was allowed to cool to room temperature, poured into 30 mL
of 10% citric acid, extracted with CH2Cl2 (3 ꢀ 50 mL), concentrated,
and purified on silica gel using an automated flash chromatography
system employing a gradient of acetone in CH2Cl2; product elutes at
∼80% acetone to yield 2.46 g of complex 8c (4.52 mmol, 84%) as a red
solid: [R]20D = þ2474.0 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3)
δ = 8.06 (d, 1H, J = 7.4 Hz, ArH-4), 7.95 (d, 1H, J = 8.6 Hz, ArH-5)
7.57-7.48 (m, 3H, ArH-11, ArH-10, and ArH-12), 7.28 (m, 1H, ArH-
2), 7.26-7.20 (m, 2H, ArH-1 and ArH-3), 7.16 (ddd, 1H, J = 8.6, 7.1,
1.3 Hz, ArH-6), 7.1 (d, 1H, J = 7.1 Hz, ArH-13), 6.97 (m, 1H, ArH-9),
6.80 (dd, 1H, J = 8.2, 1.5 Hz, ArH-8), 6.70 (m, 1H, ArH-7), 4.50 (d,
1H, J = 13.0 Hz, CHHPh), 3.80 (d, 1H, J = 13.0 Hz, CHHPh), 3.80 (d,
1H, J = 20.1 Hz, Gly R-H), 3.67 (d, 1H, J = 20.1 Hz, Gly R0-H),
3.62-3.43 (m, 3H, Pro R-H, γ-H, and δ-H), 2.78 (m, 1H, β-H), 2.56
(m, 1H, β0-H), 2.50 (s, 3H, CH3), 2.17-2.05 (m, 2H, γ0-H and δ0-H);
13C NMR (100 MHz, CDCl3) δ = 180.3 (C-1), 177.1 (C-25), 171.0
(C-17), 142.4 (C-11), 140.0 (C-27), 134.5 (C-18), 133.1 (C-8), 132.8
(C-15), 131.8 (C-13), 131.3 (C-7), 129.8 (C-10), 129.7 (C-21), 129.5
(C-20), 129.2 (C-22), 126.9 (C-26), 126.2 (C-23), 125.6 (C-19),
125.5 (C-16), 125.3 (C-9), 124.5 (C-12), 120.8 (C-14), 70.2 (C-2),
61.2 (C-24), 60.4 (C-6), 57.8 (C-5), 30.4 (C-3), 23.8 (C-4), 16.5
(C-28); HRMS-MALDI-TOF calcd for C28H28N3O3SNi (MHþ)
544.120, found 544.117.
as an oil: H NMR (400 MHz, CDCl3) δ = 7.38 (d, 1H, J = 7.2 Hz,
ArH-4), 7.32-7.27 (m, 2H, ArH-2 and ArH-1), 7.16 (ddd, 1H, J = 7.6,
5.7, 2.9 Hz, ArH-3), 4.74 (s, 2H, CH2Cl), 2.50 (s, 3H, SCH3); 13C NMR
(100 MHz, CDCl3) δ = 138.3 (C-2), 135.5 (C-1), 130.0 (C-5), 129.2
(C-3), 127.0 (C-6), 125.5 (C-4), 44.4 (C-7), 16.3 (C-8); APCI-MS 5c
(C8H9ClS) readily ionized to a benzylic cation through loss of Cl; calcd
for C8H9S (Mþ) 137.0, found 137.0.
(S)-N-(2-(Methylthio)benzyl)pyrrolidine-2-carboxylic
Acid (6c). In a round-bottomed flask equipped with a reflux condenser
was added the benzyl chloride 5c (5.14 g, 30 mmol) dropwise via syringe
through the condenser to a stirring solution of (S)-proline (3.45 g, 30
mmol) and NaOMe (3.24 g, 60 mmol) in MeOH (30 mL) at 48 °C.
After the mixture was stirred overnight at 48 °C, the reaction was allowed
to cool to room temperature, and concd HCl (30 mmol) was added via
syringe to achieve a pH of ∼5. CHCl3 (30 mL) was added and the
mixture stirred for 1 h, after which time the precipitate was filtered over
Celite and washed with CHCl3. The filtrate was concentrated, and the
residue was purified on silica gel using an automated flash chromatog-
raphy system employing a shallow gradient of methanol in CH2Cl2;
product elutes at ∼20% methanol to yield 5.57 g of the acid 6c (22.2
mmol, 74%) as a waxy solid: [R]20D = -16.9 (c 1.0, MeOH); 1H NMR
(400 MHz, CD3OD) δ = 7.47 (d, 1H, J = 7.9 Hz, ArH-1), 7.45-7.39 (m,
2H, ArH-3 and ArH-4), 7.23 (m, 1H, ArH-2), 4.48 (s, 2H, CH2Ph), 3.95
(dd, 1H, J = 9.3, 5.0 Hz, R-H), 3.59 (m, 1H, δ-H), 3.22 (m, 1H, δ0-H),
2.54 (s, 3H, CH3), 2.43 (m, 1H, β0-H), 2.21-2.04 (m, 2H, β-H and γ0-
H), 1.90 (m, 1H, γ-H); 13C NMR (100 MHz, CD3OD) δ = 171.6 (C-1),
139.2 (C-8), 131.6 (C-12), 130.5 (C-9), 128.9 (C-7), 127.9 (C-10),
125.8 (C-11), 68.6 (C-2), 55.6 (C-6), 54.4 (C-5), 28.6 (C-3), 23.1
(C-4), 15.4 (C-13); ESI-MS calcd for C13H17NO2S (MH-) 250.1,
found 250.1.
Cu(II) Complex of Schiff Base of (S)-MeS-BPB and Glycine
(MeS-BPB-Cu-Gly) (9c). Glycine (2.5 g, 33.3 mmol) and Cu-
SO4 5H2O (3.32 g, 13.3 mmol) were added to a solution of benzophe-
3
none 7c (2.87 g, 6.67 mmol) in MeOH (24 mL) at room temperature. A
4.6 M solution of KOH (2.61 g, 46.7 mmol) in MeOH was added to the
mixture in one portion. The mixture was stirred for 1 h at room tem-
perature, poured into 30 mL of 10% citric acid, extracted with CH2Cl2
(3 ꢀ 50 mL), concentrated, and purified on silica gel using an automated
flash chromatography system employing a gradient of acetone in CH2-
Cl2; product elutes at ∼80% acetone to yield 2.50 g of complex 9c (4.56
mmol, 68%) as a green solid: [R]20D = -639.4 (c 0.1, CHCl3); HRMS-
MALDI-TOF calcd for C28H28N3O3SCu (MHþ) 549.115, found
549.117.
Preparation of 10a-c and 11a,c. In a typical procedure, the
metal complex (8a-c or 9a,c, 1 equiv) was dissolved in CH3CN, and
DBU (0.15 equiv) was added at room temperature. Freshly prepared di-
tert-butyl methylenemalonate (1 equiv) was added dropwise via syringe
and stirred for 30 min. The reaction mixture was poured into 10% citric
acid, extracted with CH2Cl2 (3ꢀ), concentrated, and purified on silica
gel using an automated flash chromatography system employing a
gradient of acetone in hexanes; product elutes at ∼50% acetone to yield
red (10a-c), brown (11a), and green (11c) solids. Combined yield of
both diastereomers is shown for 10a-c, 11a, and 11c; however, only
spectral data for the major diastereomer (S,S) is listed.
(S)-N-(2-Benzoylphenyl)-1-(2-(methylthio)benzyl)pyrroli-
dine-2-carboxamide (MeS-BPB) (7c). N-Methylimidazole (1.55 mL,
19.6 mmol) was added via syringe to a solution of benzylproline 6c
(2.24 g, 8.91 mmol) in CH2Cl2 (22 mL) under Ar atmosphere. The
solution was cooled to 0 °C, and methanesulfonyl chloride (693 μL, 8.91
mmol) was added dropwise via syringe, after which the solution was
warmed to room temperature and a solution of 2-aminobenzophenone
(1.58 g, 8.02 mmol) in CH2Cl2 (8 mL) was added dropwise via addition
funnel. The reaction flask was fitted with a reflux condenser, heated to
45 °C and stirred overnight under Ar, allowed to cool to room tempera-
ture, quenched with satd aq NH4Cl (30 mL), and extracted with CH2Cl2
(3 ꢀ 50 mL). Organic extracts were concentrated, and the residue was
purified on silica gel using an automated flash chromatography system
employing a gradient of ethyl acetate in hexanes; product elutes at ∼40%
ethyl acetate to yield 2.24 g of carboxamide 7c (5.21 mmol, 65% based
on 2-aminobenzophenone) as a yellow oil: [R]20 = -120.9 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ = 10.99 (s, NH), 8.29 (d, 1H, J
= 8.3 Hz, ArH-5), 7.75 (dd, 2H, J = 8.3, 1.2 Hz, ArH-9 and ArH-90), 7.58
(m, 1H, ArH-11), 7.53-7.43 (m, 5H, ArH-6, ArH-2, ArH-4, ArH-10,
and ArH-100), 7.17-7.03 (m, 3H, ArH-8, ArH-3, and ArH-1), 6.96 (m,
1H, ArH-7), 3.84 (d, 1H, J = 13.5 Hz, CHHPh), 3.84 (d, 1H, J = 13.5 Hz,
CHHPh), 3.34 (dd, 1H, J = 10.1, 4.6 Hz, R-H), 3.22 (m, 1H, δ-H), 2.45
(m, 1H, δ0-H), 2.31 (s, 3H, CH3), 2.23 (m, 1H, β-H), 1.86 (m, 1H, β0-
H), 1.78-1.67 (m, 2H, γ-H and γ0-H); 13C NMR (100 MHz, CDCl3):
δ = 197.3 (C-17), 174.1 (C-1), 138.3 (C-11), 138.2 (C-18), 137.6 (C-8),
135.9 (C-7), 132.7 (C-13), 132.5 (C-21), 131.8 (C-24), 129.9 (C-19),
129.6 (C-10), 128.2 (C-20), 127.6 (C-15), 126.5 (C-16), 125.1 (C-9),
124.6 (C-14), 122.5 (C-23), 121.8 (C-12), 68.3 (C-2), 57.2 (C-6), 54.1
Ni(II) Complex of Schiff Base of (S)-BPB and γ-Carbox-
yglutamic Acid (BPB-Ni-Gla) (10a). Results: yield 75%; 1H NMR
(400 MHz, CDCl3) δ = 8.19 (d, 1H, J = 8.1 Hz, ArH-4), 8.06 (d, 2H,
J = 7.1 Hz, ArH-1 and ArH-10), 7.52-7.47 (m, 3H, ArH-10, ArH-11, and
ArH-9), 7.34 (m, 2H, ArH-2 and ArH-20), 7.23-7.09 (m, 4H, ArH-12,
ArH-3, ArH-8, and ArH-5), 6.67-6.59 (m, 2H, ArH-6 and ArH-7), 4.41
(d, 1H, J = 12.6 Hz, CHHPh), 3.90 (m, 1H, Gla γ-H), 3.84 (dd, 1H,
1518
dx.doi.org/10.1021/jo101940k |J. Org. Chem. 2011, 76, 1513–1520

The Journal of Organic Chemistry
FEATURED ARTICLE
J = 10.4, 5.2 Hz, Gla R-H), 3.74 (m, 1H, Pro γ-H), 3.61-3.52 (m, 2H,
Pro δ-H and CHHPh), 3.46 (dd, 1H, J = 10.9, 5.8 Hz, Pro R-H), 2.97
(m, 1H, Gla β-H), 2.84 (m, 1H, Pro β-H), 2.53 (m, 1H, Pro β0-H),
2.24-2.05 (m, 3H, Pro γ0-H, Gla β0-H, and Pro δ0-H), 1.39 (s, 9H,
’ ASSOCIATED CONTENT
S
Supporting Information. General methods and experi-
b
mental procedures for compounds (S)-6a,b, (S)-7a,b, (S)-8a,b,
1
(S)-9a, and 14; H and 13C NMR spectra for all compounds
C(CH3)3), 1.35 (s, 9H, C(CH3)3 ); 13C NMR (100 MHz, CDCl3) δ =
0
180.3 (C-1), 178.1 (C-25), 171.3 (C-17), 167.9 (C-28), 167.7 (C-280),
142.4 (C-11), 133.5 (C-15), 133.4 (C-18), 133.3 (C-7), 132.1 (C-13),
131.5 (C-8), 129.6 (C-21), 129.1 (C-20), 128.8 (C-22), 128.7 (C-9),
128.6 (C-10), 127.8 (C-23), 126.9 (C-19), 126.1 (C-16), 123.5 (C-12),
120.5 (C-14), 81.8 (C-29), 81.5 (C-290), 70.4 (C-2), 68.8 (C-24), 63.0
(C-6), 57.3 (C-5), 49.8 (C-27), 33.6 (C-26), 30.7 (C-3), 27.8 (C-30 and
C-300), 23.7 (C-4); HRMS-MALDI-TOF calcd for C39H45N3O7NiNa
(M þ Naþ) 748.251, found 748.257.
except 2, (S)-9a, (S)-9c, 11a, and 11c; UV difference spectrum of
(S)-9c and (S)-9a; MS data for all compounds; chiral HPLC
chromatograms for compounds (S)-7b,c, (S)-8b,c, (S)-9a, and
(S)-9c; crystallographic data (ORTEP file and CIF) for com-
pound (S)-8c. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Ni(II) Complex of Schiff Base of (S)-Cl-BPB and γ-Carbox-
1
yglutamic Acid (Cl-BPB-Ni-Gla) (10b). Results: yield 94%; H
Corresponding Author
*E-mail: schneiderjp@mail.nih.gov.
NMR (400 MHz, CDCl3) δ = 8.19 (dd, 1H, J = 7.6, 1.5 Hz, ArH-4), 8.07
(d, 1H, J = 8.7 Hz, ArH-5), 7.52-7.47 (m, 3H, ArH-11, ArH-12, and
ArH-10), 7.34-7.25 (m, 2H, ArH-3 and ArH-1), 7.23 (m, 1H, ArH-13),
7.18-7.08 (m, 3H, ArH-2, ArH-9, and ArH-6), 6.68-6.61 (m, 2H, ArH-
7 and ArH-8), 4.45 (d, 1H, J = 12.9 Hz, CHHPh), 3.93 (m, 1H, Gla γ-
H), 3.85-3.78 (m, 2H, CHHPh and Gla R-H), 3.72 (m, 1H, Pro γ-H),
3.57-3.45 (m, 2H, Pro R-H and Pro δ-H), 3.07 (m, 1H, Pro β-H), 2.93
(m, 1H, Gla β-H), 2.63 (m, 1H, Pro β0-H), 2.24 (m, 1H, Pro γ0-H),
2.15-2.04 (m, 2H, Pro δ0-H and Gla β0-H), 1.39 (s, 9H, C(CH3)3), 1.34
’ ACKNOWLEDGMENT
This research was supported by the Intramural Research
Program of the NIH, National Cancer Institute, Center for
Cancer Research. We are grateful to Dr. Terrence Burke at
NCI-CCR for his assistance with the blue copper protein image.
We also thank Ms. Hilary Thomas for her assistance in creating
the cover art.
(s, 9H, C(CH3)3 ); 13C NMR (100 MHz, CDCl3) δ = 179.4 (C-1),
0
178.0 (C-25), 171.3 (C-17), 167.9 (C-30), 167.6 (C-300), 142.1 (C-11),
135.6 (C-27), 133.9 (C-8), 133.4 (C-15), 133.3 (C-18), 132.1 (C-13),
131.2 (C-7), 130.4 (C-10), 130.2 (C-26), 129.6 (C-21), 129.1 (C-20),
128.7 (C-22), 127.7 (C-19), 127.0 (C-9), 126.9 (C-23), 126.4 (C-16),
123.3 (C-12), 120.6 (C-14), 81.9 (C-31), 81.5 (C-310), 70.8 (C-2), 68.7
(C-24), 59.8 (C-6), 57.3 (C-5), 49.7 (C-29), 33.6 (C-28), 30.3 (C-3),
27.7 (C-32 and C320), 23.5 (C-4); HRMS-MALDI-TOF calcd for
C39H44ClN3O7NiNa (M þ Naþ) 782.212, found 782.217.
’ ABBREVIATIONS
BPB, (S)-2-(N-benzylprolyl)aminobenzophenone; MeCN, acet-
onitrile; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DMF, dime-
thylformamide; NEt3, triethylamine; NH(iPr)2, diisopropylamine;
[NEt(iPr)2], diisopropylethylamine; DCM, dichloromethane; N-
MeIm, N-methylimidazole; MsCl, methanesulfonyl chloride; THF,
tetrahydrofuran; EDTA, ethylenediaminetetraacetic acid; Fmoc-
OSu, N-(9-fluorenylmethoxycarbonyloxy)succinimide; Fmoc-Gla-
(OtBu)2-OH, N-R-(9-fluorenylmethyloxycarbonyl)-γ-carboxy-L-
glutamic acid γ,γ0-di-tert-butyl ester.
Ni(II) Complex of Schiff Base of (S)-MeS-BPB and γ-Bar-
boxyglutamic Acid (MeS-BPB-Ni-Gla) (10c). Results: yield 81%;
1H NMR (400 MHz, CDCl3) δ = 7.90 (d, 1H, J = 7.4 Hz, ArH-4), 7.84
(d, 1H, J = 8.6 Hz, ArH-5), 7.53-7.46 (m, 3H, ArH-11, ArH-10, and
ArH-12), 7.24-7.04 (m, 6H, ArH-2, ArH-9, ArH-3, ArH-1, ArH-13, and
ArH-6), 6.68-6.58 (m, 2H, ArH-7 and ArH-8), 4.34 (d, 1H, J = 13.0 Hz,
CHHPh), 3.89 (dd, 1H, J = 7.1, 5.5 Hz, Gla γ-H), 3.85-3.71 (m, 2H,
Gla R-H and Pro γ-H), 3.65 (d, 1H, J = 13.0 Hz, CHHPh), 3.54 (dd, 1H,
J = 10.7, 6.8 Hz, Pro R-H), 3.45 (dd, 1H, J = 9.8, 7.0 Hz, Pro δ-H), 3.13
(m, 1H, Pro β-H), 3.01 (m, 1H, Gla β-H), 2.67 (m, 1H, Pro β0-H), 2.45
(s, 3H, CH3), 2.27 (m, 1H, Pro γ0-H), 2.16-2.00 (m, 2H, 0Gla β0-H and
Pro δ0-H), 1.40 (s, 9H, C(CH3)3), 1.33 (s, 9H, C(CH3)3 ); 13C NMR
(100 MHz, CDCl3) δ = 179.2 (C-1), 177.8 (C-25), 170.6 (C-17), 167.9
(C-31), 167.5 (C-310), 142.3 (C-11), 139.8 (C-27), 133.2 (C-18), 133.0
(C-15), 132.9 (C-8), 131.8 (C-13), 131.2 (C-7), 129.6 (C-10), 129.5
(C-21), 129.1 (C-20), 128.6 (C-22), 127.7 (C-23), 126.8 (C-19), 126.7
(C-16), 126.5 (C-26), 125.0 (C-9), 123.7 (C-12), 120.4 (C-14), 81.8
(C-32), 81.3 (C-320), 71.1 (C-2), 68.6 (C-24), 60.8 (C-6), 57.7 (C-5),
49.7 (C-30), 33.6 (C-29), 30.3 (C-3), 27.7 (C-33 and C330), 23.7 (C-4),
16.3 (C-28); HRMS-MALDI-TOF calcd for C40H48N3O7SNi (MHþ)
772.257, found 772.259.
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