Synthesis of carbapyochelins via diastereoselective azidation of 5-(ethoxycarbonyl)methylproline derivatives

Article abstract of DOI:10.1021/jo801294p

(Chemical Equation Presented) Two configurationally stable carbon-based analogues of pyochelin have been prepared from Boc-pyroglutamic acid-tert-butyl ester in 11 and 13 steps. Introduction of the amino group was achieved by a highly diastereoselective electrophilic azidation reaction to afford novel bis-α-amino acid proline derivatives.

Full text of DOI:10.1021/jo801294p

pathogens of this required nutrient.4 While siderocalin tightly
binds a number of small-molecule phenolate siderophores such
as carboxymycobactins, enterochelin, and parabactin, it does
not bind to pyochelin. We have proposed that the presence of
a sterically demanding sulfur-containing thiazoline ring, which
replaces the oxazoline ring present in the other phenolate
siderophores, interferes with a conserved water-mediated hy-
drogen bond between these siderophores and siderocalin.4c,d In
contrast, pyochelin does bind to chicken Ex-FABP, a protein
with high sequence homology to human siderocalin in the
binding calyx region.5 The fact that chicken Ex-FABP also
shows affinity for a variable spectrum of microbial siderophores
raises the possibility that these proteins are part of an antibacte-
rial defense strategy employed across the phylum.
Synthesis of Carbapyochelins via
Diastereoselective Azidation of
5-(Ethoxycarbonyl)methylproline Derivatives
Wathsala Liyanage,† Laksiri Weerasinghe,†
Roland K. Strong,‡ and Juan R. Del Valle*,†
Department of Chemistry and Biochemistry, New Mexico
State UniVersity, MSC3C, Las Cruces, New Mexico 88003,
and DiVision of Basic Sciences, Fred Hutchinson Cancer
Research Center, MS A3-025, Seattle, Washington 98109
delValle@nmsu.edu
ReceiVed June 21, 2008
Two configurationally stable carbon-based analogues of
pyochelin have been prepared from Boc-pyroglutamic acid-
tert-butyl ester in 11 and 13 steps. Introduction of the amino
group was achieved by a highly diastereoselective electro-
philic azidation reaction to afford novel bis-R-amino acid
proline derivatives.
FIGURE 1. Pyochelin and configurationally stable proline-based
analogues.
To parse the ligand recognition parameters of both siderocalin
and chicken Ex-FABP, we sought to design and synthesize
analogues of pyochelin that would demonstrate both protein and
iron binding capabilities. Because pyochelin undergoes epimer-
ization at the 2′′ position through the general mechanism shown
in Figure 1, efforts to synthesize and isolate 1 in diastereomeri-
cally pure form have met with limited success.6 We envisioned
this problem could be circumvented by incorporating a meth-
ylene unit in place of the ring A sulfur, a position with no
established role in iron or siderocalin binding. In addition, we
sought to target the oxazoline variant 3 to test our steric clash
hypothesis through the design of an oxo analogue. These
analogues would potentially provide useful information on the
discreet stereochemical requirements for siderophore specific
protein-ligand interactions. Here, we describe our efforts toward
novel proline-based siderophores, resulting in a diastereoselec-
tive synthesis of amino acids 2 and 3.
Pyochelin (1) is a phenolate siderophore isolated from
Pseudomonas aeruginosa that enhances microbial growth by
solublizing ferric iron and accelerating iron transport.1 Studies
on P. aeruginosa iron uptake systems have focused largely on
the recognition of pyochelin by bacterial outer membrane
receptors.2 These efforts have benefited from the synthesis and
evaluation of various pyochelin analogues, many of which
chelate and transport iron(III) with similar efficiency compared
to the natural product.3
Recently, it has been shown that the endogenous protein
siderocalin (also lipocalin 2, NGAL) is able to bind and
sequester iron as complexes with siderophores, thus starving
† New Mexico State University.
‡ Fred Hutchinson Cancer Research Center.
(1) (a) Cox, C. D.; Graham, R. J. Bacteriol. 1979, 137, 357. (b) Cox, C. D.;
Rinehart, K. L., Jr.; Moore, M. L.; Cook, J. C., Jr Proc. Natl. Acad. Sci. U.S.A.
1981, 78, 4256. (c) Raymond, K. N.; Mu¨ller, G.; Matzanke, B. F. In Topics in
Current Chemistry; Boschke, F. L., Ed.; Springer-Verlag: Berlin, Germany, 1984;
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7420 J. Org. Chem. 2008, 73, 7420–7423
10.1021/jo801294p CCC: $40.75 2008 American Chemical Society
Published on Web 08/13/2008

SCHEME 1. Attempted C-H Insertion Route
FIGURE 2. Proposed transition state models for the electrophilic
azidation of 10.
SCHEME 2. Electrophillic Azidation Reactions
N-Boc group prior to azide transfer. Thus, acidic cleavage of
the Boc group followed by treatment with anion exchange
resin in MeOH and filtration gave the crude amine, which
was then subjected to reductive alkylation to afford 10.
When N-methyl proline 10 was subjected to the same azide
transfer condition used for substrate 5, we observed a marked
increase in conversion and yield of the desired azidoester.
Optimal conditions utilized 2.2 equiv of LHMDS and 2.0
equiv of trisyl azide in THF with AcOH quench (entry 1).
Reducing the amount of LHMDS to 1.1 equiv (entry 2)
resulted in exclusive formation of the R-diazoester, as did
the use of 4-nitrophenylsulfonyl azide as an electrophile
(entry 5). The potassium enolate of 10 reacted to give only
the desired azide product, irrespective of the amount of base
used (entries 3 and 4).
Analysis of the 1H NMR of 11 indicated the presence of only
one diastereomer (under optimized azidation conditions). Al-
though the configuration of the newly formed stereocenter could
not be determined at this stage, we considered the two possible
transition states shown in Figure 2. Path A depicts the
minimization of 1,3-allylic strain, followed by approach of trisyl
azide from the Re-face of the enolate. Alternatively, a six-
membered chelation transition state may lead to axial approach
of trisyl azide onto a low-energy half-chair conformer (Fu¨rst-
Plattner principle). Both of these models result in the formation
of the anti product. On the basis of this, we anticipated that the
newly formed R-amino acid center would possess an S config-
uration to match that of the 4′ position in pyochelin.12 This
tentative assignment was later confirmed by X-ray diffraction
of an amide derivative (vide infra).
Our initial synthesis plan relied on intramolecular nitrene
insertion as the key step for introduction of the ring B nitrogen.
Toward this end, we prepared known proline diester 5,7 as an
inseparable 16:1 trans:cis mixture via lithium triethylborohydride
reduction and Horner-Wadsworth-Emmons olefination of (N-
Boc)-tert-butyl pyroglutamate (4).8 Chemoselective ester reduc-
tion was followed by carbamate formation to give 6 in 64%
yield after purification (Scheme 1). Unfortunately, rhodium(II)-
catalyzed C-H insertion9 resulted in poor yields of the desired
5-membered cyclic carbamate. Attempts to employ silver(I)-
catalyzed conditions, which have shown enhanced conversion
in the case of some secondary C-H bond insertions,10 resulted
in slightly improved albeit unsatisfactory yields.
Completion of the synthesis of pyochelin analogues 2 and 3
is depicted in Scheme 3. Thus, azide reduction of 11 and EDC-
mediated coupling of the crude amine to 2-benzyloxybenzoic
acid gave amide 12 in 93% yield. Reduction of the ethyl ester
was followed by hydrogenolysis of the benzyl ether and
dehydrative cyclization with the Burgess reagent13 to give
oxazoline 15. The thiazoline ring was formed over two steps
by thiolysis of the oxazoline ring with hydrogen sulfide in
MeOH/NEt3, and subsequent dehydration again with the Burgess
reagent.14
Given these results, we decided to explore potentially regio-
and diastereoselective electrophilic azidation11 as an alternative
strategy (Scheme 2). When 5 was treated with LHMDS and
trisyl azide at -78 °C, followed by AcOH quench, we obtained
a mixture of starting material, ring-opened starting material (9),
and low yields of desired product 8, along with unidentified
byproducts. We reasoned that the electron-withdrawing and
sterically demanding Boc -group prevents reaction of the desired
carbanion with the azide source. Anticipating the necessary
introduction of an N-methyl group, we opted to replace the
Our efforts to carry out TFA-mediated deprotection of tert-
butyl esters 14 and 15 (with anisole scavenger) were initially
(7) (a) Manzoni, L.; Arosio, D.; Belvisi, L.; Bracci, A.; Colombo, M.;
Invernizzi, D.; Scolastico, C. J. Org. Chem. 2005, 70, 4124. (b) Collado, I.;
Ezquerra, J.; Vaquero, J. J.; Pedregal, C. Tetrahedron Lett. 1994, 35, 8037.
(8) Jiang, M. X. W.; Jin, B.; Gage, J. L.; Priour, A.; Savela, G.; Miller, M. J.
J. Org. Chem. 2006, 71, 4164.
(9) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598.
(10) (a) Li, Z.; Capretto, D. A.; Rahaman, R.; He, C. Angew. Chem., Int.
Ed. 2007, 46, 5184. (b) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210.
(11) For seminal publications on electrophilic azidation of enolates, see: (a)
Wasserman, H. H.; Hlasta, D. J. J. Am. Chem. Soc. 1978, 100, 6780–6781. (b)
Ku¨hlein, K.; Jensen, H. Liebigs Ann. Chem. 1974, 369–402.
(12) (a) A similar stereochemical outcome has been observed in the
electrophilic azidation of a ꢀ-proline derivative; Hanessian, S.; Sharma, R.
Heterocycles 2000, 52, 1231. (b) See also: Yi, J. J.; Hua, Z. M.; Rong, T. G.
Synth. Commun. 2003, 33, 3913.
(13) (a) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744.
(b) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907.
(14) (a) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267. (b) Wipf,
P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397. (c) Wipf, P.; Miller, C. P.;
Venkatraman, S.; Fritch, P. C. Tetrahedron Lett. 1995, 36, 6395.
J. Org. Chem. Vol. 73, No. 18, 2008 7421

SCHEME 3. Synthesis of Carbapyochelins 2 and 3
SCHEME 4. Synthesis and X-ray Structure of 16
diluted with 100 mL of EtOAc, then evaporated under reduced
pressure and dried under high vacuum to remove excess trifluo-
roacetic acid. The crude amine trifluoroacetate salt was taken up
in 100 mL of EtOH and treated with 38 g of Dowex-X2 anion
exchange resin (OH- form). The mixture was stirred gently until
the pH of the solution reached 8-9. The resin was then removed
by filtration and washed repeatedly with EtOH. Evaporation of
filtrate gave the crude amine as a yellow oil (attempts to isolate
the free amine by aqueous extraction were hampered by its water
solubility). The amine was treated with formaldehyde (30% solution
in EtOH, 41.8 mL, 515 mmol) and 1 M aq. HCl until a pH of 2
was obtained. A catalytic amount of 10% Pd/C was added and the
flask was then purged and filled with an H2 atmosphere (balloon).
The reaction mixture was stirred 18 h at rt and purged with a stream
of Ar, then the catalyst was removed by filtration over celite with
MeOH rinsing. The filtrate was concentrated, diluted with sat. aq.
NaHCO3, and extracted with EtOAc. Drying over Na2SO4, filtration,
and concentration under reduced pressure gave a crude 16:1
diastereomeric mixture of N-methylated amines which were sepa-
rated by chromatography over silica gel (33% Et2O/hexanes as
eluant). The trans isomer 10 was obtained as a pale yellow oil (3.63
met with difficulties. The apparent sensitivity of the oxazoline
and thiazoline rings in the presence of water and excess TFA
resulted in appreciable amounts (>20%) of hydrated ring-opened
products. This side reaction could be minimized by a careful
workup procedure involving dilution of the reaction mixture
with ethyl acetate, concentration in vacuo, and addition of a
precooled diethyl ether/water mixture. Separation of the water
layer and lyophilization then gave 2 and 3 in high yields without
appreciable hydrolysis. RP-HPLC (C18) analysis of the crude
amino acids showed each to have >95% purity following
deprotection (see the Supporting Information).
To determine the configuration of the newly formed stereo-
center of 11 we relied primarily on the synthesis of crystalline
derivatives, since detailed 2D NMR studies gave ambiguous
results. While some intermediates in Scheme 3 were solids, none
of these compounds provided crystals of sufficient quality for
X-ray diffraction. We were pleased to find that reduction of
azide 11 followed by coupling to 2-methoxymethyloxybenzoic
acid15 gave 84% yield of amide 16, which readily crystallized
out of CH2Cl2/hexane. Single-crystal X-ray diffraction revealed
an S configuration at the 1′ center (IUPAC numbering), thus
confirming our earlier prediction.
In summary, we have described a route toward two configu-
rationally stable analogues of pyochelin. We are currently
investigating the ability of ferric complexes of 2 and 3 to bind
siderocalin and chicken Ex-FABP. Studies are also underway
to explore the scope of the highly diastereoselective electrophilic
azidation for the synthesis of other functionalized proline
chimeras with orthogonally protected N- and C-termini. To the
best of our knowledge, this work represents the first stereose-
lective synthesis of bis-proline structures related to 11 (Scheme
4). This class of residues should find utility in a variety of
peptidomimetic applications.
1
g, 52% from 5). H NMR (300 MHz, CDCl3) δ 4.13 (q, J ) 7.0
Hz, 2H), 3.53 (dd, J ) 8.2, 2.3 Hz, 1H), 3.42 (septet, J ) 4.4 Hz,
1H), 2.59 (dd, J ) 14.4, 4.1 Hz, 1H), 2.43 (s, 3H), 2.30-2.04 (m,
3H), 1.86-1.76 (m, 1H), 1.70-1.60 (m, 1H), 1.47 (s, 9H), 1.22 (t,
J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.3, 172.2, 80.7,
67.0, 60.2, 59.7, 38.8, 35.3, 29.9, 28.2, 27.3, 14.2. HRMS (ESI-
TOF) (m/z) [MH]+ calcd for C14H25NO4 272.1856, found 272.1859.
(2S,5S,1′S)-5-(Azidoethoxycarbonylmethyl)-1-methylpyrroli-
dine-2-carboxylic Acid tert-Butyl Ester (11). A solution of 10
(900 mg, 3.32 mmol) in dry THF (7 mL) was cooled to -78 °C
and treated with LHMDS (1 M solution in THF, 7.30 mL, 7.30
mmol) dropwise. The enolate was allowed to form over 1 h at the
same temperature and treated with a precooled (-78 °C) solution
of 2,4,6-triisopropylbenzenesulfonyl azide (2.05 g, 6.63 mmol) in
THF (12 mL). After 2 min the reaction was quenched by adding
glacial AcOH (750 µL, 13.3 mmol) and then allowed to stir 16 h
at rt. The reaction was concentrated, taken up in 10% aq. Na2CO3,
and extracted with EtOAc, then the organic extracts were dried
over Na2SO4, filtered, and concentrated in vacuo. The crude residue
was purified by chromatography over silica gel (10-20% EtOAc/
hexanes gradient as eluant). The desired azide 11 was obtained as
1
a yellow oil (735 mg, 71%). H NMR (300 MHz, CDCl3) δ 4.27
(d, J ) 2.6 Hz, 1H), 4.25 (q, J ) 7.0 Hz, 2H), 3.71 (d, J ) 7.6 Hz,
1H), 3.58 (dt, J ) 8.8, 3.5 Hz, 1H), 2.53 (s, 3H), 2.10 (m, 2H),
1.87 (m, 2H), 1.47 (s, 9H), 1.29 (t, J ) 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 173.3, 168.9, 80.9, 67.3, 64.7, 63.0, 61.7, 34.8,
28.2, 28.1, 25.1, 14.1; HRMS (ESI-TOF) (m/z) [MH]+ calcd for
C14H24N4O4 313.1876, found 313.1884.
Data for the R-diazoester byproduct: 1H NMR (300 MHz, CDCl3)
δ 4.21 (q, J ) 6.9 Hz, 2H), 4.05 (dd, J ) 8.4, 4.9 Hz, 1H), 3.56
(d, J ) 8.2 Hz, 1H), 2.43 (s, 3H), 2.14-2.03 (m, 1H), 1.90-1.72
(m, 3H), 1.26 (t, J ) 7.1 Hz, 3H), 1.48 (s, 9H); ESI-MS (m/z)
[MH]+ calcd for C14H23N3O4 298.17, found 298.26.
Experimental Section
(2S,5S,4′S)-5-[2-(2-Hydroxyphenyl)-4,5-dihydrooxazol-4-yl]-
1-methylpyrrolidine-2-carboxylic Acid (3). Oxazoline ester 14
(40 mg, 116 µmol) was treated with anisole (126 µL, 1.16 mmol)
followed by 1.5 mL of a 90% TFA/DCM solution. The reaction
was stirred at rt for 6 h, then diluted with 5 mL of EtOAc, and
concentrated in vacuo (this step is necessary to remove excess TFA
(2S,5S)-5-Ethoxycarbonylmethyl-1-methylpyrrolidine-2-car-
boxylic Acid tert-Butyl Ester (10). A solution of 5 (9.20 g, 25.7
mmol) in 50 mL of 25% TFA/DCM was stirred at rt for 30 min,
(15) Somu, R. V.; Wilson, D. J.; Bennett, E. M.; Boshoff, H. I.; Celia, L.;
Beck, B. J.; Barry, C. E., III; Aldrich, C. C. J. Med. Chem. 2006, 49, 7623.
7422 J. Org. Chem. Vol. 73, No. 18, 2008

and avoid hydrolytic opening of the oxazoline ring). The crude
residue was then partitioned between water and Et2O (precooled
to 0 °C) and separated, then the aqueous layer was washed with an
additional portion of Et2O. The aqueous layer was then frozen and
lyophilized to yield pure 3 TFA as a hygroscopic white solid (38
Hz, 1H), 4.18 (m, 1H), 3.89 (m, 1H), 3.61 (dd, J ) 11.7, 9.4 Hz,
1H), 3.22 (dd, J ) 10.9, 9.4 Hz, 1H), 2.85 (s, 3H), 2.15 (m, 2H),
2.03 (m, 1H), 1.81 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ
170.5, 168.1, 158.0 (q, TFA), 156.0, 132.3, 129.2, 118.4, 115.7,
114.9, 73.8, 67.1, 52.0, 46.0, 36.9, 34.8, 27.2; HPLC C18 retention
time (0-90% MeCN in H2O with 0.1% formic acid, linear gradient,
20 min) ) 10.38 min; mp 68-70 °C; HRMS (ESI-TOF) (m/z) [M
+ H]+ calcd for C15H18N2O3S 307.1111, found 307.1115.
1
mg, 83%). H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J ) 7.6,
1.6 Hz, 1H), 7.45 (ddd, J ) 8.6, 7.4, 2.0 Hz, 1H), 6.99 (dd, J )
8.6, 0.8 Hz, 1H), 6.92 (dt, J ) 7.4, 1.2 Hz, 1H), 4.91 (ddd, J )
10.2, 7.8, 3.9 Hz, 1H), 4.61 (t, J ) 9.4 Hz, 1H), 4.27 (t, J ) 8.4
Hz, 1H), 3.92 (m, 1H), 2.93 (s, 3H), 2.16 (m, 1H), 2.01 (m, 1H),
1.72 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 170.1, 166.3,
159.1, 158.0 (q, TFA), 134.2, 128.2, 119.1, 116.7, 109.6, 69.3, 66.7,
63.3, 51.9, 36.4, 26.7, 23.1; HPLC C18 retention time (0-90%
MeCN in H2O with 0.1% formic acid, linear gradient, 20 min) )
9.78 min; HRMS (ESI-TOF) (m/z) [MH]+ calcd for C15H18N2O4
291.1339, found 291.1349.
Acknowledgment. This research was supported by a grant
from the National Cancer Institute (NIH U54CA132383) and
by New Mexico State University. We thank Dr. Eileen Duesler
(University of New Mexico) for the X-ray structure of com-
pound 16.
Supporting Information Available: Detailed experimental
procedures for compounds 5 and 12-16, and spectral data for
all new compounds, as well as crystal structure data (CIF) for
16. This material is available free of charge via the Internet at
http://pubs.acs.org.
(2S,5S,4′S)-5-[2-(2-Hydroxyphenyl)-4,5-dihydrothiazol-4-yl]-
1-methylpyrrolidine-2-carboxylic Acid (2). Thiazoline ester 15
(35 mg, 110 µmol) was deprotected by using the same procedure
described for 14. Lyophilization of the final aqueous extracts yielded
1
pure 2·TFA as a white solid (40 mg, 86%). H NMR (400 MHz,
DMSO-d6) δ 7.48 (m, 2H), 6.99 (m, 2H), 5.17 (dt, J ) 9.3, 3.1
JO801294P
J. Org. Chem. Vol. 73, No. 18, 2008 7423