Chemoenzymatic route to stereodefined 2-(azidophenyl)oxazolines for click chemistry

Article abstract of DOI:10.1016/j.tetlet.2020.152717

Aryl-substituted esters of a racemic diprotected 2-azido-1-alkanol were submitted to the Staudinger/aza-Wittig reaction in order to assess scope and establish conditions for their cyclization to the corresponding 2,4,5-trisubstituted oxazolines. Following

Full text of DOI:10.1016/j.tetlet.2020.152717

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Chemoenzymatic route to stereodefined 2-(azidophenyl)oxazolines for click
chemistry
Paige J. Monsen, Frederick A. Luzzio
PII:
S0040-4039(20)31228-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152717
TETL 152717
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 October 2020
18 November 2020
26 November 2020
Please cite this article as: Monsen, P.J., Luzzio, F.A., Chemoenzymatic route to stereodefined 2-
azidophenyl)oxazolines for click chemistry, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
020.152717
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Paige J. Monsen and Frederick A. Luzzio*
H
H
OH
O
N
RO
O
N
N
RO
RO
RO
RO
R1
N
N
OR
N3
H
H
from pig liver esterase
R=benzyl)
R=benzyl
R =4-NO C H
F
(
R=benzyl
1
2
6
4

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Chemoenzymatic route to stereodefined 2-(azidophenyl)oxazolines for click
chemistry
Paige J. Monsen and Frederick A. Luzzioa, 
a
a
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Aryl-substituted esters of a racemic diprotected 2-azido-1-alkanol were submitted to the
Staudinger/aza-Wittig reaction in order to assess scope and establish conditions for their
cyclization to the corresponding 2,4,5-trisubstituted oxazolines. Following the cyclization study,
the (2R,3R)-antipode of the azidoalkanol was obtained in high ee by incubation of the
corresponding racemic azidoacetate with pig liver esterase (PLE). The p-nitrobenzoate of the
enantioenriched 2-azido-1-alcohol was cyclized by the Staudinger/aza-Wittig to give the
corresponding (4R,5R)-disubstituted-2-(4-nitrophenyl) oxazoline. Selective reduction of the
nitrophenyloxazoline to the corresponding aminophenyloxazoline using aluminum amalgam
followed by direct azidation of the 2-(4-aminophenyl) moiety provided the corresponding
(4R,5R)-2-(4-azidophenyl) oxazoline derivative. The azidophenyl oxazoline was reacted with a
proven click partner 4-ethynylfluorobenzene under copper/sodium ascorbate mediation to provide
the click triazole product in high yield.
Available online
Keywords:
Aza-Wittig
Oxazolines
Azides
Click chemistry
Esterase
2
009 Elsevier Ltd. All rights reserved.

Corresponding author. Tel.: +1-502-852-7323; fax: +1-502-852-8149; e-mail: faluzz01@louisville.edu

2
1
. Introduction
Oxazolines and their substituted derivatives occupy a unique niche in the realm of nitrogen-oxygen heterocycles.
Oxazoline-derived structural cores are found in natural products, medicinals, experimental therapeutics and polymers and
are also functional molecules as they have been employed as chiral directing groups, ligands and protecting groups in
1
synthetic chemistry. Our research efforts have involved the design and development of oxazole-derived azides as reacting
2
partners with arylacetylenes in the so called “click” reaction. The product triazoles of interest have evolved from the
development of oxazole-based peptidomimetic inhibitors of Porphyromonas gingivalis adherence to Streptococcus gordonii
3
using click chemistry. The adherence between P.gingivalis and S. gordonii is mediated by a protein-protein interaction
which results in the generation of a dental biofilm. In turn the microbial community becomes resistant to many types of
antibacterial therapy and ultimately leads to degradation of bone and dental structure. Consequently, any synthetic inhibitors
of the adherence process will provide a unique therapy for the treatment of gingival disease propagated by P. gingivalis and
the associated microbes. In the quest for adherence inhibitors with increased potency, we are presently exploring the
replacement of the 2,4,5-trisubstituted oxazole motif with the corresponding 2,4,5-trisubstituted oxazolines
(
dihydrooxazoles). As evidenced by recent reports, oxazoline-based scaffolds are beginning to gain ground as functional
4
peptidomimetics. In contrast to the more planar trisubstituted oxazoles, the corresponding oxazolines offer a more three-
dimensional motif with two ring stereocenters. Therefore, our goals were to develop a synthesis of stereodefined
trisubstituted oxazolines which will constitute the basic scaffold of new adherence inhibitors. The stereodefined oxazolines
should have potential for further synthetic elaboration at the 4- and 5- positions, with the aid of suitable protecting groups,
as well as suitably-positioned azide functionality for the ‘click’ cycloaddition. We carefully considered several of the more
common routes to 2-substituted oxazolines which included the dehydration of N-acylaminoalcohols and the bimolecular
cyclocondensation routes involving aminoalcohols and imidates or aminoalcohols and nitriles. Finally, we decided on
the pursuit of an oxazoline synthesis based on the relatively mild Staudinger/aza-Wittig reaction of azido esters (Scheme
5
5
6
a
6
b
6c
O
R2
R2
R1
3
R P
O
O
N2
R3P
O
+
+
R3
R1
R3
N3
N
Scheme 1. Staudinger/aza-Wittig route to oxazolines.
1
).7 The advantages of the Staudinger/aza-Wittig scheme are the effective access to the azidoester intermediates as well as
the straightforward accommodation of their stereocenters which will ultimately be expressed in the oxazoline product.
Moreover, through enzyme-mediated enantioselective hydrolysis of azido acetate derivatives, access to either antiopodal
intermediate en route to the target oxazoline can be realized.

3
O
OH
OBn
OAc
OAc
a
BnO
BnO
b
BnO
N3
BnO
BnO
3
+
+
O
OBn
OBn
N3
N3
(2R, 3R)-12a
N3
(2S, 3S)-12b
1
2
(2R,3R)-3a
c, d
unhydrolyzed
OR
BnO
N3
OBn
(
(
2R,3R)-13a, R=-methoxy--(trifluoromethyl)phenylacetyl
2R,3R)-7a, R=4-nitrobenzoyl
Scheme 3. Pig liver esterase-mediated hydrolysis of azidoacetate 12
giving (2R,3R)-3a followed by Mosher ester derivatization and
acylation with 4-nitrobenzoyl chloride. Reagents/Conditions: (a)
Ac
2%.
acid/DCC/DCM/rt/48
chloride/pyridine/DMAP/DCM/rt/16 h, 97%.
2
O/pyridine/rt/1.5 h, 89%. (b) PLE/phosphate buffer/35 °C/7 days,
(c) R-(+)--methoxy--(trifluoromethyl)phenylacetic
h, 61% (d) 4-nitrobenzoyl
4
2
. Results and Discussion
Our synthesis begins with the readily-available unsaturated dibenzyl ether 1 in which each benzyloxymethyl group is
8
positioned to become the substituent groups at positions 4 and 5 of the oxazoline target (Scheme 2). Epoxidation of 1
9
(
2 2
mCPBA/CH Cl ) gave the (dibenzyloxy)epoxide 2 (80%) which upon treatment with sodium azide (DMF/100 °C/24 h)
gave the (dibenzyloxy) azido alcohols 3 (97%). In order to establish conditions and explore the scope of the Staudinger/aza-
Wittig reaction the dibenzyloxyazidoester substrates 4, 5, 6, 7 were prepared from 3. Hence, (dibenzyloxy) azido alcohol 3
was esterified with the appropriate acid chlorides (RCOCl) in the presence of base to give azido esters 4-7 which were
purified by column chromatography on silica gel. Treatment of the azidoesters 4-7 with triphenylphosphine (1.5 eq.) in
tetrahydrofuran (rt to 40 °C/16 h) gave the corresponding oxazolines 8-11 in 50-94% isolated yield. Thus, the
reagents/conditions of the Staudinger/aza-Wittig reaction for conversions of azidoesters 4-7 to oxazolines 8-11 were found
to be of general applicability.
With the conditions of the Staudinger/aza-Wittig cyclization now established, we then prepared the
(
1
dibenzyloxy)azidoalcohol (2R,3R)-3a generated from enantioselective esterase hydrolysis of the racemic acetate derivative
2 (Scheme 3). Hence, the (dibenzyloxy)azidoalcohol 3 was then acetylated (acetic anhydride/pyridine/1.5 h/rt) to provide
1
0
the (dibenzyloxy)-azidoacetate 12 (89%). Addition of the (dibenzyloxy)azidoacetate 12 to a suspension of pig liver esterase
(
PLE) in aqueous phosphate buffer (pH=7.4, 35 °C/7 days) gave the chromatographically-separable mixture of (2R,3R)-
2
0
azidoalcohol 3a []
D 3
–14.2 (c=0.4, CHCl ) (42% based on racemic 12) and unhydrolyzed azidoacetates 12a/12b. We were
satisfied that the aqueous conditions offered by the pH=7.4 buffer ensured the optimum performance of the esterase as was
1
1
the case in our previous work with esterase enzyme systems. For comparison, we explored the enzymatic resolution of the
azidoalcohol mixture using various lipases and vinyl acetate in organic solvents and found that the “reverse” enzymatic
OH
BnO
BnO
a
BnO
BnO
b
BnO
BnO
O
N3
1
2
3
c
O
R
O
BnO
BnO
d
BnO
BnO
R
O
N
N3
8
9
1
, R= -C6H5 (55%)
, R= -4ClC6H4 (50%)
0, R= -CH2OC6H5 (81%)
4, R= -C6H5 (85%)
5, R= -4ClC6H4 (52%)
6, R= -CH2OC6H5 (73%)
7, R= -4NO2C6H4 (68%)
11, R= -4NO2C6H4 (94%)
Scheme 2. Preparation of oxazolines 8-11 from azidoesters 4-7.
Reagents/Conditions: (a) mCPBA/DCM/0 °C to rt/24 h, 80%. (b)
NaN
3
/DMF/100
°C,
24
h,
97%.
(c)
ROCl/Et
3
N
or
H
H
H
H
a
BnO
BnO
O
N
b, c
BnO
BnO
O
N
pyridine/DMAP/DCM/rt/16-48 h. (d) PPh
3
/THF/rt to 40 °C/16 h.
(2R,3R)-7a
NO2
N3
(4R,5R)-11a
(4R,5R)-14
H
H
O
N
N
N
BnO
BnO
d
N
F
(4R,5R)-15
Scheme 4. Conversion of 4-nitrobenzoyl ester (2R,3R)-7a to
oxazoline (4R,5R)-11 followed by azidation to give click partner
(
4R,5R)-14 and subsequent click reaction to afford (4R,5R)-15.
Reagents/Conditions: (a) PPh /THF/rt to 40 °C/16 h, 78%. (b)
Al(Hg)/THF/H O/rt/30 min. (c) NaNO / NaN /AcOH/H O/0 °C to
rt/1.5 h, 69% (two steps). (d) 4-
ethynylfluorobenzene/CuSO ·5H O/sodium
ascorbate/THF/H O/rt/16 h, 94%.
3
2
2
3
2
4
2

4
esterification mode was unsuccessful with these substrates. The absolute configuration of azidoalcohol (2R,3R)-3a was
confirmed by correlation with products prepared in two separate previously reported syntheses from tartaric acid
1
2a-d
derivatives.
Interestingly, after several enzymatic runs, our (2R,3R)-3a consistently gave a somewhat higher rotation
2
0
12a
than the azidoalcohol product obtained in one reported synthesis (Lit. []
D
1
–10.5, c=0.4, CHCl
3
).
The enantiomeric
3
purity of (2R,3R)-3a was determined by preparation of its Mosher ester 13a (See Supplementary Data) from (R)-(+)--
2
0
methoxy--(trifluoromethyl)phenylacetic acid [(DCC/DMAP/ CH
2
Cl
to be >99% by F NMR analysis. After chromatographic separation of azidoalcohol 3a from the unhydrolyzed azidoesters,
the presence of unhydrolyzed azidoester 12a was confirmed by saponification (LiOH/H O) of the recovered azidoacetate
mixture and revealed material of lower rotation, presumably due to the presence of the antipodal azidoalcohol derived from
2b. Therefore, the 12a/12b mixture could be recycled with fresh esterase to provide additional azidoalcohol (2R,3R)-3a.
Starting with the esterase product azidoalcohol (2R,3R)-3a, treatment with 4-nitrobenzoyl chloride
2 3
), [α]D +19.0 (c=0.18, CHCl )] and the ee was found
1
9
2
1
2
0
(
pyridine/DMAP/CH
2
Cl
2
) afforded the corresponding 4-nitrobenzoyl ester (2R,3R)-7a [97%, []D –21.8 (c=0.57, CHCl
/THF) gave the (4R,5R)-2-
)] after purification by flash-column chromatography. The
reduction-azidation of the (nitrophenyl)oxazoline (4R,5R)-11a involved a two-step sequence whereby the arylnitro group
3
)].
Staudinger/aza-Wittig cyclization of 4-nitrobenzoyl ester (2R,3R)-7a (PPh
3
2
0
(
nitrophenyl)oxazoline 11a [78%, [α]D +12.1 (c=0.34, CHCl
3
1
4,15
was reduced with aluminum amalgam (THF/H
2
O)
O) to give azidophenyl-oxazoline (4R,5R)-14 [69% over two steps, [α]D +8.0 (c=0.07, CHCl
azidophenyl)-oxazoline 14 responded well to the click reaction with 1-ethynyl-4-fluorobenzene, a common co-reactant with
followed by direct treatment with sodium nitrite/sodium azide
2
0
(AcOH/H
2
3
)]. The (4R,5R)-2-
(
3
a-c
several of our azidophenyloxazoles from previous studies. Thus, admixture of copper sulfate pentahydrate and sodium
ascorbate to a solution of azidophenyloxazoline (4R,5R)-14 and 1-ethynyl-4-fluorobenzene in THF/H O followed by stirring
16 h) gave the (4R,5R)-(oxazolinylphenyl)triazole click product (4R,5R)-15 [94%, []D20 +4.5 (c=0.16, CH
Cl )] as a white
solid after flash column chromatography on silica gel. The click product (4R,5R)-15 was characterized by H NMR as the
2
(
2
2
1
1
,4-‘anti’-disubstituted triazole whereby the regiochemistry of the cycloaddition is consistent with the copper (I)-catalyzed
1
6
dipolar cycloaddition mechanism.
3
. Conclusions
The employment of a stereoselective enzymatic hydrolysis using pig liver esterase (PLE) combined with the
Stauginger/aza-Wittig cyclization proves to be a mild and effective route to stereodefined 2-aryl-4,5-disubstituted
oxazolines. Under the ideal conditions using aqueous phosphate buffer, the key intermediary -azidoacetate is a substrate
which yields the corresponding non-racemic azido alcohol in good yield and high ee. The use of aqueous conditions in the
enzymatic step is a noteworthy example in of “green chemical” transformation and an otherwise eco-friendly step. The
reduction-azidization sequence involving the aluminum amalgam reduction of the nitrophenyloxazoline was noteworthy and
is an effective application to click chemistry as a result of our previous studies. The application of the esterase hydrolysis
scheme will be applied to the complete stereochemical array of 4,5-disubstituted oxazolinyl intermediates followed by their
conversion to adherence inhibitors and will be reported in due course.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
Funding in part was provided by a University of Louisville Dissertation Completion Fellowship and NIH/NIDCR
1
R01DE023206. Acknowledgement is made to the NSF (CHE1726633) for support of the Indiana University Mass
Spectrometry Facility.
References and notes
1
.
(a) Chaudhry, P. Schoenan, F. Neuenswander, B. Lushington, G. H. Aubé, J. J. Comb. Chem. 9 (2007) 473-476. doi:10.1021/cc060159t
b) For a recent review, See: Yoshimura, A. Saito, A. Yusubov, M. S. Zhdankin, V. V. Synthesis 52 (2020) 2299-2310. doi:10.1055/s-
040-1707122
(
0
2
3
.
.
Gehringer, M. Laufer, S. A. Angew. Chem. Int. Ed. 56 (2017) 2-4. doi:10.1002/anie.201710195
(a) Patil, P. C. Tan, J. Demuth, D. R. Luzzio, F. A. MedChemComm 10 (2019) 268-279. doi:10.1039/c8md00405f (b) Patil, P. C. Tan,
J. Luzzio, F. A. Demuth, D. R. Antimicrob. Agents. Chemother. 62 (2018) e00400-18. doi:10.1128/AAC.00400-18 (c) Patil, P. C. Tan,
J. Demuth, D. R. Luzzio, F. A. Bioorg. Med. Chem. 24 (2016) 5410-5417. doi:10.1016/j.bmc.2016.08.059 (d) Loner, C. M. Luzzio, F.
A. Demuth, D. R. Tetrahedron Lett. 53 (2012) 5641-5644. doi:10.1016/j.tetlet.2012.08.032 (e) Demuth, D. R. Luzzio, F. A. Antibiofilm
N
N
Ar
Ar
C6H4-4F
O
N
N

5
Compounds US 9,167,820, 2015. (f) A typical oxazole-based adherence inhibitor motif is shown below whereby the acetylenic click
partner is 4-ethynylfluorobenzene (Ref 3c).
4
.
(a) Zhou, M. Qian, Y. Xie, J. Zhang, W. Jiang, W. Xiao, X. Chen, S. Dai, C. Cong, Z. Ji, Z. Shao, N. Liu, L. Wu, Y. Liu, R. Angew.
Chem. Int. Ed. 59 (2020) 7412-6419. doi:10.1002/anie.202000505 (b) Taechalertpaisarn, J. Lyu, R. L. Arancillo, M. Lin, C.-M. Jiang,
Z. Perez, L. M. Ioerger, T. R. Burgess, K. Org. Biomol. Chem. 17 (2019) 908-915. doi:10.1039/c8ob02901f (c) Li, X. Taechalertpaisarn,
J. Xin, D. Burgess, K. Org. Lett. 17 (2015) 632-635. doi:10.1021/ol5036547
5
6
.
.
(a) Liu, G.-Q. Yang, C.-H. Li, Y.-M. J. Org. Chem. 80 (2015) 11339-11350. doi:10.1021/acs.joc.5b01832 (b) Castellano, S. Kuck, D.
Sala, M. Novellino, E. Lyko, F. Sbardella, G. J. Med. Chem. 51 (2008) 2321-2325. doi:10.1021/jm7015705
(a) Phillips, A. J. Uto, Y. Wipf, P. Reno, M. J. Williams, D. R. Org. Lett. 2 (2000) 1165-1168. doi:10.1021/ol005777b (b) Meyers, A.
I. Slade, J. J. Org. Chem. 45 (1980) 2785-2791. Doi:10.1021/jo01302a008 (c) Trose, M. Lazreg, F. Lesieur, M. Cazin, C. S. J. J. Org.
Chem. 80 (2015) 9910-9914. doi:10.1021/acs.joc.5b01382
7
.
(a) Wang, L. Ren, Z. L. Chen, M. Ding, M. W. Synlett 25 (2014) 721-723 doi:10.1055/s-0033-1340596 (b) Loos, P. Ronco, C. Riedrich,
M. Arndt, H. D. Eur. J. Org. Chem. (2013) 3290-3315. doi:10.1002/ejoc.201300160 (c) Nebot, J. Romea, P. Urpi, F. Org. Biomol.
Chem. 10 (2012) 6395-6303. doi:10.1039/c2ob25793a (d) Wu, J. Liu, J. C. Wang, L. Ding, M. W. Synlett 19 (2011) 2880-2882.
doi:10.1055/s-0031-1289865 (e) De Moliner, F. Crosignani, S. Banfi, L. Riva, R. Basso, A. J. Comb. Chem. 12 (2010) 613-616.
doi:10.1021/cc100122n (f) Takeuchi, H. Yanagida, S. Ozaki, T. Hagiwara, S. Eguchi, S. J. Org. Chem. 54 (1989) 431-434.
doi:10.1021/jo00263a033
8
9
.
.
(a) Schill, H. DeMeijere, A. Yufit, D. S. Org. Lett. 9 (2007) 2617-2620. doi:10.1021/ol070707r (b) Charette, A. B. Gagnon, A. Fournier,
J. F. J. Am. Chem. Soc. 124 (2002) 386-387. doi:10.1021/ja017230d (c) Wu, F. L. Ross, B. P. McGeary, R. P. Eur. J. Org. Chem. 10
(2010) 1989-1998. doi:10.1002/ejoc.200901264
(a) Schmidt, Y. Breit, B. Chem. Eur. J. 17 (2011) 11780-11788. doi:10.1002/chem.201100843 (b) Hachiya, I. Matsumoto, T. Inagaki,
T. Takahashi, A. Shimizu, M. Heterocycles 82 (2010) 449-460. doi:10.3987/COM-10-S(E)16 (c) Schomaker, J. M. Bhattacharjee, S.
Yan, J. Borhan, B. J. Am. Chem. Soc. 129 (2007) 1996-2003. doi:10.1021/ja065833p
1
1
0. For a recent review see: Musa, M. M. Hollmann, F. Mutti, F. G. Catal. Sci. Technol. 9 (2019) 5487-5503. doi:10.1039/c9cy01539f
1. (a) Luzzio, F.A. Fitch, R.W. J Org. Chem. 64 (1999) 5485-5493. doi:10.1021/jo990293i (b) Luzzio, F.A. Duveau, D.Y. Tetrahedron
Asymm. 13 (2002) 1173-1180. doi:10.1016/S0957-4166(02)00313-0
1
1
2. (a) Aboulaala, K. Goux-Henry, C. Sinou, D. Safi, M. Soufiaoui, M. J. Mol. Catal.
doi:10.1016/j.molcata.2005.05.006 (b) Tanner, D. Birgersson, C. Gogoll, A. Tetrahedron 50 (1994) 9797-9824. doi:10.1016/S0040-
020(01)85546-0 (c) Kinugasa, M. Harada, T. Oku, A. Tetrahedron Lett. 39 (1998) 4529-4532. doi:10.1016/S0040-4039(98)00823-5
d) The second previously reported synthesis of (2R,3R)-3a (rotation not reported) culminated in the corresponding (2R,3R) amino
A 237 (2005) 259-266.
4
(
2
0
alcohol ([]
comparable rotation ([]
D
+11.8, c=1.1, CHCl
3
), and accordingly, we reduced our (2R,3R)-3a to the corresponding amino alcohol which gave a
2
0
D
+13.6, c=0.08, CHCl ).
3
3. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Carbon Compounds (1994) John Wiley &Sons: New York, pp 222-223.
ISBN: 0-471-01670-5
1
1
1
4. Keck, G. E. Fleming, S. Nickell, D. Weider, P. Synthetic Commun. 9 (1979) 281-286. doi:10.1080/00397917908064153
5. Monsen, P. J. Luzzio, F. A. Tetrahedron Lett. 61 (2020) 152575-152579. doi:10.1016/j.tetlet.2020.152575
6. Meldal, M. Tornøe, C. W. Chem. Rev. 108 (2008) 2952-3015. doi:10.1021/cr0783479
Supplementary Data
Supplementary data features detailed experimental procedures, characterization data ( H, 13C and 19F NMR, FTIR, and
1
HRMS data), and copies of spectra is provided.
TETL-D-20-01402
Luzzio/Monsen
“
Chemoenzymatic route to stereodefined 2-(azidophenyl)oxazolines for click chemistry”
Highlights



Cyclization under Mild Conditions
Enzyme Hydrolysis under Aqueous Conditions
High ee’s

6
Luzzio, Monsen
Figures:
Scheme 1
O
R2
R2
R1
3
R P
O
O
N2
R3P
O
+
+
R3
R1
R3
N3
N
Scheme 1. Staudinger/aza-Wittig route to oxazolines.
Scheme 2
OH
BnO
BnO
a
BnO
BnO
b
BnO
BnO
O
N3
1
2
3
c
O
R
O
BnO
BnO
d
BnO
BnO
R
O
N
N3
8
9
1
, R= -C6H5 (55%)
, R= -4ClC6H4 (50%)
0, R= -CH2OC6H5 (81%)
4, R= -C6H5 (85%)
5, R= -4ClC6H4 (52%)
6, R= -CH2OC6H5 (73%)
7, R= -4NO2C6H4 (68%)
11, R= -4NO2C6H4 (94%)
Scheme 2. Preparation of oxazolines 8-11 from azidoesters 4-7.
Reagents/Conditions: (a) mCPBA/DCM/0 °C to rt/24 h, 80%. (b)
NaN
3
/DMF/100 °C, 24 h, 97%. (c) ROCl/Et
3
N
or
3
pyridine/DMAP/DCM/rt/16-48 h. (d) PPh /THF/rt to 40 °C/16 h.
Scheme 3

7
O
OH
OBn
OAc
OAc
a
BnO
BnO
b
BnO
N3
BnO
BnO
3
+
+
O
OBn
OBn
N3
N3
(2R, 3R)-12a
N3
(2S, 3S)-12b
1
2
(2R,3R)-3a
c, d
unhydrolyzed
OR
BnO
N3
OBn
(
(
2R,3R)-13a, R=-methoxy--(trifluoromethyl)phenylacetyl
2R,3R)-7a, R=4-nitrobenzoyl
Scheme 3. Pig liver esterase-mediated hydrolysis of azidoacetate 12
giving (2R,3R)-3a followed by Mosher ester derivatization and
acylation with 4-nitrobenzoyl chloride. Reagents/Conditions: (a)
Ac
2%.
acid/DCC/DCM/rt/48
2
O/pyridine/rt/1.5 h, 89%. (b) PLE/phosphate buffer/35 °C/7 days,
(c) R-(+)- -methoxy--(trifluoromethyl)phenylacetic
h, 61% (d) 4-nitrobenzoyl
4
chloride/pyridine/DMAP/DCM/rt/16 h, 97%.
Scheme 4
H
H
H
a
BnO
BnO
O
N
b, c
BnO
BnO
O
(2R,3R)-7a
NO2
N3
N
H
(4R,5R)-11a
(4R,5R)-14
H
H
O
N
N
N
BnO
BnO
d
N
F
(4R,5R)-15
Scheme 4. Conversion of 4-nitrobenzoyl ester (2R,3R)-7a to
oxazoline (4R,5R)-11 followed by azidation to give click partner
(
4R,5R)-14 and subsequent click reaction to afford (4R,5R)-15.
Reagents/Conditions: (a) PPh /THF/rt to 40 °C/16 h, 78%. (b)
Al(Hg)/THF/H O/rt/30 min. (c) NaNO / NaN /AcOH/H O/0 °C to
rt/1.5 h, 69% (two steps). (d) 4-
ethynylfluorobenzene/CuSO ·5H O/sodium
ascorbate/THF/H O/rt/16 h, 94%.
3
2
2
3
2
4
2
2
Reference 3 Figure
N
N
Ar
C6H4-4F
O
N
N
Ar
TETL-D-20-01402
Luzzio/Monsen
Abstract Graphic

8
H
H
H
H
OH
O
N
RO
O
N
N
RO
RO
RO
RO
R1
N
N
OR
N3
from pig liver esterase
R=benzyl
R =4-NO C H
F
(
R=benzyl)
R=benzyl
1
2
6
4