Modular synthesis of amine-functionalized oxazolines

Article abstract of DOI:10.1021/ol0264758

(matrix presented) Substituted oxazoline amines have been prepared in high yield from β-amino alcohols and Fmoc-protected α-amino acids using CCl₄, PPh₃, and HUnig's base in a one-pot procedure followed by base-mediated deprotection.

Full text of DOI:10.1021/ol0264758

ORGANIC
LETTERS
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002
Vol. 4, No. 20
399-3401
Modular Synthesis of
Amine-Functionalized Oxazolines
3
Sridhar Rajaram and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 S. 1400 East,
Salt Lake City, Utah 84112-8500
sigman@chem.utah.edu
Received July 8, 2002
ABSTRACT
4 3
Substituted oxazoline amines have been prepared in high yield from â-amino alcohols and Fmoc-protected r-amino acids using CCl , PPh ,
and H u1 nig’s base in a one-pot procedure followed by base-mediated deprotection.
1
The oxazoline scaffold is prevalent both in natural products
and ligands for asymmetric catalysis.2,3 Consequently, the
synthesis of oxazolines has generated intense interest among
pool, and (3) the pendant amine can be systematically
elaborated. Markedly, this scaffold is also present in biologi-
1
b-e
cally relevant natural products.
In this communication,
4
organic chemists. In asymmetric catalysis, bis(oxazolines)
have evolved as a “privileged” ligand structure, while other
structurally divergent oxazolines have received considerably
we report a one-pot, modular synthesis of the oxazoline
amine core from commercially available chiral building
blocks.
5
6
less attention. In an effort to explore new oxazoline ligand
The synthetic plan of the oxazoline amine reveals that
templates for catalytic enantioselective reactions, we have
targeted oxazoline amines (Figure 1). This oxazoline template
contains three noteworthy features: (1) introduction of
multiple chiral centers in which a variety of different
substituents can be integrated, (2) the building blocks are
commercially accessible with many available from the chiral
the oxazoline core can be synthesized by cyclic dehydration
of a â-hydroxyamide (Figure 1). This is the most common
method for oxazoline synthesis and is achieved by converting
4
the hydroxyl group into a good nucleofuge. The â-hy-
droxyamides can be accessed through amide bond formation
using commercially available â-amino alcohols and suitably
protected R-amino acids. A synthetically concise approach
(1) Some examples include: (a) Agrobactin: Peterson, T.; Neilands, J.
B. Tetrahedron Lett. 1979, 20, 4805. (b) Ascidiacyclamide: Hamamoto,
Y.; Endo, M.; Nakagawa, M.; Nakanishi, T.; Mizukawa, K. Chem. Commun.
1
983, 323. (c) Lissoclinamides: Hawkins, C. J.; Lavin, M. F.; Marshall,
K. A.; Brenk, A. L. v. d.; Watters, D. J. J. Med. Chem. 1990, 33, 1634. (d)
Westiellamide: Prinsep, M. R.; Moore, R. E.; Levine, I. A.; Patterson, G.
M. L. J. Nat. Prod. 1992, 55, 140. (e) Bistratamide D: Foster, M. P.;
Concepci o˘ n, G. P.; Caraan, G. B.; Ireland, C. M. J. Org. Chem. 1992, 57,
6
671. (f) Acinetobactin: Yamamoto, S.; Okujo, N.; Sakakibara, Y. Arch.
Microbiol. 1994, 162, 249. (g) Ceratospongamide: Tan, L. T.; Williamson,
R. T.; Gerwick, W. H.; Watts, K. S.; McGough, K.; Jacobs, R. J. Org.
Chem. 2000, 65, 419.
(
2) For a review of bis(oxazoline) ligands, see: Ghosh, A. K.;
Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1.
3) For an account of the use of Cu-bis(oxazoline) complexes in
asymmetric catalysis, see: Johnson, J. S.; Evans, D. A. Acc. Chem Res.
000, 33, 325.
(
Figure 1. Oxazoline amine synthetic plan.
2
1
0.1021/ol0264758 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

Table 1. One-Pot Synthesis of Protected Oxazoline Amines
can be realized by combining the amide-bond formation and
the cyclic dehydration in a single reaction pot. To effect this,
precise control of the nucleophilicity of the various reactive
groups has to be achieved.
maintain low concentrations of the chlorophosphonium salt.
At higher concentrations of the chlorophosphonium salt, the
hydroxyl group of the â-amino alcohol competes with the
carboxylate anion leading to the formation of acyl aziridines
and isomeric oxazolines. Application of the Vorbr u¨ ggen
procedure to the synthesis of oxazoline amines generates an
additional level of complexity. The protecting group on the
amino functionality of the R-amino acid must be stable to
the basic conditions of the reaction and cannot be cleaved
under acidic conditions since oxazolines are generally acid
sensitive.
A survey of the literature revealed that the largely under-
utilized procedure developed by Vorbr u¨ ggen and Krolik-
7
iewicz could be ideal. In this procedure, the acid and
â-amino alcohol are treated with CCl
generate the oxazoline in a single step. To prevent side
reactions, either the CCl or PPh is added over 3 h to
4 3
, PPh , and a base to
4
3
Preliminary experiments ruled out several protecting
groups. The triflouroacetamide protecting group led to
racemization of the R-amino acid under the reaction condi-
(
4) Recent examples include the following. (a) PPh3/DEAD: Roush, D.
M.; Patel, M. M. Synth. Commun. 1985, 15, 675. (b) Burgess reagent: Wipf,
P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907. (c) SOCl2: Gou, D.-M.;
Liu, Y.-C.; Chen. C. S. J. Org. Chem. 1993, 58, 1287. (d) Polymer-supported
Burgess reagent: Wipf, P.; Venkataraman, S. Tetrahedron Lett. 1996, 37,
8
tions. In contrast, the Cbz-, Boc-, and Alloc-protected
4
659. (e) TsCl: Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D.
R-amino acids all cyclized cleanly, but removal of these
M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541. (f)
DAST (diethylaminosulfur trifluoride): Phillips, A. J.; Uto, Y.; Wipf, P.;
Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165. (g) Vilsmeir
reagent: Wuts, P. G. M.; Northuis, J. M.; Kwan, T. A. J. Org. Chem. 2000,
9
protecting groups proved to be difficult. Therefore, we
redirected the effort toward a base-cleavable protecting
group, which might be stable under oxazoline cyclization
conditions. Fmoc offers the most convenient choice due to
commercial availability of diverse Fmoc R-amino acids and
a mild deprotection protocol. Modulating the basicity of the
reaction conditions rendered Fmoc-protected R-amino acids
6
5, 9223. (h) Polymer-supported TsCl: Pirrung, M. C.; Tumey, L. N. J.
Comb. Chem. 2000, 2, 675.
5) For a recent review, see: Braunstein, P.; Naud, F. Angew. Chem.,
Int. Ed. 2001, 40, 680 and references therein.
6) For the synthesis of oxazoline amines, see the following. (a)
Ascidiacyclamide: Hamada, Y.; Kato, S.; Shiori, T. Tetrahedron. Lett. 1985,
(
(
2
1
6, 3223. (b) Westiellamide: Wipf, P.; Miller, C. P. J. Am. Chem. Soc.
992, 114, 10975. (c) Lissoclinamide 7: Wipf, P.; Fritch, P. C. J. Am.
Chem. Soc. 1996, 115, 8449. (d) Bistratamide D: Downing, S. V.; Aguilar,
E.; Myers, A. I. J. Org. Chem. 1999, 64, 826.
(8) Benourgha, A.; Verducci, J.; Jacquier, R. Bull. Soc. Chim. Fr. 1995,
135, 824.
(9) Oxazolines with R ) Ph were destroyed during reductive removal
of the Cbz. Removal of Boc under acidic conditions led to decomposition.
Removal of Alloc with Pd(0) proceeded very slowly.
2
(
7) (a) Vorbr u¨ ggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9353.
b) For a recent application, see: Ousmer, M.; Braun, N. A.; Bavoux, C.;
Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534.
(
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Org. Lett., Vol. 4, No. 20, 2002

stable. The modifications include the following: (1) altering
the solvent from CH CN/pyridine to dichloromethane, (2)
substituting (iPr) NEt for pyridine and NEt , and (3) holding
the concentration <0.05 M.10
3
Table 2. Deprotection of Fmoc-oxazoline Amines
2
3
Using the modified conditions, we initially tested Fmoc-
(S)-phenylalanine and (1R-2S)-norephedrine in the oxazoline-
forming reaction. Gratifyingly, the corresponding oxazoline
was isolated in 92% yield after flash chromatography (Table
1, entry 1). Encouraged by this initial result, the scope of
the one-pot oxazoline synthesis was examined using various
â-amino alcohols and Fmoc-protected R-amino acids (Table
1
, entries 1-12). Using either enantiomer of the Fmoc-
protected R-amino acids (entries 1-2) or the â-amino alcohol
entries 5-6), the desired diastereomers are formed in
(
uniformly high yields. Large substituents are tolerated on
the R-amino acid to the extent that tert-leucine cyclizes
efficiently to the corresponding oxazoline in 78% yield (entry
With the scope of this procedure examined, the stage was
set for the crucial deprotection reaction. Trans-substituted
oxazolines are known to be especially acid sensitive and
3
). Primary and secondary alcohols on the â-amino alcohol
cyclize to provide the corresponding oxazolines in high yields
valinol, phenylglycinol, and norepheridine). Oxazoline
1a
therefore are difficult structures to access. To demonstrate
the efficacy of this procedure in accessing these structures,
oxazolines 3 and 6 were selected for deprotection (Table 2).
Two common deprotection protocols for Fmoc were used
in which oxazoline 3 was cleanly deprotected with 50%
diethylamine in methanol in quantitative yield and oxazoline
(
formation using secondary alcohols gives a single diastere-
omer with inversion at the alcohol center, consistent with
previously reported results.7 Other potentially useful ox-
azolines are prepared using this method, including pyridine-
a
6
was deprotected with 50% piperidine in methanol in
1
1
12
and phenol-substituted oxazolines (entries 13 and 14).
14
slightly reduced yield (85%) after chromatography.
Notably, the phenol does not need to be protected in the
oxazoline formation.7b
In conclusion, we have developed a concise, one-pot
procedure for the synthesis of protected oxazoline amines.
The reaction proceeds in good to excellent yields and uses
commercially available chiral building blocks. Significant
diversity can be readily integrated into the scaffold by control
of three stereocenters. The free oxazoline amine is prepared
in excellent yields by removal of the Fmoc protecting group
under mild conditions. Screening of oxazoline amines and
A concern with this method is the possibility of race-
mization of the chiral center on the R-amino acid during
activation for coupling. Racemization during coupling will
be reflected in formation of epimeric products. Use of Fmoc-
1
3
phenylglycine as a test substrate for this (entries 4 and 12)
1
afforded minimal epimeric product, as observed by H NMR
analysis (<10%). Importantly, no detectable racemization
of the other R-amino acids is observed.
15
derivatives for catalytic asymmetric reactions and applica-
tions of this method in target-oriented synthesis are currently
under investigation.
(
10) Low concentrations were necessary to control Fmoc decomposition
during the reaction.
11) For the recent use of this ligand class, see: (a) Zhang, Q.; Lu, X.;
Acknowledgment. We thank the National Science Foun-
dation for Support of this research through a CAREER award
to M.S.S. (CHE-0132905). We thank Ben Dible for prepara-
tion of 14 and for verifying the yield of 1.
(
Han, X. J. Org. Chem. 2001, 66, 7676. (b) Davenport, A. J.; Davies, D. L.;
Fawcett, J.; Garratt, S. A.; Russell, D. R. Dalton 2000, 23, 4432. (c) Zhang,
Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (d) Perch, N. S.; Pei, T.;
Widenhoefer, R. A. J. Org. Chem. 2000, 65, 3836. (e) Brunner, H.;
Obermann, U. Chem. Ber. 1989, 122, 499.
Supporting Information Available: Experimental pro-
1
(12) For the use of these ligands, see: (a) Sibi, M. P.; Sausker, J. B. J.
cedures, characterization, and H NMR spectral data. This
Am. Chem. Soc. 2002, 124, 984. (b) Zondervan, C.; Feringa, B. L.
Tetrahedron: Asymmetry 1996, 7, 1895. (c) Cozzi, P. G.; Gallo, E.; Floriani,
C.; Chiesi-Villa, A.; Rizzoli, C. Organometallics 1995, 14, 4994. (d) Cozzi,
P. G.; Gallo, E.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Inorg. Chem.
material is available free of charge via the Internet at
http://pubs.acs.org.
1
1
1
995, 34, 2921. (e) Yang, H.; Khan, M. A.; Nicholas, K. M. J. Mol. Catal.
994, 91, 319. (f) Yang, H.; Khan, M. A.; Nicholas, K. M. Organometallics
993, 12, 3485.
OL0264758
(14) Using diethylamine to deprotect oxazoline 6 was unreliable.
(15) For recent examples of the use of oxazoline amine cores in
asymmetric catalysis, see: (a) Pastor, I. M.; Adolfsson, H. Tetrahedron
Lett. 2002, 43, 1743. (b) Wipf, P.; Wang, X. Org. Lett. 2002, 4, 1197.
(13) Phenylglycine is often a test substrate for racemization in peptide
couplings; see: Bodanszky, M. Principles of Peptide Synthesis, 2nd ed.;
Springer-Verlag: Berlin, 1993.
Org. Lett., Vol. 4, No. 20, 2002
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