Synthesis of tert-alkyl amino hydroxy carboxylic esters via an intermodular ene-type reaction of oxazolones and enol ethers

Article abstract of DOI:10.1021/ol702941f

terf-Alkyl amino hydroxy carboxylic acids are abundantly present within the structure of many biologically active natural products. We describe herein the synthesis of these substrates using an oxazolone-mediated ene-type reaction with enol ethers followed by NaBH₄ reduction of the intermediate oxazolone.

Full text of DOI:10.1021/ol702941f

ORGANIC
LETTERS
2008
Vol. 10, No. 5
825-828
Synthesis of tert-Alkyl Amino Hydroxy
Carboxylic Esters via an Intermolecular
Ene-Type Reaction of Oxazolones and
Enol Ethers
Robert A. Mosey,† Jason S. Fisk,† Timothy L. Friebe,‡ and Jetze J. Tepe*,†
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824,
and Department of Chemistry, Eastern Michigan UniVersity, Ypsilanti, Michigan 48197
tepe@chemistry.msu.edu
Received December 5, 2007
ABSTRACT
tert-Alkyl amino hydroxy carboxylic acids are abundantly present within the structure of many biologically active natural products. We describe
herein the synthesis of these substrates using an oxazolone-mediated ene-type reaction with enol ethers followed by NaBH4 reduction of the
intermediate oxazolone.
Highly substituted amino hydroxy carboxylic acids are struc-
tural features present in numerous microorganism metabolites
including the sphingofungins, lactacystins, altemicidin, ox-
azolomycins, and many others (Figure 1).1 The diverse and
depth biological evaluations.2a,3a,b,5a,6,7 Construction of the
densely functionalized quaternary carbon center found within
these molecules has proven to be
a
significant
(1) For reviews on tert-alkyl amino hydroxy carboxylic acids, see: (a)
Kang, S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Chem. ReV. 2005, 105,
4537. (b) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127.
(2) For a review on syntheses and biological activities of sphingofungins,
see: (a) Byun, H.-S.; Lu, X.; Bittman, R. Synthesis 2006, 15, 2447. For a
recent synthesis of sphingofungin F, also see: (b) Li, M.; Wu, A. Synlett
2006, 18, 2985.
(3) For reviews on syntheses and biological activities of lactacystin and
omuralide, see: (a) Corey, E. J.; Li, W.-D. Z. Chem. Pharm. Bull. 1999,
47, 1. (b) Masse, C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org.
Chem. 2000, 2513. For other syntheses, see: (c) Green, M. P.; Prodger, J.
C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609. (d) Brennan, C. J.;
Pattenden, G.; Rescourio, G. Tetrahedron Lett. 2003, 44, 8757. (e) Donohoe,
T. J.; Sintim, H. O.; Sisangia, L.; Harling, J. D. Angew. Chem., Int. Ed.
2004, 43, 2293. (f) Ooi, H.; Ishibashi, N.; Iwabuchi, Y.; Ishihara, J.;
Hatakeyama, S. J. Org. Chem. 2004, 69, 7765. (g) Balskus, E. P.; Jacobsen,
E. N. J. Am. Chem. Soc. 2006, 128, 6810. (h) Hayes, C. J.; Sherlock, A.
E.; Selby, M. D. Org. Biomol. Chem. 2006, 4, 193. (i) Fukuda, N.; Sasaki,
K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki, M. J. Org. Chem. 2006, 71,
1220. (j) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9,
3631. (k) Yoon, C. H.; Flanigan, D. L.; Yoo, K. S.; Jung, K. W. Eur. J.
Org. Chem. 2007, 37.
Figure 1. Natural tert-alkyl amino hydroxy carboxylic acids.
(4) For a synthesis of altemicidin, see: Kende, A. S.; Liu, K.; Jos Brands,
K. M. J. Am. Chem. Soc. 1995, 117, 10597.
(5) For a review of syntheses and biological activities of oxazolomycins,
see: (a) Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z. Curr.
Drug DiscoVery Technol. 2004, 1, 181. For a recent synthesis of neoox-
azolomycin, also see: (b) Onyango, E. O.; Tsurumoto, J.; Imai, N.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2007,
46, 6703.
potent biological activity of these metabolites has stimulated
many researchers to pursue their total syntheses2-5 and in-
† Michigan State University.
‡ Eastern Michigan University.
10.1021/ol702941f CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

synthetic challenge and has been the focus of many research
groups.8-10
Recently, we reported an intermolecular ene-type reaction
utilizing oxazolones (also referred to as azlactones) and enol
ethers via its oxazole tautomer (Figure 2).11 The reaction
of 2-phenyl-4-carbomethoxy-5-oxazolone and tert-butyl vinyl
ether was performed in various solvents, and it was found
that the use of less polar solvents such as benzene not only
provided stereoselectivity but also decreased the rate of
reaction in most cases (Table 1, conditions 1-3).16 Upon
Table 1. Catalysis of Ene-Type Reaction Using Brønsted
Acids
Figure 2. Intermolecular ene reaction utilizing oxazolones and enol
ethers followed by reduction.
timeb
solvent (h) A/Bc yieldd
%
results in the formation of a highly functionalized quaternary
center as a pivotal intermediate for the synthesis of R,R-
disubstituted amino acids.12 Reduction of the intermediate
oxazolone ester products with sodium borohydride13-15
results in the formation of quaternary nonproteinogenic
amino esters, ideally functionalized for the synthesis of many
of these biologically interesting metabolites. Herein, we
report the application of our ene-type methodology of
oxazolones toward the synthesis of tert-alkyl amino hydroxy
carboxylic esters along with additional insight into the
reaction’s mechanism.
During our previous studies, we observed the formation
of quaternary oxazolones using these ene-type reactions and
found the reactions to proceed with little or no diastereo-
selectivity.11 In an effort to make this synthetic approach
more broadly applicable, we investigated several reaction
conditions to improve the diastereoselectivity. The reaction
conditions
catalyst
1
2
3
4
5
6e
none
none
none
CH3CN
CH2Cl2
3
1
50:50 90
55:45 91
benzene 36 67:33 90
3,5-dinitrobenzoic acid benzene 16 70:30 90
diphenyl phosphate benzene 75:25 90
3
(R)-(-)-1,1′-binaphthyl- benzene 13 79:21 90
2,2′-diyl hydrogen-
phosphate
7
8
9
10
11
12
13
CSA
TFA
benzene
1
74:26 83
benzene 48 67:33 81
benzene 48 67:33 61
Ti(OiPr)4
Yb(OTf)3
TMSOTf
Zn(OTf)2
Cu(OTf)2
benzene 48
benzene 48
0
0
benzene 48 52:48 24
benzene 48
0
a Reaction conditions: 2-phenyl-4-carbomethoxy-5-oxazolone (0.5 mmol),
tert-butyl vinyl ether (0.7 mmol), catalyst (10 mol %), solvent (20 mL), rt.
b Time is based on the completion of the ene-type reaction. c Ratios based
on 1H NMR integration of both the oxazolone intermediate and product.
d Yield of isolated product. e Low solubility of catalyst attributed to increase
in reaction time and selectivity.
(6) For biological studies of lactacystin, see: (a) Fenteany, G.; Standaert,
R. F.; Lane, W. S.; Choi, S.; Corey, E. J.; Schreiber, S. L. Science 1995,
268, 726. (b) Borissenko, L.; Groll, M. Chem. ReV. 2007, 107, 687. (c)
Powers, J. C.; Asgian, J. L.; Ekici, O. D.; James, K. E. Chem. ReV. 2002,
102, 4639.
(7) For biological studies of altemicidins and analogues, see: (a)
Takahashi, A.; Kurasawa, S.; Ikeda, D.; Okami, Y.; Takeuchi, T. J. Antibiot.
1989, 42, 1556. (b) Banwell, M. G.; Crasto, C. F.; Easton, C. J.; Forrest,
A. K.; Karoli, T.; March, D. R.; Mensah, L.; Nairn, M. R.; O’Hanlon, P.
J.; Oldham, M. D.; Yue, W. Bioorg. Med. Chem. Lett. 2000, 10, 2263.
(8) Bennett, N. J.; Prodger, J. C.; Pattenden, G. Tetrahedron 2007, 63,
6216.
(9) Mohapatra, D. K.; Mondal, D.; Gonnade, R. G.; Chorghade, M. S.;
Gurjar, M. K. Tetrahedron Lett. 2006, 47, 6031.
(10) Donohoe, T. J.; Chiu, J. Y. K.; Thomas, R. E. Org. Lett. 2007, 9,
421.
(11) Fisk, J. S.; Tepe, J. J. J. Am. Chem. Soc. 2007, 129, 3058.
(12) For reviews of R,R-disubstituted amino acids, see: (a) Cativiela,
C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517. (b)
Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11,
645.
(13) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532.
(14) Tice, C. M.; Hormann, R. E.; Thompson, C. S.; Friz, J. L.;
Cavanaugh, C. K.; Michelotti, E. L.; Garcia, J.; Nicolas, E.; Albericio, F.
Bioorg. Med. Chem. Lett. 2003, 13, 475.
screening a variety of potential protic catalysts, we found
that a substoichiometric amount of diphenyl phosphate
improved both the reaction rate and diastereoselectivity
(Table 1, condition 5). Brønsted acids less acidic than
diphenyl phosphate also improved the diastereoselectivity
of the reaction but did little toward increasing the reaction
rate (Table 1, condition 4). The use of more acidic Brønsted
acids resulted in lower yields of desired product, presumably
due to enol ether decomposition (Table 1, conditions 7 and
8). Chiral Brønsted acid (R)-(-)-1,1′-binaphthyl-2,2′-diyl
hydrogenphosphate provided the highest diastereoselectivity
(79:21) of the catalysts investigated but provided no observ-
able enantioselectivity as determined by chiral HPLC (Table
(15) Garcia, J.; Mata, E. G.; Tice, C. M.; Hormann, R. E.; Nicolas, E.;
Albericio, F.; Michelotti, E. L. J. Comb. Chem. 2005, 7, 843.
(16) See the Supporting Information for additional details.
826
Org. Lett., Vol. 10, No. 5, 2008

1, condition 6). Several additional Lewis acids were screened,
resulting in little or no product formation and low diaste-
reoselectivity (Table 1, conditions 9-13). The significant
rate enhancement found when using Brønsted acids and not
other Lewis acids is suggestive that the catalyst protonates
the enol ether forming an oxonium ion, although coordination
to the oxazolone substrate cannot be dismissed. The con-
ditions used in Table 1 produced the same major diastere-
omer whose crystal structure is depicted in Figure 3.
Table 2. Two Step Synthesis of Quaternary Amino Hydroxy
Carboxylic Esters.
Figure 3. X-ray crystal structure of the major diastereomer of entry
1, Table 2.
Utilizing conditions optimized for diastereoselectivity, the
scope of the reaction was further explored. Exposing
2-phenyl-4-carbomethoxy-5-oxazolone to various vinyl enol
ethers in the presence of 10% of diphenyl phosphate resulted
in high yields of the desired products after sodium borohy-
dride reduction (Table 2). The tert-butyl and benzyl protect-
ing groups yielded better diastereoselectivity than the ethyl
protecting group (Table 2, entries 1-3), which indicates that
enol ethers containing more sterically demanding oxygen
protecting groups generally produce better diastereoselec-
tivities. The less reactive higher substituted enol ethers gave
lower yields and required the use of heat (Table 2, entries
4-6) to produce the desired products in good yields. Both
butoxyethyne and 2-methoxypropene (Table 2, entries 7 and
8, respectively) also provided reasonable yields of products.
The role of the 2-position of the oxazolone scaffold was
investigated for its effect on reactivity and selectivity (Table
3). Several oxazolones with substitutions in the 2-position
were prepared and reacted with tert-butyl vinyl ether in the
presence of diphenyl phosphate. Oxazolones with aryl
substituents gave high yields, and erosion of diastereoselec-
tivity was observed as electron deficiency increased (Table
3, entries 9-11). Selectivity was all but lost when oxazolones
containing alkyl substituents were used (Table 3, entries 12
and 13).
a Reaction conditions: 2-phenyl-4-carbomethoxy-5-oxazolone (0.5 mmol),
enol ether (0.7 mmol), diphenyl phosphate (10 mol %), benzene (20 mL),
rt. b Ratios based on 1H NMR integration of both the oxazolone intermediate
and product. c Yield of isolated product. d CH2Cl2 used as solvent. e No
catalyst used.
ether in the absence of catalyst (Scheme 1). Analysis of the
crude reaction mixtures revealed an O-alkylated oxazole
intermediate in the reaction involving 2-ethyl-4-carbomethoxy-
5-oxazolone, while the 2-phenyl-4-carbomethoxy-5-oxazolo-
Table 3. Alkylation of Various Oxazolones Using tert-Butyl
Vinyl Ether
entry
R
A/Bb
% yieldc
9
10
11
12
13
Ph
75:25
74:26
67:33
43:57
52:48
90
88
81
50
58
4-MeO-Ph
4-CF3-Ph
Et
The decrease in both stereoselectivity and yield in the
reactions involving 2-alkyloxazolones as compared to those
involving 2-aryloxazolones may potentially be explained by
a difference in mechanism. To investigate this phenomenon,
we treated both 2-ethyl-4-carbomethoxy-5-oxazolone and
2-phenyl-4-carbomethoxy-5-oxazolone with tert-butyl vinyl
Bn
a Reaction conditions: oxazolone (0.5 mmol), tert-butyl vinyl ether (0.7
mmol), diphenyl phosphate (10 mol %), benzene (20 mL), rt. b Ratios based
on 1H NMR integration of both the oxazolone intermediate and product.
c Yield of isolated product.
Org. Lett., Vol. 10, No. 5, 2008
827

significant rate enhancement found using only Brønsted
acids, we hypothesize that the acidic proton of the oxazo-
lone19 in the absence of catalyst, or in this case the catalyst
itself, protonates the enol ether, forming an oxonium ion.
However, coordination of the catalyst to the oxazolone
substrate, as typically seen with oxazolones, cannot be
dismissed.20 Therefore, it is likely that the mechanistic nature
of these ene-type reactions is highly dependent on both the
oxazolone and enol ether being used in the reaction. Further
studies to characterize the mechanistic details of these new
ene-type reactions are currently under examination in our
laboratories.
Scheme 1. Mechanistic Investigation Using Various
Oxazolones
In summary, we report here the efficient synthesis of tert-
alkyl amino hydroxy carboxylic esters via a two-step
sequence using oxazolones with enol ethers or alkoxy ethynes
followed by hydride reduction. Additionally, the mechanistic
nature of these ene-type reactions using oxazolones and enol
ethers appears to be substrate dependent. The role of the
catalyst, asymmetric version of these reactions, and mecha-
nistic effect of substrate variation are under further investiga-
tion in our laboratory.
ne reaction produced only C-alkylated product. Upon stand-
ing, we observed the conversion of the O-alkylated
intermediate to the C-alkylated product along with some
degradation of the enol ether component. This observation
infers that these ene-type reactions might proceed through
an O to C migration,13,17,18 although this was never observed
for any of the 2-aryl-substituted oxazolones.
The possibility of these reactions proceeding via an O to
C migration contrasts our original hypothesis that they occur
via a stereospecific-concerted mechanism.11 To provide
additional insight into the nature of the mechanism, we
conducted a deuterium study using a deuterium-labeled
alkoxyalkyne and 2-phenyl-4-carbomethoxy-5-oxazolone
(Scheme 2). The reaction resulted in a 1:1 mixture of
Acknowledgment. We gratefully acknowledge the fi-
nancial support provided by the American Cancer Society
and Michigan State University and Dr. Richard J. Staples
of Michigan State University for helpful discussions and
X-ray crystallography.
Supporting Information Available: Experimental pro-
cedures, IR and 1H and 13C NMR data for all new
compounds, and X-ray structures for entry 1, Table 2 (major
diastereomer), and entry 12, Table 3 (major diastereomer).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 2. Labeling Studies Using Deuterium-Labeled
Alkoxyalkyne
OL702941F
(17) Steglich, W.; Ho¨fle, G. Tetrahedron Lett. 1970, 4727.
(18) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.
(19) Goodman, M.; Levine, L. J. Am. Chem. Soc. 1964, 86, 2918.
(20) (a) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. ReV. 2007, 36,
1432. (b) Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc.
2007, 129, 12638.
diastereomers, indicating that these ene-type reactions may
also proceed via a stepwise mechanism. Supported by the
828
Org. Lett., Vol. 10, No. 5, 2008