Preparation of Keto-Isoxazole Polyketide Synthons

Article abstract of DOI:10.1055/s-2003-42052

The Dess-Martin periodinane (DMP) oxidation of alcohols, proceeds in good to excellent yield in the presence of the isoxazole ring, and other nitrogen-containing functional groups. The DMP route allows for the preparation of highly branched polyketide syn

Full text of DOI:10.1055/s-2003-42052

LETTER
2213
Preparation of Keto-Isoxazole Polyketide Synthons
P
J
reparatio
a
n of
K
eto-I
r
soxazole
e
P
olyketide
d
S
ynthons K. Nelson, David J. Burkhart, Andrew McKenzie, Nicholas R. Natale*
3
01 Renfrew Hall, Department of Chemistry, University of Idaho, Moscow ID 83844-2343, USA
Fax +1(208)8856173; E-mail: nrnatale@uidaho.edu
Received 25 September 2002
isoxazoles to the ketones in the presence of oxazolines, we
observed b-elimination as the main isolable product in
low yield with chromium(VI) reagents.1 We had previ-
ously reported a comparative study of oxidizing agents for
isoxazoles,11 but in a recent study, had found that the
DMP gave superior yields in one case of selective oxida-
Abstract: The Dess–Martin periodinane (DMP) oxidation of alco-
hols, proceeds in good to excellent yield in the presence of the isox-
azole ring, and other nitrogen-containing functional groups. The
DMP route allows for the preparation of highly branched polyketide
synthetic equivalents.
0b
Key words: isoxazole, oxazoline, dihydropyridine, periodinane,
oxidation
12
tion of a primary alcohol to an aldehyde. The Dess–Mar-
tin periodinane (DMP) has found wide applicability in the
selective oxidation of functionally complex molecules,13
however, many of the examples which contain nitrogen
are either sterically hindered and/or N-protected with
electron withdrawing substituents.14 Selective oxidation
in the presence of aromatic heterocycles including ben-
zoxazoles, oxazoles, and benzthiazoles has also been re-
ported.15 Edwards has reported a systematic comparison
of DMP oxidation in the presence of benzoxazoles, and
found DMP to give superior yields to Swern, Collins, and
Pfitzner–Moffat oxidation methods.16 The mild condi-
tions for use of the DMP allow for some remarkable selec-
tivity.17 We therefore turned back to this long standing
problem, to examine the utility, scope and limitations.
The polyketides are a class of structurally diverse natural
products that include important therapeutic agents used
as antibacterials (erythromycin), immunosuppressants
(
FK506), cholesterol-lowering agents (lovastatin), and
1
others. Currently, there are about 7,000 identified
polyketides, but this may represent only a small part of
2
nature’s potential. DNA sequencing of genes encoding the
enzymes that produce modular polyketide synthases
(
PKSs) has unveiled the remarkably logical organization
of these multifunctional enzymes, and progress has been
made towards practical combinatorial biosynthesis tech-
3
nology – notably by Khosla’s group – that could equal
and perhaps exceed the diversity of polyketide structures The isoxazolyl alcohols used for this study were available
1
8
so far known in nature. Thus, the number of targets for from ongoing lateral metalation studies: Davis oxidation
biomimetic polyketide synthesis would logically be antic- for 1,5b aldehyde addition for 3 and 13, and epoxide
12
19
2
0
ipated to expand in the near future. Keto-isoxazoles have ring opening for 5 and 7. The results in Table 1 are rep-
been used in polyketide synthesis, exemplified by the resentative. The emerging trend observed to date is that
4
classic work of Harris. Our interest in synthetic method- the a-hydroxy compounds gave good yields, whereas, b-
ology leading to highly functionalized isoxazoles as and g-produced excellent yields after isolation and purifi-
5
,6
branched polyketide synthons, has compelled us to ex- cation. In addition to the isoxazole being tolerated under
amine a tandem lateral metalation/oxidation route to keto- the reaction conditions, esters, acetals and oxazolines also
isoxazoles. In the course of these studies not only have we survive unscathed. We found that superior results were
7
found that the Dess–Martin periodinane (DMP) is the obtained in the presence of oxazolines using buffered re-
method of choice for oxidation of carbinols in the pres- action conditions.
ence of the isoxazole, but we also have observed some in-
teresting selectivity, which we now report.
Birch pioneered the use of dihydropyridines as synthons
21
for 1,5-diketones, later this tactic was elegantly applied
2
2
Keto-isoxazoles have been prepared directly in low to by Danishefsky to steroid synthesis. Furthermore, there
modest yield by reaction of lithio-alkyl isoxazoles with have been several reports of carbocycles isolated from the
8
esters, or with acid chlorides in the presence of cerium Hantzsch dihydropyridine synthesis when N-substituted
9
23
trichloride. The latter method suffers from modest yields amines are employed. Having established the utility of
arising from by-products due to double addition of the nu- the DMP reagent for our isoxazole system, we were inter-
cleophile, and from the acidity of the b-keto methylene ested in conducting the oxidation in the presence of a di-
protons which unproductively protonates the lithio-alkyl hydropyridine group. However, in the event of a test
9
b
24
isoxazole. An alternative route would involve addition reaction with 4-phenyl-1,4-dihydropyridine (DHP, 9), a
of the isoxazole anion to an aldehyde, followed by oxida- 55% conversion to pyridine 10 was observed (Scheme 1).
1
0
tion. In previous studies, attempts to oxidize b-hydroxy
Intermolecular competition was performed using sec-phe-
nyl alcohol 11 and dihydropyridine 9 with 1.0 equivalent
of DMP. In the event, the alcohol 11 was oxidized in 91%
conversion to acetophenone (12), while only 9% of the
DHP 9 was oxidized to the pyridine 10 (Scheme 2).
SYNLETT 2003, No. 14, pp 2213–2215
0
6
.1
1
.2
0
0
3
Advanced online publication: 07.10.2003
DOI: 10.1055/s-2003-42052; Art ID: S05002ST
©
Georg Thieme Verlag Stuttgart · New York

2
214
J. K. Nelson et al.
LETTER
Table 1 Selective Oxidation of Isoxazole Carbinols with the Dess–
To confirm this selectivity, we next examined an intra-
molecular competition using one equivalent of the oxidant,
which after reaction for one hour produced the keto-isox-
azole-DHP 14 in 93% yield after isolation and purifica-
tion, with no detectable pyridine (Scheme 3). While
extended reaction times, and excess oxidizing agent, do
lead to over oxidation to the pyridine, careful attention to
stoichiometry, and direct monitoring of the reaction
progress by thin layer chromatography can produce this
remarkable selectivity.
Martin Periodinane25
Isoxazole carbinol
Keto-isoxazole
Yield
%)
(
6
0
OH
O
N
O
O N
CO2Et
CH3
CO2Et
CH3
C
C
Ph
Ph
O
O
CH2
CH2
CH3
CH3
O
O
CH3
CH3
1
2
OH
O
N
O
C
O
N
OH
O
C
97
86
O
N
O
N
DMP,
.05 equiv
CH3
CH3
1
CO2Et
CH3
CO2Et
CH3
Ph
Ph
Ph
CH2
CH3
Ph
CH2
CH3
O
O
EtO2C
CO2Et r.t., CH Cl2
EtO2C
CO2Et
2
2 h, 93 %
O
O
CH3
CH3
CH3
N
H
CH3
CH3
N
H
CH3
1
3
14
3
4
OH
O
C
O
N
O
N
Scheme 3
CH3
CH3
Ph
(CH2) 2
2
(CH ) 2
Ph
In conclusion, we have found that the DMP is the method
of choice for the oxidation of a-, b- and g-hydroxy isox-
azoles, with none of the complications of elimination,
which we previously observed. Furthermore, other basic
functional groups such as oxazolines and, amazingly, 4-
aryl-1,4-dihydropyridines are oxidized more slowly than
carbinols, permitting selective reactions.
O
N
O
N
CH3
CH3
CH3
O
CH3
5
6
OH
O
C
78
N
O
N
CH3
CH3
CH3
(CH2) 2
2
(CH ) 2
CH3
Acknowledgment
O
N
O
N
The authors thank the National Institute of Neurological Disease
and Stroke for Grant 2R15-NS38444. JKN and AM acknowledge
the Malcolm and Carol Renfrew Scholarship Endowment, Univer-
sity of Idaho. AM was supported in part by the NSF-Idaho EPSCoR
Program and by the National Science Foundation under award num-
ber EPS-0132626.
CH3
CH3
CH3
CH3
7
8
References
DMP, 1.8 equiv
r.t., CH Cl
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(2) O’Hagan, D. The Polyketide Metabolites; E. Horwood: New
York, 1991.
EtO2C
CO2Et
CH3
EtO2C
CO2Et
CH3
2
2
2
h, 55 %
(
3) (a) Kao, C. M.; Luo, G.; Katz, L.; Cane, D. E.; Khosla, C. J.
Am. Chem. Soc. 1994, 116, 11612. (b) Xue, Q.; Ashley, G.;
Hutchinson, C. R.; Santi, D. V. Proc. Nat. Acad. Sci., U.S.A.
1999, 96, 11740.
CH3
N
H
N
CH3
9
10
(
4) Gilbreath, S. G.; Harris, C. M.; Harris, T. M. J. Am. Chem.
Soc. 1988, 110, 6172.
Scheme 1
(5) (a) Natale, N. R.; Mirzaei, Y. R. Org. Prep. Proced., Int.
1993, 25, 515. (b) Natale, N. R.; McKenna, J. I.; Niou, C.-S.;
Borth, M.; Hope, H. J. Org. Chem. 1985, 50, 5660.
6) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates in Organic Synthesis; VCH Publishers:
(
OH
O
DMP, 1.05 equiv
r.t., CH Cl
Weinheim, 1988. (b) Jones, R. C. F.; Bhalay, G.; Carter, P.
A. J. Chem. Soc., Perkin Trans. 1 1993, 1715.
CH3
CH3
+
9
+ 10, 9%
2
2
(
(
7) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
8) (a) Kashima, C.; Yamamoto, Y.; Tsuda, Y. Bull. Chem. Soc.
Jpn. 1976, 49, 2254. (b) Alreja, B. D.; Kattige, L. S.; Lal, B.;
de Souza, N. J. Heterocycles 1986, 24, 1637. (c) Alberola,
A.; Serrano, A. P.; Rodriquez, M.; Orozco, C. Heterocycles
1
1
12, 91%
2
h
Scheme 2
1989, 29, 667.
Synlett 2003, No. 14, 2213–2215 © Thieme Stuttgart · New York

LETTER
9) (a) Natale, N. R.; Yocklovich, S. G.; Mallet, B. M.
Preparation of Keto-Isoxazole Polyketide Synthons
2215
(
J = 11 Hz, 2 H), 4.19 (s, 2 H), 4.36 (q, 2 H), 7.16–7.27 (m, 5
1
3
Heterocycles 1986, 24, 2178. (b) Mallett, B. M. M.S. Thesis;
University of Idaho: Idaho, 1988.
H). C NMR: d = 14.3, 22.1, 22.7, 29.2, 49.2, 63.4, 72.3,
72.8, 96.3, 122.1, 128.1, 129.4, 130.3, 132.2, 157.8, 162.1,
163.9, 188.2. Accurate Mass for C H NO : calcd
(10) (a) Nadelson, J. US Patent, 4,122,182, 1979; Chem. Abstr.
2
1
25
6
1979, 90, 203873t. (b) Borth, M. B. M.S. Thesis; University
387.1682. Found: 387.1691.
of Idaho: Idaho, 1987.
3-Isoxazolecarboxylic Acid 5-[(2,2-Ketophenyl) Ethyl]-
(
(
(
11) Bowles, K. D.; Quincy, D. A.; McKenna, J. I.; Natale, N. R.
4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl Ester (4). Yield
96%, clear solid. H NMR: d = 0.67 (s, 3 H), 1.09 (s, 3 H),
1
J. Chem. Ed. 1986, 358.
12) Burkhart, D. J.; Twamley, B.; Natale, N. R. Tetrahedron
Lett. 2001, 42, 8415.
13) Boeckman, R. J. In Encyclopedia of Reagents for Organic
Synthesis, Vol. 7; Paquette, L. A., Ed.; Wiley: New York,
1.33 (t, J = 7.2 Hz, 3 H), 1.61 (s, 3 H), 3.31 (dd, J = 10.8 Hz,
4 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.51 (s, 2 H), 7.45 (m, 2 H),
1
3
7.57 (m, 1 H), 7.82, (m, 2 H). C NMR: d = 14.1, 21.6, 22.5,
29.3, 29.6, 34.6, 62.5, 71.8, 96.3, 115.2, 125.5, 128.1, 128.4,
143.0, 156.5, 161.0, 168.6, 197.6. Anal. Calcd for
1995, 4982.
(
(
14) (a) Martin, S. F.; Hida, T.; Kym, P. R.; Loft, M.; Hodgson,
A. J. Am. Chem Soc. 1997, 119, 3193. (b) Cao, B.; Park, H.;
Joullie, M. M. J. Am. Chem Soc. 2002, 124, 520.
15) (a) Edwards, P. D.; Wolanin, D. J.; Andisik, D. W.; Daivs,
M. W. J. Med. Chem. 1995, 38, 76. (b) Constanzo, M. J.;
Maryanoff, B. E.; Hecker, L. R.; Schott, M. R.; Yabut, S. C.;
Zhang, H.-C.; Andradra-Gordon, P.; Kauffman, J. A.;
Lewis, J. M.; Krishnan, R.; Tulinsky, A. J. Med. Chem.
C H NO : C, 65.10; H, 6.50; N, 3.62. Found: C, 64.77; H,
6.38; N, 3.69.
2
1
25
6
3-[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-
methylisoxazol-5-yl]-1-phenylpropan-1-one (6).
Isoxazolyl alcohol 5 (420 mg, 1.35 mmol) was placed in a
dry 50 mL round bottom flask and taken up in 20 mL freshly
distilled CH Cl . Dry pyridine (0.80 mL, 9.9 mmol) was
2
2
added to the reaction flask via syringe. A second flask was
charged with 10 mL CH Cl to which was added 1.5 equiv
1996, 39, 3039.
2
2
(
(
16) Edwards, P. D.; Zottola, M. A.; Davis, M.; Williams, J.;
Tuthill, P. A. J. Med. Chem. 1995, 38, 3972.
17) Williams, R. M.; Rollins, S. B.; Judd, T. C. Tetrahedron
DMP (880 mg, 2.1 mmol). Flask 2 was cannulated into flask
1 dropwise over 2 min. The reaction was monitored by TLC
until no starting material remained (ca 2 h), at which time 10
mL each of sat. Na S O and NaHCO solutions were added
2000, 56, 521.
2
2
3
3
(
(
18) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.
19) Natale, N. R.; Rogers, M. E.; Staples, R.; Triggle, D. J.;
Rutledge, A. J. Med. Chem. 1999, 42, 3087.
to the reaction flask. The reaction mixture was stirred
vigorously until phases became homogenous (about 15 min).
After extraction with Et O (3 × 15 mL), the combined
2
(
20) Smith, M. P. Ph.D. Dissertation; University of Idaho: Idaho,
organic layers were washed with 30 mL sat. NaCl solution,
1993.
then dried over MgSO , filtered, concentrated and purified
4
(
(
21) Birch, A. J. J. Chem. Soc. 1947, 1270.
22) Danishefsky, S.; Cain, P. J. Am. Chem. Soc. 1976, 98, 4975;
and references cited therein.
by flash chromatography (1:1 petroleum ether:EtOAc) to
produce compound 6 as a yellow solid (360 mg, 86%). If run
without pyridine as a buffer, the yield was much lower (268
1
(23) (a) Natale, N. R.; Hope, H. J. Heterocycl. Chem. 1986, 23,
mg, 39%). H NMR (300 MHz, CDCl ): d = 1.32 (s, 3 H),
3
711. (b) Kukla, M. J.; Breslin, H. J.; Gill, A. J. Med. Chem.
2.44 (s, 3 H), 3.46 (m, 4 H), 3.99 (s, 2 H), 7.47–8.00 (m, 5
1
3
1990, 33, 223. (c) Gordeev, M. F.; Patel, D. V.; Gordon, E.
H). C NMR (500 MHz, CDCl ): d = 197.8, 173.7, 159.8,
155.7, 136.4, 133.4, 128.7, 128.1, 106.0, 78.4, 67.5, 35.7,
28.5, 21.9, 11.8. Anal. Calcd for C H N O : C, 69.21; H,
3
M. J. Org. Chem. 1996, 61, 924.
(
(
24) Boecker, R. H.; Guengerich, F. P. J. Med. Chem. 1986, 29,
1
8
20
2
3
1596; and references cited therein.
6.45; N, 8.97. Found: C, 69.01; H, 6.57; N, 8.80.
4-[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-
methylisoxazol-5-yl]butan-2-one (8). Prepared from
isoxazolyl alcohol 7 to produce 8 as a golden oil (350 mg,
25) General Procedure for the Dess–Martin Oxidation of
Isoxazolyl Alcohols:
To an oven dried round bottom flask (50mL) was added 2.3
g (11.5 mmol) of the isoxazole alcohol and a magnetic stir
78%). If run without pyridine as buffer, the yield was much
1
bar, under a N (g)atmosphere. An amount of 40 mL of
lower (279 mg, 49%). H NMR (300 MHz, CDCl ): d = 1.31
2
3
freshly distilled CH Cl were added and the solution stirred
(s, 3 H), 2.18 (s, 3 H), 2.41 (s, 3 H), 2.88 (t, J = 7.6 Hz, 2 H),
3.27 (t, J = 7.6 Hz, 2 H), 3.97 (s, 2 H). C NMR (500 MHz,
2
2
1
3
until the isoxazole alcohol completely dissolved. 4.87 g (1.0
equiv) of Dess–Martin periodinane were added in one
portion and the solution stirred for 2–3 h as the reaction
progress was monitored by thin layer chromatography. Upon
depletion of the starting alcohol the reaction was
CDCl ): d = 206.2, 173.4, 159.7, 155.6, 105.8, 78.4, 67.5,
3
40.2, 29.8, 28.5, 21.4, 11.8. Anal. Calcd for C H N O : C,
1
3
18
2
3
62.38; H, 7.25; N, 11.19. Found: C, 61.54; H, 7.29; N, 10.83.
Diethyl 2,6-Dimethyl-4-[3-methyl-5-(2-oxo-2-
concentrated under vacuum and diluted with diethyl ether
phenylethyl)isoxazol-4-yl]-1,4-dihydropyridine-3,5-
dicarboxylate (14). Prepared from IDHP alcohol 13 to
(100 mL). The periodinane byproduct, which precipitates
was then filtered and the diethyl ether solution combined
produce compound 14 as a pale yellow solid (970 mg, 97%).
1
with 25 mL sat. NaHCO , and 25 mL of sat. sodium sulfide
H NMR (300 MHz, CDCl ): d = 1.13 (t, J = 7.1 Hz, 6 H),
3
3
in a 250 mL flask. The biphasic mixture was stirred
vigorously for 15 min and then transferred to a separatory
funnel. The organic phase was separated, washed with brine
2.12 (s, 6 H), 2.27 (s, 3 H), 4.03 (m, 4 H), 4.30 (s, 2 H), 4.86
1
3
(s, 1 H), 5.51 (s, 1 H), 7.37–7.90 (m, 5 H). C NMR (500
MHz, CDCl ): d = 193.7, 167.6, 163.2, 160.3, 144.0, 136.6,
3
(
25 mL), dried with anhyd Na SO , and concentrated. Purity
133.8, 129.1, 128.7, 122.7, 101.9, 60.4, 37.1, 29.6, 19.8,
14.8, 10.6. Anal. Calcd for C H N O : C, 66.36; H, 6.24;
2
4
1
was determined by H NMR and the compounds purified by
column chromatography (hexanes:EtOAc) on silica gel.
Final compounds were fully characterized by H NMR, 13C
NMR, mass spectrometry, and elemental analysis.
2
5
28
2
6
N, 6.19. Found: C, 65.98; H, 6.43; N, 6.19.
1
3-Isoxazolecarboxylic Acid 5-(2-Phenyl-1-keto-ethyl)-4-
(
7
1
2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl Ester (2). Yield
4%, colorless oil. H NMR: d = 0.38 (s, 3 H), 1.02 (s, 3 H),
.33 (t, 3 H), 1.66 (s, 3 H), 2.84 (d, J = 11 Hz, 2 H), 3.12 (d,
1
Synlett 2003, No. 14, 2213–2215 © Thieme Stuttgart · New York