New synthetic technology for the synthesis of aryl ethers: Construction of C-O-D and D-O-E ring model systems of vancomycin

Full text of DOI:10.1021/ja9636350

J. Am. Chem. Soc. 1997, 119, 3421-3422
3421
Scheme 1. Strategy and Presumed Mechanistic Rationale
for the Triazene Based Synthesis of Diaryl Ethers
New Synthetic Technology for the Synthesis of Aryl
Ethers: Construction of C-O-D and D-O-E Ring
Model Systems of Vancomycin
K. C. Nicolaou,* C. N. C. Boddy, S. Natarajan, T.-Y. Yue,
H. Li, S. Bra¨se, and J. M. Ramanjulu
Department of Chemistry and The Skaggs Institute for
Chemical Biology, The Scripps Research Institute
10550 North Torrey Pines, La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California San Diego
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed October 18, 1996
The aryl ether linkage is frequently encountered both in
natural products and designed molecules. Much chemistry1 has
recently been extended for the construction of such systems,
particularly as they relate to vancomycin type structures.2 These
glycopeptide antibiotics are becoming increasingly important
as clinical agents against a growing number of drug resistant
bacterial strains and have been the target of synthesis by several
groups.3 Although several cyclic diaryl ether systems related
to vancomycin have been reported, a number of challenges still
remain in this field. In this paper we report a new method for
the construction of aryl ethers and its application to the synthesis
of vancomycin (1) model D-O-E (9) and C-O-D (15) ring
systems.
II through coordination with a suitable metal counterion5 (e.g.,
Cu(I), see structure III, Scheme 1). This scenario was expected
to lead to the desired diaryl ether V via intermediate IV.
Triazenes are easily prepared and can be converted to a variety
of functional groups such as halides, amines, and phenols.6
As demonstrated in Table 1, the triazene approach to aryl
ethers is highly efficient and quite general. After considerable
experimentation it was discovered that o-haloaryl triazenes react
smoothly with phenols in the presence of K2CO3 and CuBr‚-
Me2S in MeCN-pyr (ca. 5:1) at 80 °C to afford, in good to
excellent yields, diaryl ethers and triaryl bis-ethers. It is
interesting to note that 2,6-disubstituted triazenes (entries 6-13,
Table 1) react faster, and often more efficiently, than the corre-
sponding monosubstituted aryl triazenes (entries 1-5, Scheme
1). This observation, which is in accord with the proposed
mechanism, can be explained by assuming a preference for
conformation I′ for the o-monosubstituted aryl triazenes,7 an
option not available to the 2,6-disubstituted aryl triazenes. From
among the halides, iodides and bromides exhibited the best
mobilities for this reaction. Thiophenols also enter this process
to produce triaryl bis-thioethers (e.g., entry 13, Table 1).
The D-O-E vancomycin model system 9 (Scheme 2) was
successfully synthesized as follows. p-Aminobenzoic acid was
converted to the dibromo derivative 2 by bromination of its
methyl ester (>95%). Reduction of 2 with lithium aluminium
hydride gave alcohol 3 (93%) which was subjected to diazoti-
zation8 followed by quenching of the diazonium salt with
pyrrolidine to give triazene 4 in 73% overall yield. Conversion
of 4 to the corresponding azide via a Mitsunobu displacement9
with Ph3P, diethyl diazodicarboxylate (DEAD), and DPPA (5,
82%) was followed by reduction to an amino group10 with Ph3P
and H2O (6, 80%). Coupling of triazene 6 with dipeptide 711
with EDC and HOBt gave tripeptide 8 (45%), setting the stage
for the macrocyclization reaction. Treatment of precursor 8 with
CuBr‚Me2S (2.5 equiv), K2CO3 (2.5 equiv), and pyridine (3.0
The design of this new reaction was based on the mechanistic
rationale shown in Scheme 1. A triazene unit4 was, thus,
strategically placed ortho to a leaving group on the aromatic
nucleus of substrate I to serve both as a potential “electron sink”
and to attract the attacking nucleophilic species derived from
(1) (a) Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem.
ReV. 1995, 95, 2135 and references therein. (b) Glycopeptide Antibiotics.
Nagarajan, R., Ed.; Dekker: New York, 1994.
(2) (a) McCormick, M. H.; Stark, W. M.; Pittenger, R. C.; McGuire, G.
M. Antibiot. Ann. 1955-1956, 606. (b) Griffith, R. S. J. Antimicrob.
Chemother., Suppl. D 1984, 14, 1. (c) Sheldrick, M. P.; Jones, P. G.;
Kennard, O.; Williams, D. H.; Smith, G. A. Nature 1978, 271, 223. (d)
Williams, D. H.; Kalman, J. R. J. Am. Chem. Soc. 1977, 99, 2768. (e) Harris,
C. M.; Harris, T. M. J. Am. Chem. Soc. 1982, 104, 4293. (f) Harris, C. M.;
Harris, T. M.; Kopecki, H. J. Am. Chem. Soc. 1983, 105, 6915.
(3) (a) Burgess, K.; Lim, D.; Martinez, C. I. Angew. Chem. 1996, 108,
1162. (b) Evans, D. A.; Ellman, J. A.; DeVries, K. M. J. Am. Chem. Soc.
1989, 111, 8912. (c) Evans, D. A; Watson, P. S. Tetrahedron Lett. 1996,
37, 3251. (d) Pearson, A. J.; Bignan, G. Tetrahedron Lett. 1996, 37, 735.
(e) Pearson, A. J.; Bignan, G.; Zhang, P.; Celliah, M. J. Org. Chem. 1996,
61, 3940. (f) Boger, D. L.; Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem.
Lett. 1995, 5, 3091. (g) Boger, D. L.; Zhou, J. J. Org. Chem. 1996, 61,
3938. (h) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastaner, J.;
Zhu, J. J. Org. Chem. 1994, 59, 5535. (i) Zhu, J.; Bouillon, J. P.; Singh, G.
P.; Chastanet, J.; Beugelmans, R. Tetrahedron Lett. 1995, 36, 7081. (j)
Beugelmans, R.; Choussy, M. B.; Vergne, C.; Bouillon, J. P.; Zhu, J. J.
Chem. Soc., Chem. Commun. 1996, 1029. (k) Inoue, T.; Sasaki, T.;
Takayanagi, H.; Harigaya, Y.; Hoshino, O.; Hara, H.; Inaba, T. J. Org.
Chem. 1996, 61, 3936. (l) Rao, A. V. R.; Reddy, K. L.; Rao, A. S.; Vittal,
T. V. S. K.; Pathi, P. L. Tetrahedron Lett. 1996, 37, 3203 and references
therein.
(4) (a) Wallach, O. Liebigs Ann. Chem. 1886, 235, 233. (b) Wallach,
O.; Heusler, F. Ibid. 1888, 243, 219. (c) Merkushev, E. B. Synthesis 1988,
923.
(5) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. ReV. 1974, 43, 679.
(6) (a) Gross, M. L.; Blank, D. H.; Welch, W. M. J. Org. Chem. 1993,
58, 2104 and references therein. (b) Satamurthy, N.; Barrio, J. B.; Bida, G.
T.; Phelps, M. E. Tetrahedron Lett. 1990, 31, 4409. (c) Cohen, T.; Dietz,
A. G., Jr.; Miser, J. R. J. Org. Chem. 1977, 42, 2053.
(7) Stepanov, B. I. Zh. Obshch. Khim. 1962, 32, 3741 and references
therein.
(8) Foster, N. J.; Heindel, N. D.; Burns, H. D.; Muhr, W. Synthesis 1980,
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Lett. 1977, 18, 1977.
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763.
(11) Peptide 7 was prepared, in 85% overall yield, by coupling
commercially available N-Boc-(R)-tyrosine with (S)-alanine methyl ester
using EDC and HOBt as coupling reagents in DMF, followed by hydrolysis
of the methyl ester using aqueous LiOH and MeOH.
S0002-7863(96)03635-9 CCC: $14.00 © 1997 American Chemical Society

3422 J. Am. Chem. Soc., Vol. 119, No. 14, 1997
Communications to the Editor
Scheme 3. Synthesis of C-O-D Cyclic Aryl Ether 15a
Table 1. Synthesis of Triaryl Ether via Reaction of Triazenes with
Phenols
a Reagents and conditions: (a) 2.2 equiv of Br2, AcOH, 25 °C, 0.5
h, 99%; (b) 1.3 equiv of NaNO2, 5 equiv of 12 N HCl, THF-H2O
(10:1), 0 °C, 0.5 h; then 10 equiv of pyrrolidine, satd. aq. K2CO3, 1 h,
84%; (c) 1.5 equiv of TEMPO, 3 equiv of 5% aq. NaOCl, NaBr cat.,
Me2CO, 0 °C, 2 h, 82%; (d) 1.5 equiv of HBTU, 2 equiv of 13, 1.5
equiv of NEt3, DMF, 0 °C, 18 h, 63%; (e) 2.5 equiv of K2CO3, 2.5
equiv of CuBr‚Me2S, 3 equiv of pyridine, MeCN (0.01 M), 75 °C, 15
h, 77%; (f) Raney Ni, MeOH, ∆, 2 h, 71%; (g) (i) t-BuONO, BF3‚OEt2,
THF, -20 to -5 °C, 0.5 h; (ii) Cu(NO3)2/Cu2O, H2O, 25 °C, 3 h, 60%
(TEMPO ) 2,2,6,6-tetramethylpiperidin-1-oxyl. HBTU ) O-benzo-
triazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate).
a Amounts: 1.2 equiv of ArOH; 5.0 equiv of CuBr‚SMe2; 5.0 equiv
of K2CO3. b Amounts: 2.4 equiv of ArOH; 10.0 equiv of CuBr‚SMe2;
10.0 equiv of K2CO3.
Scheme 2. Synthesis of D-O-E Cyclic Aryl Ether 9a
performed by exposure of 14 to K2CO3 (2.5 equiv), CuBr‚-
Me2S (2.5 equiv), and pyridine (3.0 equiv) in degassed MeCH
(0.01 M) at 75 °C for 15 h, furnishing cleanly, and without
significant loss of stereochemical integrity,14 the targeted C-O-D
vancomycin ring model system 15 (77%).
Conversion of the synthesized triazenes to the corresponding
phenols under acidic conditions (Dowex H+ resin 50WX8-200,
H2O/MeCN, ∆, 10 min) was demonstrated with several acyclic
aryl systems (e.g., VI, entry 7, Table 1, 92%).6b However, treat-
ment of the cyclic triazene system 15 with the above conditions
led to only traces of phenol 16. After considerable experimen-
tation it was found that reduction of 15 with Raney Ni cleanly
furnished the amine 16 (71% yield), which in turn was converted
to the phenol 17 upon diazotization and treatment with Cu(I)/
Cu(II) (60% from 16). The unusual behavior of triazene 15 is
presumably due to the special conformational preferences of
the monocyclic aryl ether, effects which may not necessarily
be operating in the bicyclic system of vancomycin.
The described chemistry provides a new synthetic avenue to
a wide variety of aryl ethers from readily available aniline
derivatives. The method is mild enough to accommodate
racemization-prone amino acids and to be successfully applied
to the construction of vancomycin type model systems. Further
studies in this field are in progress.15
a Reagents and conditions: (a) 3.0 equiv of LAH, THF, 0 °C, 4 h,
93%; (b) 1.3 equiv of NaNO2, 5 equiv of 12 N HCl, THF-H2O (10:
1), 0 °C, 0.5 h; then 10 equiv of pyrrolidine, satd. aq. K2CO3, 1 h,
73%; (c) 1.5 equiv of Ph3P, 1.5 equiv of DEAD, then 1.5 equiv of
DPPA, THF, 25 °C, 2 h, 82%; (d) 2.0 equiv of Ph3P, 10 equiv of H2O,
THF, 45 °C, 8 h, 80%; (e) 1.5 equiv of 7, 3 equiv of EDC, 1.5 equiv
of HOBt, DMF, 0 °C, 8 h, 45%; (f) 2.5 equiv of K2CO3, 2.5 equiv of
CuBr‚Me2S, 3 equiv of pyridine, MeCN (0.01 M), 75 °C, 6 h, 54%
(87% conversion) (DPPA ) (PhO)2P(O)N3, EDC ) 1-ethyl-3-(3-
dimethylamino)propylcarbodiimide hydrochloride, HOBt ) N-hydroxy-
benzotriazole).
equiv) in degassed MeCN (0.01 M) at 75 °C for 3 h, led
smoothly to the D-O-E ring system 9 in 54% yield (87%
conversion).
Acknowledgment. We thank Drs. Gary Siuzdak and Dee H. Huang
for mass and NMR spectroscopic assistance. This work was financially
supported by the National Institutes of Health, The Skaggs Institute
for Chemical Biology, and Merck Sharp and Dohme and by postdoctoral
fellowships from NATO/DAAD (S.B.) and the NIH (J.M.R.).
The C-O-D vancomycin model system 15 was synthesized
as shown in Scheme 3. (4-Aminophenyl)ethyl alcohol (10) was
sequentially subjected to bromination, diazotization,8 and reac-
tion with pyrrolidine to furnish the triazene 11 (84% overall).
Oxidation12 of the primary alcohol of 11 with TEMPO and
NaOCl gave the carboxylic acid 12 in 82% yield. Coupling of
12 with dipeptide 1313 with HBTU and Et3N gave tripeptide
14 in 63% yield. The key cyclization reaction was then
Supporting Information Available: Selected data for compounds
VI and VII (entries 6-10 and 13, Table 1) and 4-17 (14 pages). See
any current masthead page for ordering and Internet access instructions.
JA9636350
(14) The phenylglycine epimer of 14 was prepared in an analogous
manner and cyclized under identical conditions leading to the corresponding
epimer of 15. The reaction mixtures of both cyclizations showed, by 1H
NMR (500MHz), <5% epimerization of the phenylglycine residue.
(15) All new compounds exhibited satisfactory spectral and exact mass
data. Yields refer to spectroscopically and chromatographically homoge-
neous materials.
(12) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987,
52, 2559.
(13) Peptide 13 was prepared by coupling (S)-tyrosine methyl ester with
N-CBZ-(R)-phenylglycine using EDC and HOBt as coupling reagents in
DMF, followed by deprotection of the N-terminal CBZ group by hydro-
genolysis using Pd(OH)2/C (10 mol %) in MeOH (91% overall yield).