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Scheme 4. Synthesis of oxazole building blocks 24 and 25. Reagents and conditions: a) EDC (1.05 equiv), HOBt (1.05 equiv), THF, 258C, 5 min, then Et3N
(2.0 equiv), 258C, 15 h, 96%; b) Burgess reagent (1.5 equiv), THF, 658C, 4 h, 61%; or c) DAST (1.1 equiv), CH2Cl2, ꢀ788C, 1.5 h, then K2CO3 (1.5 equiv), ꢀ788C!
258C, 1.5 h, 100%; d) BrCCl3 (1.1 equiv), DBU (1.1 equiv), CH2Cl2, 08C!258C, 18 h, 91%; e) LiBH4 (2.0m in THF, 3.0 equiv), EtOH (5.0 equiv), THF, 08C!258C,
3 h, 95%; f) NaHMDS (1.0m in THF, 2.1 equiv), THF, ꢀ788C, 10 min, then nBu4NI (0.1 equiv), BnBr (0.8 equiv), ꢀ788C!258C, 24 h, 61%; g) nBuLi (2.5 equiv),
THF, ꢀ788C, 1 h, then B(OMe)3 (7.0 equiv), ꢀ788C, 1 h, then 258C, 2 h, HCl, 80% crude; h) nBuLi (2.5 equiv), THF, ꢀ788C, 1 h, then I2 (2.0 equiv), ꢀ788C, 1 h,
74%.
previously described.[5] Lithium borohydride reduction of ester
21 was followed by benzylation of the primary alcohol 22 to
give oxazole 23. Subsequent lithiation at the 5-position was
followed by quenching with trimethyl borate to give, after acid
hydrolysis, the boronic acid 24, or with iodine to give iodide
25 (Scheme 4).
were conducted using the aforementioned ipso-borodesilyl-
ation with boron trichloride followed by Suzuki reaction carried
out in situ.[23] The optimized Suzuki conditions employed
Finally a number of tyrosine derivatives containing different
protecting groups were prepared as coupling partners. These
were obtained from iodotyrosine using standard methods as
outlined in Scheme 5. For the formation of compound 29,
some problems were encountered with the palladium-cata-
lysed borylation reaction, since the boronate was difficult to
purify by flash chromatography over silica gel due its tendency
to remain adsorbed on the column. Indeed, only a small
amount of compound 29 could be isolated in this manner, and
elution with more polar solvents resulted in contamination
with polar byproducts. To address this problem, the purifica-
tion process was performed using freshly prepared silica gel
impregnated with boric acid, which is reported to help in the
purification of pinacolboronates and boronic acids by column
chromatography.[25]
Scheme 5. Synthesis of tyrosine building blocks 27–29 [PinB=4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl]: Reagents and conditions: a) SOCl2
(1.1 equiv), MeOH, 258C, 20 h, 100%; b) Boc2O (1.2 equiv), Et3N (2.0 equiv),
CH2Cl2, 258C, 3.5 h, 72%; c) BnBr (1.3 equiv), K2CO3 (1.4 equiv), nBu4NI
(0.15 equiv), acetone, 568C, 16 h, 89%; d) pinacolborane (3.0 equiv),
Pd(OAc)2 (0.1 equiv), iPr2NEt (5.0 equiv), 2-(biphenyl)dicyclohexylphosphine
(0.4 equiv), 1,4-dioxane, 858C, 3 h, 73%; e) CbzCl (1.0 equiv), Na2CO3
(3.0 equiv), Et2O/H2O (1:1), 258C, 16 h, 100%; f) BTEAC (2.4 equiv), tert-BuBr
(46 equiv), K2CO3 (25 equiv), H2O, THF, 608C, 48 h, 57%; or tert-butyl 2,2,2-tri-
chloroacetimidate (3.5 equiv), CH2Cl2/THF (4:1), 258C, 16 h, 100%; g) BnBr
(1.3 equiv), K2CO3 (1.4 equiv), nBu4NI (0.15 equiv), acetone, 568C, 16 h, 88%;
h) SOCl2 (1.1 equiv), MeOH, 08C to reflux, 100%; i) CbzCl (1.1 equiv), Na2CO3
(1.0 equiv), acetone/H2O (1:1), 258C, 2 h, 100%; j) BnBr (1.2 equiv), K2CO3
(2.4 equiv), nBu4NI (0.10 equiv), acetone, reflux, 18 h, 97%; k) pinacolborane
(3 equiv), Et3N (4 equiv), Pd(OAc)2 (0.05 equiv), 2-(biphenyl)dicyclohexylphos-
phine (0.4 equiv), 1,4-dioxane, 508C, 1 h, 84% (Purification by flash column
chromatography over boric acid-impregnated silica gel).
Oxidative rearrangement model studies
A crucial question for our oxidative strategy as set out in
Scheme 2 is the relative propensity of tyrosine-derived frag-
ments versus oxazole moieties to migrate from C-2 to C-3 in
the key rearrangement step. To this end we investigated two
simpler model systems 32 and 35 as substitutes for the real
systems 12 and 14, wherein a phenyl group replaces the tyro-
sine fragment, not only as model substrates, but also as
a chance to develop and optimize the critical sp2–sp2 coupling
methodology. Both compounds 32 and 35 were synthesized
by the initial coupling of either iodobenzene or iodooxazole
moiety 25 with the indole derivative 18. The coupling steps
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Chem. Eur. J. 2016, 22, 1 – 11
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