Angewandte
Communications
Chemie
the production of secondary metabolites in a range of other
Streptomyces strains,[1a] and although the mechanism of action
is unknown, the reasons for immunity in the producing strain
have been investigated.[1c] In continuation of our interest in
the synthesis and properties of post-translationally modified
peptide antibiotics such as the amythiamicins,[5] telomesta-
tin,[6] and plantazolicin,[7] we embarked upon a total synthesis
of goadsporin. We herein report the first synthesis of this
complex polyazole antibiotic in which the four five-mem-
bered oxazole rings of the natural product are formed from
simple precursors, such as carboxamides or nitriles, as
facilitated by metallocarbene chemistry.
Our synthetic strategy involves protection of the serine
side chain alcohol and the C-terminal valine carboxylic acid
with a tert-butyl ether and ester, respectively, orthogonal to
silyl protection of the two serine residues that will serve as
precursors to the dehydroalanine functionalities. Disconnec-
tion at a central amide bond in the protected compound 2
leads to the two fragments 3 and 4, adorned with suitable
protecting groups, which can both be broken down further at
an amide bond (Scheme 1) to give four approximately equally
sized fragments.
Although some of the building blocks required for the
synthesis of goadsporin are readily available proteinogenic l-
amino acids, the heterocyclic components need to be
accessed. Whilst the two thiazoles should be approachable
through the well-established Hantzsch reaction, we elected to
synthesize the four oxazoles by using rhodium carbene
chemistry, a mild and versatile method used previously in
the synthesis of azole-containing natural products.[5–7] Reac-
tion of diazocarbonyl compounds with catalytic amounts of
rhodium(II) complexes forms an intermediate metallocar-
Scheme 3. Synthesis of bis-oxazole 12. Reagents and conditions:
a) Rh2(OAc)4, methyl 2-diazo-3-oxobutanaote 6, CHCl3, 808C, 16 h,
56%; b) NEt3, PPh3, I2, CH2Cl2, 16 h, 73%; c) LiOH, MeOH/H2O, 1 h,
quantitative; d) valine methyl ester hydrochloride, DIPEA, HATU, DMF,
16 h, 82%; e) HCl in dioxane, 4 h, 91%; f) DIPEA, Ac2O, CH2Cl2, 56 h,
93%; g) LiOH, MeOH/H2O, 4 h, 96%; h) Rh2(OAc)4, 6, CHCl3, 808C,
16 h, 73%; i) NEt3, PPh3, I2, CH2Cl2, 16 h, 74%; j) TFA/CH2Cl2 (95:5),
08C, 20 min, 90%; k) 2,6-di-tert-Bu-4-Me-pyridine, HBTU, HOAt,
CH2Cl2, 16 h, 75%; l) Me3SnOH, DCE, 808C, 16 h, quantitative.
DIPEA=diisopropylethylamine, HATU=1-[bis(dimethylamino)methy-
lene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate,
HBTU=N,N,N’,N’-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexa-
fluorophosphate, HOAt=1-hydroxy-7-azabenzotriazole, DCE=1,2-
dichloroethane.
À
bene, which can undergo an N H insertion reaction into
a carboxamide, followed by cyclodehydration to give the
heteroaromatic oxazole. Alternatively, the steps can be
reversed, with the carboxamide dehydrated to a nitrile that
reacts to give substituted oxazoles directly (Scheme 2).[8] Both
methods are used in the present study, with oxazoles 7, 11, and
À
20 produced through N H insertion (Scheme 3 and
Scheme 5), and oxazole 21 produced through nitrile addition
(Scheme 5).
The synthesis started with the N-terminal bis-oxazole
fragment 12. Reaction of Boc-protected alaninamide 5 with
diazo-b-ketoester 6 in chloroform with 2 mol% of rhodium-
(II) acetate dimer, followed by dehydration using iodine,
triphenylphoshine, and triethylamine[9] in dichloromethane
gave the 5-methyloxazole 7. Ester hydrolysis and amide
coupling with valine methyl ester hydrochloride gave com-
pound 8. At this point the acetyl group was introduced
through Boc-deprotection, followed by acetylation (structure
confirmed by X-ray crystallography; see the Supporting
Information). Subsequent ester hydrolysis of the acetylated
product gave acid 9 (Scheme 3). The second oxazole was
synthesized analogously: rhodium(II) acetate catalyzed the
reaction of the serine carboxamide 10, which is readily
obtained in two steps from the Boc-serine methyl ester, to
give the desired oxazole after cyclodehydration, which was
then Boc-deprotected with trifluoroacetic acid to give oxazole
11. Amide coupling between 9 and 11 under standard
conditions (HATU, HOAt, DIPEA, and DMF) gave high
levels of racemization of the valine residue,[10] with a d.r. of
1.0:0.9 as observed by HPLC. After optimization, which led to
Scheme 2. Construction of oxazole rings from carboxamides or nitriles
using rhodium carbene chemistry.
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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