Letter
Synthesis of Breitfussin B by Late-Stage Bromination
Akbar H. Khan and Jason S. Chen*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: The breitfussins are halogenated natural prod-
ucts whose structures were determined with the assistance of
atomic-force microscopy. The site selectivity of N-bromosuc-
cinimide-mediated bromination of a model breitfussin core
was found to be strongly dependent on solvent selection; use
of acetone led to oxazole bromination, and use of a pyridine-
containing mixture led to pyrrole bromination. This tunable
site-selective bromination was used in a protecting-group-free
synthesis of breitfussin B that proceeded in 9.2% yield over 12
reactions and five chromatographic separations. A bromooxazole analogue of breitfussin A was also prepared by late-stage
bromination but isomerized on silica gel to form breitfussin B. This isomerization appeared to proceed through a unimolecular
pathway.
reitfussins A and B (1 and 2, Figure 1) are halogenated
natural products isolated from the Arctic hydrozoan
heterocycles such as pyrroles6 and oxazoles7 are well studied,
comparatively little is known about selectivity in substrates
containing multiple aromatic heterocycles. Indeed, at the time we
started this research, a SciFinder search revealed no examples of
halogenation of a pyrrole or oxazole (selective or otherwise) on a
substrate containing both ring systems.8,9 Therefore, we decided
to investigate halogenation site selectivity on a model substrate.
Inspired by the isolation team’s description of the breitfussins
as highly oxidized dipeptides,1 we envisioned synthesis of the
central oxazole ring from substituted tryptamine 4 and 2-
(trichloroacetyl)pyrrole (3) as high oxidation state surrogates for
tryptophan and proline. Thus, the synthesis of a simplified model
breitfussin (8, Scheme 1) commenced with the coupling of
tryptamine (5) and 2-(trichloroacetyl)pyrrole (3) to afford
amide 6 in 100% yield. DDQ-promoted heterobenzylic
oxidation10 gave ketone 7 in 84% yield. A subsequent
Robinson−Gabriel reaction delivered oxazole 8 in 83% yield.
We selected N-bromosuccinimide (NBS) as a convenient
source of electrophilic bromine. Bromination of model
compound 8 in acetonitrile (Table 1, entry 1) was sluggish but
yielded a trace of the desired breitfussin B analogue (9).
Although we were concerned about the possibility of competitive
bromination at C4″ on the pyrrole, all of the pyrrole bromination
proceeded at the C5″ position. However, even though
bromooxazole 10 was not found, a surprisingly large amount of
dibromide 11 was present even at low conversion, suggesting
that the rate constant for the second bromination was greater
than that for the initial bromination.11
B
Figure 1. Retrosynthetic analysis of breitfussins A and B.
Thuiaria breitfussi collected at Bjørnøya (Bear Island), Norway.1
The paucity of hydrogen atoms hamstrung NMR-based structure
determination, and thus atomic-force microscopy (AFM)2 and
computational tools3 were called upon to complete the
assignment. This unprecedented AFM-assisted structure deter-
mination revealed the breitfussins to be related to the
phorbazoles.4 Of note, breitfussin A is the only known naturally
occurring iodooxazole. Synthetic validation of the assigned
structures was a high priority because of the promising capability
of AFM as a structure elucidation tool. Recently, Hedberg, Bayer,
and co-workers synthesized breitfussins A and B using Suzuki
coupling reactions to join the heteroaromatic rings, thus
confirming the assigned structure of these natural products.5
Herein we report a conceptually distinct synthesis of breitfussin
B through late-stage bromination of the breitfussin core.
Speculating that the higher acetonitrile solubility of the
monobromide product (9) as compared with its precursor (8)
may be promoting a faster second bromination, we switched
solvents to THF (Table 1, entry 2). The second bromination still
We envisioned site-selective late-stage halogenations for the
synthesis of breitfussins A and B (1 and 2) from a common
precursor. Although site-selective halogenations of aromatic
Received: June 10, 2015
© XXXX American Chemical Society
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Org. Lett. XXXX, XXX, XXX−XXX