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Scheme 4. Transannular cyclization of a partially reduced macrocyclic polyketide substrate with catalyst control over the oxygenation pattern. [a]
Yield determined by NMR using an internal standard. [b] Reactions performed with 10.0 mmol of substrate 17 in CDCl3 (7.00 mmolLÀ1).
(83% and 14% isolated yield for 10F and 11S, respectively),
indicating the viability of small-molecule catalysis to govern
polyketide cyclization cascades. Intriguingly, the extent of
divergent cyclizations was further noticeable when employing
the organic base diazabicycloundecen (DBU), leading to the
differently folded product 13S (36%), together with 10F
(37%) and intermediate 14F (26%, Scheme 3e).[24] Subse-
quent aerobic oxidation[27] of 13S led to naphthoquinone 15S
(76%) with reported activity against mycobacterium tuber-
culosis.[28,29] Moreover, 5 treated with DBU in acetonitrile
exclusively yielded the fungal intermediate 14F (63%), which
was eliminated to 10F and oxidized to the biologically active
naphthoquinone 16F (96%).[29]
We next set out to investigate whether the oxygenation
pattern of partially reduced aromatic polyketide products
may be governed by small-molecule catalysis (see Page S35 of
the Supporting Information for an overview). To emulate
enzymatic keto-processing (Scheme 4a),[2] the partially re-
duced precursor 4 was ozonolyzed and treated with catalytic
amounts of HCl to induce a mild deprotection, affording
substrate 17 as a mixture of several tautomers (Scheme 4b).
Since five different aldol addition products are feasible from
the transannular aldol cyclization of substrate 17,[24] a precise
differentiation is required to control the oxygenation pattern
by small-molecule catalysts. Gratifyingly, thiourea catalysts
initiated the divergent aldol additions, forming differently
oxygenated intermediates (Æ)-18 and (Æ)-19 (Scheme 4c).
The Takemoto catalysts were found to be particularly active
and the catalytic performance and selectivity with modifica-
tions of the basic functional group and the backbone were
thus tested. Experiments with imidazole-based catalyst (cat.
1) showed good yields but moderate selectivity (22% (Æ)-18,
40% (Æ)-19), whereas a catalyst bearing a pyridine moiety
(cat. 2) increased the overall yield (21% (Æ)-18, 53% (Æ)-19).
Catalysts with secondary amine moieties (cat. 3 or cat. 4) led
to little or no activity and a propyl-linked tertiary amine (cat.
5) also provided low conversions (3% (Æ)-18, 6% (Æ)-19).
However, the ethylene bridged tertiary amine congener (cat.
6) revealed a high selectivity and excellent yields (15% (Æ)-
18, 85% (Æ)-19).[24] Isolation of the sensitive product (Æ)-19
(72%) allowed to determine the relative diastereomeric
configuration (NOE measurements) and also the aldol
addition product (Æ)-18 with a different oxygenation pattern
was isolated in low amounts (10%). The catalyst-controlled
aldol addition was next combined with the developed
protocols to complete the cyclization cascades to aromatic
polyketide natural products and compared to reactions
without thiourea catalysts. Treatment of the partially reduced
macrocycle 17 with DBU in acetonitrile without cat. 6 yielded
the unknown naphthalene diol 20S, which decomposed over
the course of a few hours even under inert conditions
(Scheme 5a, 34%).[24] Strikingly, the transformation of 17
using cat. 6 affected a catalyst-controlled aldol/ retro-Claisen/
aldol condensation/ decarboxylation cascade to fungal poly-
ketide 21F with excellent selectivity and a 63% isolated yield.
Moreover, while treatment of the macrocycle 17 with excess
TfOH only led to decomposition, addition of cat.
6
(15 mol%) gave (Æ)-19 in 71% isolated yield, which could
be converted to chromone 22 using equimolar amounts of
TfOH (Scheme 5b, 49%).[24] To further demonstrate the
utility of the catalyst-controlled polyketide cyclization cas-
cades for natural product synthesis, we examined the aerobic
oxidation of naphthalene diol 21F, which efficiently provided
plumbagin (23F) and 7-methyl-juglone (24F) (Sche-
me 5c).[24,29]
In conclusion, a regioselective methodology for biomim-
etic polyketide cyclization cascades of macrocyclic polyketide
substrates was developed. The substrates showed significantly
improved stability, allowing selective cyclizations controlled
by small-molecule catalysts that govern the folding and
oxygenation pattern of nonreduced and partially reduced
aromatic polyketide products. Chromones were obtained by
an aldol addition/retro-aldol/aromatization/hemiketalization/
dehydration mechanism, while aromatic polyketides with
a fungal or bacterial folding pattern resulted from an aldol
addition/divergent retro-Claisen/aldol condensation/decar-
boxylation sequence. The addition of thiourea catalysts to
a partially reduced substrate selectively led to a fungal
naphthalene diol, which was aerobically oxidized to naphtho-
quinone natural products. The synthesis of the 18 isolated
Angew. Chem. 2020, 132, 1 – 6
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