Organic Letters
Letter
The overall cyanide-catalyzed transformation consists of two
steps: retro-Dieckmann reaction followed by lactonization. A
mechanistic proposal is shown in Scheme 3. The nucleophile
adds into the endocyclic carbonyl group forming anion 10,
which undergoes retro-Dieckmann reaction under formation of
ester−enolate 11. Tautomerism forms alcoholate 13, which
attacks the acyl cyanide moiety forming anion 12 from which
the catalyst is eliminated and δ-lactone 8a liberated. In
principle, all steps are reversible, but with two ester moieties
the product 8a is thermodynamically more stable then
hydroxyketone 7a because the C−C and O−H bonds were
replaced by C−O and C−H bonds and ring strain was released
by transforming the five- into a six-membered ring. The
method is failing for the preparation of ε- and ζ-lactones with
seven- and eight-membered rings, presumably because the
conformational flexibility of a longer alkylidene chain makes
the intramolecular attack of the alcoholate to the acyl cyanide
in structure 13 more unlikely.
In conclusion, we report on a new reaction to access δ-
valerolactone derivatives 8. Conversion of 1-hydroxy-2-
oxocyclopentane-1-carboxylic esters 7 with catalytic amounts
of KCN in boiling toluene leads in a sequence of retro-
Dieckmann reaction and transacylation to the target structures
8. Apart from the fact that the δ-valerolactone moiety is a
structural motif of several natural and synthetic products with
prominent biological activities, the great advantage of this new
synthetic method is the straightforward accessibility of the
starting materials 7 by cerium-catalyzed aerobic oxidation of
cyclic β-oxoesters 6. Yields of δ-lactones range up to 99%.
Scheme 3. Mechanistic Proposal
All 22 compounds 7a−7v were submitted to standard
reaction conditions (Scheme 2). Yields of lactones 8a−8d
from cyclopentanone derivatives 7a−7d (entries 1−4) were
good to excellent (86−99%). The introduction of the
pulegone-derived auxiliary gave the product 8c (entry 3)
without any stereoselectivity, although the starting material 7c
was almost diastereometrically pure (dr 95:5). We then
investigated starting materials 7e−7g with a heteroatom within
the five-membered ring (entries 5−7). Conversion of
tetrahydrofuran derivative 7e yielded the respective lactones
8e only in traces (entry 5). However, when we tried to
improve the yield of α-hydroxy compound 7e by oxidation of
the oxoester 6e with 1 atm O2 in the presence of Cs2CO3 and
P(OEt)3,18 we surprisingly obtained 1,4-dioxane derivative 8e
directly, but in low yield (entry 5). Analogous experiments
with other oxoesters 6 failed to give any lactone 8. Conversion
of tetrahydrothiophene derivative 7f with KCN did not yield
the respective lactone 8f (entry 6). Conversion of N-
benzylpyrolidine derivative 7g (entry 7) gave the morpholine
derivative 8g, in 35% yield. We then converted the benzo- and
heteroarene-annulated compounds 7h−7m (entries 8−13),
and the yields of lactones with an annulated six-membered ring
were good to very good (81−89%; products 8h, 8i, 8l, 8m).
For furo- and thieno-annulated lactones 8j and 8k, the yields
were lower (58% and 76%, entries 10 and 11). The α-hydroxy
diketone 7n gave (entry 14) the rearranged product 8n in 77%
yield. The α-acetoxycyclopentanone 9n was obtained as
byproduct in 6% yield. Its formation could be rationalized by
attack of the cyanide ion to the exocyclic carbonyl group and
cleavage of the adjacent C−C bond in a retro-Claisen reaction.
The acetyl cyanide then acylated the α-hydroxy ketone, giving
ester 9n. Reaction of α-acetyl-α-hydroxybutyrolactone 7o
(entry 15) proceeded along the same pathway, and the α-
acetoxylactone 9o was obtained as the only unique product
isolated (34% yield) from the reaction mixture. Lactam 7p
with an ester moiety in the α-position remains inert under the
reaction conditions (entry 16). We investigated the formation
of ε- and ζ-lactones by conversion of starting materials with
six- (entries 17 and 18) and seven-membered ring (entry 19).
Neither cyclohexanone derivative 7q nor its benzannulated
congener 7r gave respective ε lactones 8q or 8r. However, the
starting material with a seven-membered ring 7s (entry 19)
gave the ζ-lactone 8s, though the yield was low (17%). Next,
we investigated whether α-(hydroxymethyl)-β-oxoesters 7t and
7u would furnish ε- and ζ-lactones 8t and 8u (entries 20 and
21), but no conversion was observed. Finally, we inspected the
acyclic compound 7v (entry 22), which would actually lead to
the ethyl lactate derivative 8v;22 however, no conversion was
observed.
ASSOCIATED CONTENT
* Supporting Information
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sı
The Supporting Information is available free of charge at
Synthesis, analytical data, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
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Jens Christoffers − Institut für Chemie, Universität
Fax: +49 441 798 3873
Author
David Kieslich − Institut für Chemie, Universität Oldenburg,
D-26111 Oldenburg, Germany
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We gratefully acknowledge support by the Deutsche
Forschungsgemeinschaft within the framework of the GRK
2226 “Chemical bond activation”. MTBE was obtained as a
generous gift from Evonik Industries, Marl, Germany.
REFERENCES
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(1) Armanino, N.; Charpentier, J.; Flachsmann, F.; Goeke, A.;
956
Org. Lett. 2021, 23, 953−957