C O M M U N I C A T I O N S
Scheme 2. Reactions of Spiroepoxy-â-lactones
Scheme 3. Proposed Mechanistic Pathways for Base-Initiated
Transformations of Spiroepoxy-â-lactones Leading to Amide 7
amides 7 following protonation of the intermediate enolate. With
the less sterically demanding diethylamine, classical addition-
elimination at the â-lactone carbonyl carbon presumably occurs to
provide diethylamide 8 with retention of stereochemistry at the
R-carbon. In the presence of DBU, ketene 14 could ultimately
provide butenolide 12; however, other mechanistic scenarios can
be envisioned.
In summary, we have synthesized the first examples of spiroe-
poxy-â-lactones and found them to be surprisingly stable. This may
be due to a double anomeric effect garnered from analysis of bond
lengths by X-ray crystallography. Initial studies of their reactivity
demonstrate interesting potential for these intermediates, and their
reactivity contrasts significantly from related systems previously
described by Howell4 and Crandall.5 At the present time, a limitation
is the symmetry of the ketene dimer substrates. We are continuing
to explore the unique reactivity of these new spiro systems and
their potential as synthetic intermediates and enzyme inhibitors.
rings leading to increased p-orbital character, which occurs to relieve
ring strain and results in concomitant increased s-orbital character
in exocyclic bonds leading to shorter bonds. Alternatively, bond
shortening could be rationalized by nfσ* overlap of an epoxide
(O6) and a â-lactone (O1) lone pair with the σ* orbitals of the
C4-O1 and C4-O6 bond of the epoxide and â-lactone, respec-
tively, indicative of a double anomeric effect. Calculations per-
formed on related systems suggest that, while hybridization effects
play a role in bond shortening (Table 1), this is insufficient to
explain the degree of bond shortening observed, thus pointing to a
greater role of anomeric effects. The observed anomeric effects
may be more pronounced in these systems due to the rigidity of
the spirocycle and may contribute to the unexpected stability of
these systems. The C5-O6 bond of the epoxide is also lengthened
predictive of the greater reactivity of this bond (vide infra). Further
bond length comparisons between these systems and those of
spiroepoxycyclobutanes, spirocyclopropyl-â-lactones, and spiroe-
poxyoxetanes indicate the greatest degree of C4-O6 bond shorten-
ing for the present systems also pointing to a double anomeric effect
(Table 2).
Acknowledgment. We thank the NSF (CHE-9624532), the
Welch Foundation (A-1280), and Pfizer for support of these
investigations. We thank Dr. Huda Henry-Riyad and Prof. Dan
Singleton (TAMU) for performing some of the calculations and
helpful discussions, Prof. Michael Calter (Wesleyan) and Dr. Ziad
Moussa for helpful discussions, and Dr. Joe Reibenspies (TAMU)
for X-ray analysis. We thank Mr. Vikram Purohit for providing
some of the ketene dimers used in this study.
Initial studies of these spiro systems with nucleophiles reveal
some unique reactivity that differs significantly from spiroepoxy-
oxetanes and spirobisepoxides, including increased stability. Initial
reactions to effect regioselective C-O cleavage were unfruitful as
several conditions (e.g., TESOTf, Et3SiH, -78 f 23 °C; KHB-
(Oi-Pr)3, THF, -78 °C) only returned starting material. Subse-
quently, it was found that TMSOTf in conjunction with Hu¨nig’s
base led to low conversion to enone 10.11 Reaction with tetrabu-
tylammonium chloride and sodium azide led to the R-chloroketone
5 and R-azidoketone 6, respectively, likely resulting from invertive
opening of the longer epoxide C5-O6 bond and â-lactone cleavage
followed by decarboxylation. Addition of neutral water led to
epoxide cleavage, as determined by incorporation of 18O in the
hydroxy group of ketone 9 when H218O was employed. Reduction
with LiAlH4 gave triol 11 as expected. In attempts to generate a
tertiary amide that would be immune to epimerization at the
R-carbon,12 addition of diisopropylamine provided a 1:1 mixture
of syn:anti diastereomeric amides 7. On the other hand, addition
of diethylamine led to a single diastereomeric amide 8. Addition
of the non-nucleophilic base, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), led to butenolide 12 (Scheme 2).
Supporting Information Available: General procedures for ep-
oxidation and subsequent transformations with characterization data
(including 1H and 13C NMR spectra) for ketene dimers 1d-e,
spiroepoxy-â-lactones 2a-e, and products 5-12. This material is
References
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14 (Scheme 3).13 Two base-initiated reaction pathways (red and
blue arrows) could ultimately lead to this intermediate by stepwise
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ketoketene 14 could occur leading to a mixture of diastereomeric
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(13) Attempts to observe a ketene intermediate by ReactionView IR or by
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