Organic Letters
Letter
trifluoroethyl ester of 2 gave 4ab in high yield (up 86%) with
excellent enantioselectivity (99% ee). Further exploration
revealed that the reactions exhibited little electronic or steric
influence on the reactivity or selectivity. Comparable yields
(4ac−4ag, up to 81%) with excellent enantioselectivities
(>96% ee) were obtained from different benzyl esters.
Furthermore, enoldiazoacetates containing a γ-substituent
showed a slight effect on the reactivity. Substituents including
methyl (2h), ethyl (2i), and benzyl (2j) produced the target
products in high yields (75−78%) with excellent enantiose-
lectivities (95−97% ee). Modest product yields (4ba−4da,
63−75%) but high enantioselectivities (95−98% ee) were
observed when 1 bearing electron-neutral, electron-rich, or
electron-deficient substituents on the aryl group was tested in
this reaction. The ortho-substituted congeners were also
tolerated under the current conditions (1e and 1f), delivering
the desired products in good yields with excellent enantiose-
lectivities (4ea in 71% yield with 95% ee and 4fa in 81% yield
with 96% ee, respectively). In addition to aryl-substituted
dihydrooxazoles, the desired products (4ga and 4ha) were
smoothly generated in isolated yields above 73% with
enantioselectivities up to 98% ee when 1-naphthyl and
heterocyclic 2-furyl-substituted dihydrooxazoles (1g and 1h)
were employed. The introduction of E-cinnamyl-substituted
dihydrooxazole (1i) resulted in a high yield (4ia, 82%) with
excellent enantioselectivity (4ia, 99% ee) without detecting any
reaction at the cinnamyl group. Changing the substitution at
the 2-position of the dihydrooxazole from an aryl to an
Scheme 3. Control Experiments
the low% ee is due to the rearrangement step rather than
cyclopropanation. The functional group is not stable,10 and it
undergoes spontaneous ring-opening to the zwitterion
intermediate with subsequent recyclization with 0% ee (eq
3). Furthermore, only the acetyl group provides this rearrange-
ment (eq 3). As predicted, when the donor−acceptor diazo
compound 5d was employed in this reaction, the stable
cyclopropane 6ad was generated in high yield with high
enantioselectivity (88% yield, 99% ee) (eq 4), which further
supports our hypothesis that the reaction involves a concerted
and subsequent asynchronous annulation process. However, to
our disappointment, dihydrooxazole 1k without the geminal
dimethyl group failed to give the corresponding spiroketal
product, even though cyclopropane 3ka having a high % ee
value was detected. Because of the driving force to achieve
aromaticity, the racemic proton-transfer product 8ka was
isolated in 78% yield (eq 5). To our surprise, when 1-
methylenetetrahydronaphthalene 1l without a heteroatom was
employed, the desired product 4la was obtained with excellent
enantioselectivity in moderate yield (eq 6, 66% yield, 94% ee),
which has potential implication for similar transformations
with other methylene substrates.
t
aliphatic Bu group was also compatible with this catalytic
process in somewhat lower yield but with excellent
enantioselectivity (4ja, 53% yield and 99% ee). However, an
internal 5-(R)-methylenedihydrooxazole (R = C6H5) without
4,4-dimethyl substitution failed to deliver the target spiroketal
product due to its low reactivity, and decomposition of the
diazo compound 2a was detected only in this reaction. The
structure and absolute configuration of spiroketal (S)-4ai were
established by X-ray diffraction (Figure 1).
A tentative reaction mechanism is proposed in Scheme 4.
Initially, the carbene complex A is formed from diazo
compound 2 in the presence of the Rh(II) catalyst, followed
by cyclopropanation to form B. When R1 is an acetyl group, B
undergoes spontaneous ring-opening to the zwitterion
intermediate C with subsequent recyclization to furnish 4
with low enantiomeric excess. However, when R1 is a silyl enol
ether group, intramolecular C−C bond displacement, triggered
by fluoride-promoted removal of the TBS group, occurs to
generate intermediate E from D, and subsequent protonation
completes the transformation. The aromatic product 8 is
obtained through direct proton transfer of the intermediate D.
In summary, a highly efficient asymmetric CP-RA approach
of enoldiazoacetates with methylenedihydrooxazoles has been
achieved by a one-pot cascade reaction catalyzed by a chiral
Rh(II) catalyst and promoted by TBAF sequentially. Chiral
spiroketals were generated in up to 86% yield with >95% ee
Figure 1. ORTEP diagram of the X-ray crystal structure of (S)-
methyl-7-ethyl-4,4-dimethyl-2-phenyl-1,6-dioxa-3-azaspiro-[4.4]nona-
2,7-diene-8-carboxylate 3a.
To gain insight into the reaction mechanism, we carried out
control experiments (Scheme 3). α-Benzoyldiazoacetate 5b
was reacted with 1a under standard conditions. Unlike α-
acetyldiazoacetate 5a, which directly generated the spiroketal
product 3aa, this diazoacetate formed cyclopropane 6ab as the
major product in 87% yield with 98% ee along with a minor
amount of spiroketal product 7ab in 7% yield with a poor 25%
ee. Further treatment of 6ab at room temperature with or
without Rh(II) catalyst resulted in the same outcome: 85%
yield with 25% ee after 48 h (eq 2). This result indicated that
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Org. Lett. 2021, 23, 3955−3959