Angewandte
Communications
Chemie
or tBuMe2Si- groups were chosen as substrates. However,
these stable and isolable silyl enol ethers 3a–c are known to
be rather weak nucleophiles which react with simple carbonyl
compounds only in the presence of strong Lewis or Brønsted
acids.[13] Following a screening of potential Lewis acids[14] (see
the supporting information), we were delighted to observe
that Sc(OTf)3 catalyzed a smooth and selective Mukaiyama-
aldol reaction with acetals 4 at low temperature in CH2Cl2 to
provide the expected products 5 in high yield and diastereo-
selectivity (Scheme 2).[15] When silyl enol ether 3a was
reacted with acetal 4a under the experimental conditions
described in Scheme 2, Mukaiyama-aldol product 5a was
isolated in 82% yield with excellent diastereoselectivity
(95:05 dr). Importantly, the complementary diastereomer is
accessible as well, with similar diastereoselectivity and yield,
by simply inverting the stereochemistry of the starting enol
silyl ether (3b provides 5b in 78% yield and 96:04 diaste-
reomeric ratio, Scheme 2). The relative stereochemistry of 5b
has been determined by comparison with a previously
reported product[10] and all other configurations were
assigned by analogy. This transformation is stereoselective,
as the two starting silyl enol ethers 3a and 3b are of E:Z ratios
of 02:98 and 96:04 and provide the two aldol products with
95:05 and 96:04 diastereomeric ratios, respectively. Notably,
even for the simplest monosubstituted enolates, stereospecific
transformations with acetals as proelectrophiles are very
rare.[16] TBS-silyl enol ether 3c reacted with acetal 4a
delivering 5a with very similar selectivity, suggesting that
the nature of the silyl group does not dramatically influence
the mechanism of the reaction. To access free aldol products
(R4 = H), acetal 4k possessing a removable allyl group[17] was
also tested, and we were pleased to observe similar selectiv-
ities and yields for the diastereomeric pair 5c and 5d (from 3a
and 3b, respectively). Aromatic aldehydes featuring substi-
tution at either the para, meta or ortho-position proceed with
satisfactory levels of diastereoselectivity (Scheme 2, compare
5e with 5 f and 5g). Disappointingly, electron withdrawing or
donating groups slightly decrease the selectivity of the
reaction (Scheme 2, 5i and 5j, respectively). Still, we were
pleased to observe that acetals derived from aliphatic
aldehydes smoothly participated in the Sc-catalyzed
Mukaiyama-aldol reaction, and that increasing the steric
hindrance of the acetal (R = Me, to Bu and c-Hex) doesnꢀt
impede reactivity (Scheme 2, compare 5k with 5l and 5n),
although the diastereoselectivity is slightly lower in these
cases (Scheme 2, 5k–5n). Still, both diastereomers (5l and
5m) of a given aldol product could be accessed from the two
stereomeric enolates 3a and 3b. Acetals are the reactive
partners of choice for the addition of these disubstituted silyl
enol ethers, as the corresponding aldehydes do not react
under the same experimental conditions.[16]
We next wondered whether this Mukaiyama-aldol reac-
tion performs equally well for the less sterically demanding
monosubstituted silyl enol ethers 6. The two stereoisomers E-
and Z-6 were readily synthesized by using the complementary
procedures that we have previously developed for the
preparation of disubstituted enolates of aldehydes
(Scheme 3).[9,10] The excellent stereoselectivity in both cases
shows that these two methods can also be successfully applied
to enolates of different substitution patterns.
Under the standard reaction conditions, Z-enolate 6
provided the anti-aldol derivatives 7a–c, whereas the E-
isomer gave the syn products 7d–f in good yields with
moderate to good selectivities. The relative stereochemistry
of the aforementioned products can be determined by careful
1
[18]
analysis of H NMR J coupling constants (Janti > Jsyn
)
and
chemical correlation with published structures.[17]
Two striking aspects of the stereoselection in this aldol
addition attracted our attention. First, the reaction is stereo-
Scheme 2. Sc(OTf)3-catalyzed Mukaiyama-aldol reaction of disubsti-
tuted enolates of aldehydes with acetals.
2
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!