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the N-protecting group to a tosyl group (i.e., compound 9d)
we only observed the formation of the cis-aziridine 10d,[18] but
no formation of the products 11 and 12.
than for DABCO, which seems to be mainly due to a higher
stabilisation of the DABCO ylide as compared to the trimethyl-
amine derivative,[20] thus resulting in an overall higher reactivi-
ty towards epoxidation of the trimethyl ammonium salts.
To elucidate if the formation of compound 12 may be ra-
tionalised by an in situ hydrolysis of the tert-butyloxycarbonyl
(Boc)-protected imines 9 to aldehydes 2 and reaction of com-
pound 2 with the ylide, we carried out the direct reaction of
compound 4b with benzaldehyde (2a) (Scheme 3, lower part).
Interestingly, we did not observe any formation of compound
12, but instead small quantities of the epoxide 5b was isolat-
ed. This came as a big surprise as so far we have never been
able to obtain even trace quantities of compound 5. Obviously,
the crucial role in this reaction seems to be the solid carbonate
base. It was reported in the past that solid inorganic bases,
that is, carbonates, can have a very special effect on sulfonium
ylide-mediated reactions.[19] We thus wondered, whether the
liquid–solid combination of CH2Cl2/Cs2CO3 may also allow us to
increase the yield for the analogous sulfonium ylide-mediated
epoxidation by using ester 13. We were indeed able to isolate
the epoxide 5b in 37% yield, which proves the positive effect
of Cs2CO3 as compared to other previously used bases (i.e.,
tBuOK, KOH or K2CO3), but it must be admitted that this meth-
odology could not further be improved by using alternative
sulfur leaving groups or conditions.
Enantioselective epoxidation
Controlling the absolute configuration in ammonium ylide-
mediated epoxidation reactions has so far been a very chal-
lenging task. Although the use of Cinchona alkaloids is the
method of choice for ammonium ylide-mediated cyclopropa-
nations,[5] their use in epoxidation reactions does not allow for
any product formation (Scheme 1).[6,7] Kimachi et al. showed
that brucine can be used as a chiral leaving group for benzylic
ammonium ylide-based epoxidations.[6b] We have recently re-
ported an alternative strategy by using chiral trimethylammo-
nium-based acetamides with a phenylglycinol-based amide
auxiliary,[7c] which allowed for high selectivities in epoxidation
and aziridination reactions. However, based on the fact that
this protocol requires the cleavage of the auxiliary in a subse-
quent step, a strategy by using a chiral amine leaving group in
ammonium ylide-mediated epoxidations would be much more
appealing. Based on the low reactivity associated with the use
of simple Cinchona alkaloids we therefore, decided to system-
atically screen a variety of other chiral tertiary amines. Table 1
gives an overview of the most significant results obtained in
a detailed screening of different chiral tertiary amines under
different reaction conditions.
Finally, we also calculated the energy profile for the reaction
of the DABCO- and quinuclidine-based amide-stabilised ammo-
nium ylides 1 to rationalise the significant yield differences
when using them for epoxidation reactions[7b] (compare with
Scheme 1).
Because DABCO itself was a reasonably good leaving group
in our racemic approach (Scheme 1),[7a] we first focused on the
known chiral DABCO derivative A.[21] Under liquid/liquid bipha-
sic conditions we obtained some product 3b in high enantio-
purity (Table 1, entry 1). Unfortunately, the yield was rather low
and no further improvement with alternative solvents and
bases was possible (e.g., Table 1, entry 2). We next attempted
the use of the proline dimer B,[21] which unfortunately gave
only a slightly higher yield, but with significantly lower enan-
tioselectivity (Table 1, entries 3 and 4). Similar observations
were made by using the trans-cyclohexane diamine C (Table 1,
entries 5 and 6) or derivatives thereof as the auxiliary. Finally,
we reasoned that it may be possible to increase the leaving-
group ability of the amine by using an (hemi)aminal-type struc-
ture with a less basic nitrogen.[23] We thus, synthesised a small
collection of the proline-derived amines D.[24,25] Gratifyingly, al-
ready the use of the most simple derivative D1 proved our hy-
pothesis right, giving the target epoxide 3b in more than 60%
yield with a promising initial level of enantioselectivity (enan-
tiomeric ratio (e.r.) =76:24) under biphasic liquid/liquid condi-
tions (Table 1, entry 7). Testing alternative reaction conditions
showed us that liquid/solid conditions by using Cs2CO3 as the
base gave compound 3b in more than 80% and comparable
selectivity in solvents like iPrOH or dichloromethane (Table 1,
entries 8 and 9). It should be noted that changing the reaction
temperature did not have any beneficial effect and we thus,
kept these room-temperature conditions to further optimise
the auxiliary next (Table 1, entries 9–15). Changing the aryl
moiety did not allow us to improve the outcome (see Table 1,
First, these calculations show that the barrier to ring closure
is higher for quinuclidine (8.5 kcalmolÀ1) as compared to trime-
thylamine (7.7 kcalmolÀ1) and DABCO (7.5 kcalmolÀ1), thus pro-
viding a reasonable explanation for the lower yields obtained
with this leaving groups. However, this step alone does not ex-
plain why trimethylamine allows for significantly higher epoxi-
dation yields than DABCO. As it can be seen in Figure 3, the
whole energy profile for trimethylamine is energetically lower
Figure 3. Computed free energy profiles [kcalmolÀ1] for the epoxidation by
using trimethylamine, DABCO and quinuclidine-based ammonium ylides
1.[20]
Chem. Eur. J. 2016, 22, 11422 – 11428
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