Organic Letters
Letter
but not with the original first-generation oxazaborolidines. We
find it to be a very useful and practical equivalent of N-
protected 1,2-diaminoethylenes. This approach is exemplified
for three common dienes in Scheme 2. In each case, excellent
Scheme 2. Fumaryl Chloride as a Useful Equivalent of N-
Protected (E)-1,2-Diaminoethylene
Figure 3. Diels−Alder products from α,β-unsaturated acid chlorides.
Figure 4. Useless but replaceable dienophiles.
A specific method for the enantioselective synthesis of two
different N-protected chiral 1,2-amino alcohols is shown in
Scheme 1 using catalyst 2 with Ar = 2,4-difluorophenyl (F2/F2
Scheme 1. Synthetic Route to 1,2-Amino Alcohols
enantioselection (>95:5) resulted along with good overall yield.
The method is also flexible with regard to the choice of the
group used for N-protection as well as for the diene component
for the (4 + 2)-cycloaddition reaction.
In contrast, the development of a dienophilic equivalent of
(
E)-3-aminoacrylic acid (14) turned out to be unexpectedly
challenging despite the availability of multiple precatalysts
based on core structures 1−5) and four different modes of
(
2
,3
activation (TfOH, Tf NH, Tf NH−TiCl , and AlBr ). The
2
2
4
3
(
4 + 2)-cycloaddition reactions of 1,3-cyclopentadiene with a
variety of (E)-fumaryl monoacid chloride monoesters and a
range of catalysts was found to be surprising non-regioselective.
The endo-ester/exo-acid chloride generally predominated but
only by 1.5:1 to 2.5:1 with methyl, tert-butyl, or trifluoroethyl
esters. This result is noteworthy in view of results from earlier
work demonstrating, for example, that trifluoroethyl acrylate
undergoes much slower (4 + 2)-cycloaddition than methyl
acrylate even though the latter coordinates more strongly to the
5
catalytic boron, and the same is true for the corresponding
symmetrical fumarate esters. This divergence of binding
5
catalyst) and (E)-β-boroacrylyl chloride 15 with either
cyclopentadiene or 1,3-cyclohexadiene. Acid chloride 15 is
readily available from the known ester by hydrolysis to the acid
affinity and reaction rate appears to manifest itself in the case
of unsymmetrical fumarate esters as diminished regioselectivity,
which is clearly shown by the results summarized in Scheme 3.
4
using LiOH and reaction with oxalyl chloride. The dienophile
5
1
5 is potentially quite versatile as a precursor of chiral (4 + 2)-
As mentioned in the introduction, previous research with
cycloaddition adducts since the boron is also a replaceable
the first-generation precatalyst 1 showed that the reaction of
acrylyl chloride with cyclopentadiene gave only racemic adduct,
indicating that the uncatalyzed reaction was very fast. Acrylyl
chloride also did not retard the reaction of cyclopentadiene
group. The boron in the adduct 18 from cyclopentadiene and
1
5 was readily converted to the more reactive boronic acid
equivalents 19 and 20 (R = COOMe) (Figure 5).
5
Fumaryl chloride is a readily available and reactive dienophile
that undergoes enantioselective (4 + 2)-cycloaddition with the
second-generation F2/F2 catalyst/Tf NH−TiCl combination
with methyl acrylate. Thus, it is clear that protonated 1 is not
sufficiently strong as a Lewis acid to bind or activate α,β-
unsaturated acid chlorides, which must therefore be much less
basic than, for example, the corresponding esters. In contrast,
the second-generation catalysts based on 2−5 are capable of
binding to and activating acid chlorides. Acrylyl fluoride is even
less basic than acrylyl chloride and does not react with
cyclopentadiene even with second-generation activated oxaza-
borolidines such as 2−5. Thus, it is of great interest that the
reaction of fumaryl methyl ester fluoride (26) with cyclo-
pentadiene using Tf NH−TiCl or Tf NH-activated F2/F2
2
4
Figure 5. Some boronic acid derivatives from 18.
2
4
2
B
Org. Lett. XXXX, XXX, XXX−XXX