Synthesis of ꢀ-Substituted-R,γ-Diaminobutyric Acids
attention was paid probably due to the lack of a general method
for their syntheses.
Pyrrolidines are of the important class of five-membered
heterocycles, which not only are common structural subunits
present in natural and unnatural products9 but also are widely
used as chiral auxiliaries in asymmetric organic synthesis.10
Depending on the substitution pattern and functionalization,
pyrrolidines have been reported to possess different important
biological activities. They can act as antibacterials,11 neuroex-
citatory agents,12 glycosidase inhibitors,13 and fungicides.14
However, their construction with predictable regio- and stereo-
control still constitutes a challenge in organic chemistry.
Michael addition of electron-deficient olefins is without
question one of the most classical and fundamental car-
bon-carbon bond formation reactions.15,16 Nitroalkenes have
been attracting continuous attention as electron acceptors
because the nitro group can only lead to 1,4-addition as a result.
This reaction and its similar variants have been extensively used
in organic synthesis.17 Thus, it is not surprising that the
development of enantioselective catalytic protocols for this
reaction has received much attention.16d-k The chiral auxiliary
methods are attractive approaches to stereocontrolling in such
reactions. Important examples involved the stereocontrolled
Michael addition of chiral glycine-derived enolates to electron-
poor olefins.18 Tricyclic iminolactones19a could act as effective
equivalents of chiral amino acids in Michael addition reactions
to nitroalkenes, thus allowing the convenient synthesis of
enantiomerically enriched R,γ-diaminobutyric acids after sub-
sequent manipulation of the nitro group and removal of the
camphor-based protecting group. This process leads to the
generation of up to two new stereogenic centers in the product.
FIGURE 1. Tricyclic iminolactones 1 and 2.
In this study, we focused our attention on the convenient
asymmetric synthesis of the optically active ꢀ-substituted-R,γ-
diaminobutyric acids via Michael addition followed by hydroly-
sis. In addition, high diastereoselectivity was obtained in the
synthesis of pyrrolidines containing multichiral centers via
Michael-Mannich tandem reaction in the presence of Cu(OTf)2
or AgOTf.
Results and Discussion
Recently, we reported the synthesis of two novel chiral
tricyclic iminolactones, (1S,2R,8R)-8,11,11-trimethyl-3-oxa-6-
azatricyclo[6.2.1.02,7]undec-6-en-4-one (1) and (1R,2S,8S)-
1,11,11-trimethyl-3-oxa-6-azatricyclo[6. 2.1.02,7]undec-6-en-4-
one (2), prepared from (1R)-(+)-camphor as glycine equivalents,
which have been successfully applied to the asymmetric
synthesis of R-monosubstituted-R-amino acids, R,R-disubsti-
tuted-R-amino acids, and R,ꢀ-diamino acids.19 Nitroalkenes,20
as electron-deficient alkenes, were easily prepared via Henry
reaction and subsequent dehydration procedure, which could
be ideal acceptors for these two iminolactones 1 and 2 to prepare
R,γ-diaminobutyric acids (Figure 1).
In order to find the experimental conditions most suitable
for Michael addition, chiral tricyclic iminolactone (1) as the
nucleophile and trans-ꢀ-nitrostyrene (a) as the Michael acceptor
were selected at first for our model reactions. Representative
results are listed in Table 1. To maximize diastereoselectivity,
we performed the reaction at -78 °C as we did before.19
Considering the solvent effect,21 different solvents in the
presence of LiCl and LDA were examined initially. The results
showed that THF gave good diastereoselectivity and conversion
rate compared with dichloromethane and toluene (entries 1-3).
The effects of base and additives were also investigated.
Specifically, both n-BuLi and LHMDS in THF afforded poor
diastereoselectivities (dr 62:38 in LHMDS and dr 59:41 in
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