Enantioselective Alkylation of the
Indole Nucleus - Part One of Two:
Enantioselective Organocatalytic Indole Alkylation
The indole nucleus, known as a privileged platform, is present in a wide
range of natural products and important synthetic molecules. Many strategies
have been developed for the catalytic asymmetric alkylation of indoles; however,
only recently have enantioselective methods been reported.
Part I. Enantioselective Organocatalytic Indole Alkylation
Austin and MacMillan (J. Am. Chem. Soc. 2002, 124, 1172.
the enantioselective organocatalytic alkylation of the indole nucleus using the
imidazolidinone catalyst 1 (Scheme 1).
Scheme 1 - Enantioselective alkylation of indole using
1 as organocatalyst.
The catalyst design was based on kinetic studies and enantiocontrol criteria:
control of iminium ion geometry ((E)-isomer), enantiofacial
discrimination, and avoidance of nonbonding interactions between the olefin and
the t-butyl group present in 1 (the Re-face is left free
for the addition reaction - see Figure 1). This catalyst proved to be very
effective for the enantioselective alkylation of several indoles (up to 97% ee
and up to 94% yield), including indoles that contain electron-deficient groups
such as 6-chloroindole. These halogenated indole adducts are important building
blocks for drug synthesis, as they can be used in coupling processes.
Figure 1 - Computational model of iminium ion of 1,
showing freedom from steric hindrance.
Recently, this concept has been extended to the synthesis of pyrroloindoline
alkaloids (PNAS 2004, 101, 5482.
These alkaloids exhibit diverse biological activity and are structurally
complex, making them challenging synthetic targets that attract the attention of
many research groups. Austin and MacMillan developed a new catalytic
enantioselective approach that allows the construction of the pyrroloindoline
skeleton in one step, with stereocontrol at C(3a) (for example, in
(-)-Flustramine B, Figure 2).
Figure 2 - (-)-Flustramine B, a representative example of
The authors’ strategy consisted of a cascade sequence (conjugate
addition-cyclisation) to form the pyrroloindoline skeleton from tryptamines and
simple α,β-unsaturated aldehydes (Scheme 2), using the chiral amine catalyst
1. These authors call our attention to the fact that the solvent proved
to be very important. While best results were obtained with CH2Cl2-H2O
for reactions with acrolein, the use of dry CH2Cl2
resulted in higher enantioinduction with β-substituted α,β-unsaturated
aldehydes. The versatility of this method has been demonstrated by the results
obtained with diverse tryptamine derivatives 5 which were used
successfully with unsaturated aldehydes 6 (high yield up to 99% and high
enantioselectivity up to 99% ee).
Scheme 2 - Enantioselective construction of the
pyrroloindoline system by conjugate addition-cyclisation process.
The Denhart group applied this method to the synthesis of homotryptamines in
one-pot directly from indoles and acrolein with subsequent reductive amination (Tetrahedron
2004, 45, 3803.
However, only indoles without strong electron-withdrawing groups and
α,β-unsaturated aldehydes that possesses no α-substituents were tested.
Recently, this group (Org. Lett. 2005, 7, 3437.
enlarged the scope of this method, by applying the MacMillan/Northrup catalyst
8 (J. Am. Chem. Soc. 2002, 124, 2458.
to the synthesis of the highly potent Selective Serotonin Reuptake
Inhibitor (SSRI) 12 (Scheme 3).
Scheme 3 - Synthesis of (SSRI) 12 via
enantioselective alkylation of indole 9 catalysed by 8.
Catalyst 1 was not effective on alkylations with α-branched
substrates, whilst catalyst 8 proved to be very effective at allowing the
formation of the corresponding adducts with high enantiocontrol (up to 85% ee).
The synthesis of 12 was performed with 5-iodoindole (9), since
5-cyanoindole only gave trace amounts of the desired product. In this case the (S)-product
11 was isolated, instead of the (R)-product isolated by MacMillan.
The authors give an explanation for the observed preference based on molecular
modelling studies: the (E)-iminium ion A has the Si-face
sterically blocked by the benzyl group so the indole cannot add to the
cyclopentene; the trans-Z-iminium
B is preferred to the cis-Z-iminium C since the latter is
0.94 Kcal/mol higher in energy. The trans-Z-iminium B represents
the more favourable conformation that avoids the steric interactions between C-5
and benzyl group (Scheme 4).
Scheme 4 - Proposed mechanism for the observed
enantioselectivity of the indole alkylation.
The use of an organocatalyst derived from phenylalanine was developed as a
new strategy in asymmetric synthesis, in particular in indole alkylation by
lowering the LUMO of the olefin via the reversible formation of an iminium ion.