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of type 1, bearing either the Moc- or benzyl group at the
indole nitrogen atom, were tested in reactions with 2a.
profiles rendered them promising candidates to be tested in
the asymmetric HVMAR addition to 2g (for 13C NMR-based pre-
diction of reactivity, see below). Pleasingly, under slightly modi-
fied reaction conditions (reaction temperature À308C and
10 mol% TBAOTf additive), both nucleophiles 1h and 1i react-
ed with 2g to yield the bisvinylogous adducts 3hg and 3ig,
respectively, with high regio-, diastereo- and enantiocontrol,
albeit in rather modest yields of the isolated products (40 and
50%, respectively). To our knowledge, this is the first example
of catalytic, enantioselective, bisvinylogous Mukaiyama aldol
reactions on aliphatic aldehyde acceptors.
Variation of the R3 and R4 substituents within the C3 diene
appendages as well as the R2-benzo-ring substituent were well
tolerated, returning the corresponding products 3ca, 3da, and
3ga in good yields and stereoselectivities. The 6-methoxy de-
rivative 1 f, reminiscent of the natural soulieotine precursor, in-
stead furnished product 3 fa with a diminished yield (55% iso-
lated), albeit with good E,E-diastereocontrol and excellent
enantioselectivity. Among the above examples, particularly
noteworthy is triene 1d, which embodies a prochiral terminal
alkene as an inseparable 2:1 E/Z mixture; it could react produc-
tively with benzaldehyde 2a to form carbinol 3da as a single
3E,2’E-, anti-configured isomer with high levels of enantioselec-
tivity (94% ee). As an exception, siloxyindole 1e, bearing
a highly congested tetrasubstituted terminal olefin, failed to
couple to benzaldehyde 2a, and no traces of the expected
product 3ea were obtained. We also investigated reactions
with diverse electron-rich and electron-poor aldehydes, namely
4-bromobenzaldehyde (2b), 4-methoxybenzaldehyde (2c), and
trans-cinnamaldehyde (2d). We were pleased to find that all al-
dehydes were converted into the corresponding 3E,2’E-adducts
(e.g., 3ab, 3bc, and 3bd) in 80–90% yields and 99% enantio-
selectivities. The viability of the hypervinylogous protocol was
further demonstrated by treating several N-benzyl silyloxyte-
traene indole substrates with a range of aromatic aldehydes.
Precise control of the geometry, regiochemistry, and stereo-
chemistry was attained in all cases, to deliver oxindole trienes
7ca, 7da, 7ea, 7be, and 7bf isolated in acceptable 60–85%
yields and rewarding selectivities. Once more, when a 2:1
(1’E,3’E,5’Z:1’E,3’E,5’E) mixture of prostereogenic derivative 6d
reacted with 2a, the all-E-configured carbinol 7da was formed
in 60% yield, with excellent anti/syn diastereoselectivity and
high enantiocontrol (95% ee). Switching to higher homo-
logues, the reaction of nPr-protected silyloxypentaene donor
with 4-bromobenzaldehyde 2b was carried out, affording crys-
talline tetraene carbinol 9cb, isolated in a pleasing yield of
70%, with good diastereoselectivity and almost complete
regio- and enantioselectivities (>99% ee). These reactions
demonstrated perfect relaying of the N,O-silylketene acetal
functionality along the limiting series of five conjugated
double bonds.
The overall alkene geometry and absolute configuration of
homoallylic tetraeneoxindole 9cb was unequivocally deter-
mined as 3E,2’E,4’E,6’E,9’R, based on the X-ray diffraction analy-
sis of its enantiomer ent-9cb (obtained using catalyst (S,S)-I).[17]
To ascertain the configuration of triene oxindole 7da, chemi-
cal correlation studies were performed, definitively assessing
its relative and absolute configuration (see the Supporting In-
formation). The absolute configurations of all other products in
this work were assigned by analogy. Polyenic alcohol products
in this study (coming from catalyst (R,R)-I) turned out to pos-
sess (R)-configuration at the carbinol center (S for compounds
3hg and 3ig, due to formal priority exchange according to CIP
rules), resulting from an attack of the polyene donor on the
Re-face of the aldehyde acceptor. This is in full accordance
with previous experimentation where Mukaiyama aldol (and vi-
nylogous aldol) reactions were carried out under the same
bisphosphoramide/SiCl4 activation modality.[12a]
HVMAR of 3-polyenyl 2-silyloxyindoles: Electronic and con-
formational clues
At this point, we reasoned that rationalization of the experi-
mental evidences could be useful to better evaluate successful
results and failures and, even more importantly, to find out
a reliable method upon which prediction abilities could be es-
tablished. The efficiency in channeling the nucleophilicity of
the indole N,O-silyl ketene acetals through the p-conjugate
system to the very remote w-site is likely dependent upon
a combination of electronic, steric, and conformational factors.
As a first point, the nucleophilic w-reactivity (HOMO activation)
proved strongly influenced by the indole N-substituent, whose
electron-withdrawing or electron-donating nature modulates
the charge distribution along the polyene chain up to the reac-
tive w-site. In this study, as a rule, the “activating” action fol-
lowed the progression: nPrꢀallyl>benzyl>methoxycarbon-
yl.[18]
As pointed out in the introduction, one of the challenging
goals of this work was to demonstrate the feasibility of the
HVMAR involving aliphatic aldehydes, whose behavior as slug-
gish or unreactive acceptors in Mukaiyama-type aldol reactions
catalyzed by the Denmark’s bisphosphoramide I/SiCl4 system is
renowned.[16] In our hands, when coupled to N-Moc or N-
benzyl-protected 3-butadienyl-2-siloxyindoles 1a or 1b, ali-
phatic 3-phenylpropanal (2g) failed to deliver any addition
product, testifying its poor reactivity vis-ꢁ-vis the aromatic
counterparts. Aware of the previous results likely suggesting
vinylogous reactivity amplification of polyene donors as a func-
tion of the electronic properties of the indole N-substituent,
a brief survey of differently protected trienolates of type 1 was
carried out. N-Allyl- and N-n-propyl silyloxyindoles 1h and 1i
were identified and selected, as their 13C NMR spectroscopic
In this context, analysis of diagnostic C-w peaks in the
13C NMR spectra of polyenolates 1, 4, 6, 8, and 10 was found
to be helpful in deciphering the behavior of these donor spe-
cies during the asymmetric catalytic HVMAR (Figure 2).
13C NMR chemical shift is primarily controlled by the s and p
electron density located on each carbon atom, undergoing an
upfield shift when the electron density increases.[19] In other
words, the more the C-w 13C NMR peak shifts to the right side
of the spectrum, the higher the nucleophilicity.[20]
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Chem. Eur. J. 2015, 21, 1 – 11
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!