Organic Letters
Letter
very few catalytic, enantioselective methods exist that afford
products in high diastereo- and enantioselectivities. Our
objective was the development of a general protocol for
setting quaternary centers in homoallylic alcohols by employ-
ing γ,γ-disubstituted allylic 1,1-diboronate esters. Allylic 1,1-
diboronic esters have been employed in the crotylation and
optimization. In the presence of 5 mol % CuOtBu, 10 mol %
ligand, and 1.05 equiv MeOH in THF at −60 °C, several
classes of chiral ligands were examined. Bidentate phosphines
L1−3 proved ineffective, <2−8% conversion to 3a (entries 3−
5). Switching to phosphoramidite L4 delivered 3a in 89% yield
(>98:2 γ-allylation) in 2.7:1 dr and >99:1 er (entry 6).
Notably, < 2% conversion to 3a is observed in the absence of
methanol (entry 7). Investigation of phosphoramidite 3,3′-aryl
substitution (entries 8−10) identified 3,5-i-Pr-4-OMe sub-
stitution (L7) as optimal (>99:1 er, 4:1 dr) (entry 10). In an
effort to further improve the dr, the reaction with L7 was run
at −78 °C; however, this resulted in no improvement in
selectivity. To test if a reductive workup was necessary given
the high conversion with L7 in 16 h, the equivalent reaction
with aqueous workup was found to afford a near identical
result (98% NMR yield, 4:1 dr, 98.5:1.5 er). Consequently,
provided catalytic reactions proceed to >98% consumption of
14,15
prenylation of aldehydes;
however, extension of these
methods for enantio- and diastereoselective allyl addition
beyond prenylation to set quaternary stereocenters has not
been achieved.
Encouraged by our previous studies regarding the enantio-
and diastereoselective reactions of γ,γ-disubstituted allylic 1,1-
16
17
bis(boronates) with aldimines and ketones, we envisioned
the stereoselective reaction in Scheme 1E. The enantio- and
diastereoselective preparation of complex secondary homoallyl
alcohols with vicinal quaternary carbon stereocenters bearing a
functional E-alkenylboron can be achieved by catalytic
reactions between an array of aldehydes (1) and readily
accessible stereodefined 2.
18
aldehyde, a reductive workup is not required.
The robustness of the reaction conditions was surveyed, and
it was found to be broad. As shown in Scheme 2A, a wide
variety of aromatic substrates are tolerated, including those
containing electron-donating groups (3b), halogens (3c−d),
and electron-withdrawing ester (3e), nitrile (3f), nitro groups
We began our studies with the reaction of benzaldehyde
(1a) and allyl diboronic ester 2a (Table 1). An initial control
reaction between 1a and 2a in THF at −60 °C, followed by an
aqueous (entry 1) and NaBH (entry 2) workup, revealed
4
(
3g−h) and trifluoromethyl (3i), to deliver products in
significant background addition of unreacted 2a occurs upon
workup (38% conv, >20:1 dr vs <2% conv). This outcome
highlighted the need for a reductive quench during catalyst
excellent yields and er. Notably, meta and ortho substituted
arenes undergo efficient and selective reaction (3h−k).
Furthermore, a range of heteroarene products including
pyridine (3k), furan (3l), and thiophene (3m) moieties are
accessible in excellent yield and er albeit in 3:1−4:1 dr. In
reactions with aldehydes containing extended π-systems, such
as indole (3n), benzofuran (3o), and benzothiophene (3p),
products are generated in higher diastereoselectivity in
excellent yields and enantioselectivities. Moreover, synthesis
of indole 3n on a 1.0 mmol scale demonstrated robustness of
the protocol.
a
Table 1. Reaction Optimization
The catalytic protocol also extends to alkenyl, alkynyl, and
alkyl aldehydes (Scheme 2B). Unsaturated cinnamyl, tiglic, and
cyclohexenyl aldehyde substrates are converted to homoallylic
alcohol products 5a−c in excellent yield and ≥99:1 er, and
4
:1−6:1 dr, respectively. In addition, reaction with enantioen-
riched (−)-myrtenal delivers 5d in 82% yield and 9:1 dr.
Reactions of alkynyl aldehydes also react efficiently; however, a
decrease in diastereoselectivity results. For example, prop-
argylic alcohol 5e is formed in 84% yield, 2:1 dr, and 98.5:1.5
er (major) and >99:1 er (minor). High yields and selectivity
are similarly observed with more challenging, less electrophilic
aliphatic aldehydes. For example, a variety of alkyl-substituted
aldehydes bearing t-Bu (5f), cyclic (5g−i), and β-branching
(
5j) were found to react smoothly to deliver desired products
in 68−99% yield, ≥ 99:1 er, and >20:1−4:1 dr. Additionally,
no adverse effects arising from a pendant alkene moiety in
reactions with 4-pentenal and (−)-citronellal to afford 5k and
5
l were observed.
Finally, the scope of the quaternary carbon stereocenter was
investigated by varying the substituents introduced on the
allyldiboron reagent (Scheme 3). Notably, diastereomers 6b
and 6c could be synthesized stereospecifically by subjecting
either E- or Z-allyldiboronates to the reaction conditions, with
both obtained in high dr and er. The increased sterics
associated with α-branched cyclohexyl and cyclopropyl
reagents are tolerated to produce 6d and 6e in excellent
yield and selectivity. Moreover, after a single recrystallization,
6e could be enriched to 20:1 dr, and the X-ray structure was
a
b
Reactions performed under a N2 atmosphere. NMR yield and
1
diastereomeric ratios (dr) determined by analysis of H NMR spectra
of crude reactions with hexamethyldisiloxane as the internal standard.
c
d
Enantiomeric ratios (er) determined by SFC analysis. No CuOtBu,
e
f
ligand, or NaBH quench. Reaction at −78 °C. No NaBH quench.
4
4
B
Org. Lett. XXXX, XXX, XXX−XXX
Wheatley, Emilie
