Organic Letters
Letter
a,b
(1) in the presence of the catalytic complex [Ir/(R)-L],
dichloroacetic acid and secondary amine (S)-A1 afforded γ,δ-
unsaturated aldehyde 3a in 16% yield and excellent
enantioselectivity (>99% ee). Notably, under these biphasic
reaction conditions no double allylation was observed. With
less bulky or primary amine catalysts such as proline or
benzhydrylamine, respectively, significant amounts of the bis-
allylated products as well as aldol side reactions were observed.
Further optimization revealed that more lipophilic Brønsted
acid promoter dibenzenesulfonimide in combination with [Ir/
(R)-L], (S)-A1 and allylic alcohol 2a afforded product 3a in
83% yield and >99% ee.10
Scheme 2. Preparation of α,β-Disubstituted Aldehydes
With the optimized reaction conditions in hand, we next
examined the substrate scope of this transformation with
regard to allylic alcohols (Table 1). A series of electron rich
Table 1. Allylic Alcohol Scope of the α-Allylation of
a−d
Aqueous Acetaldehyde
a
b
tion. Diastereomeric ratios were determined by 1H NMR analysis of
unpurified reaction mixtures. HQ = hydroquinone.
acetaldehyde with [Ir/(R)-L] and allylic alcohol 2a in the
presence of chiral amine A4 followed by the addition of
hexachloro-2,5-cyclohexadien-1-one afforded α-chlorinated
aldehyde 6 in good yield and high stereoselectivity. Similarly,
fluorinated product 7 could be obtained when A3 and N-
fluorobenzesulfonimide were employed.13 Hence, we have
established conditions for the rapid generation of molecular
complexity starting from acetaldehyde derived allylation
adducts.
To highlight the potential of the iridium-catalyzed allylation
of acetaldehyde in the context of target-oriented synthesis, we
undertook the formal syntheses of heliannuols C and E as well
as heliespirones A and C (Scheme 3). These sesquiterpenes
were isolated from the cultivated sunflower Helianthus annuus
and display herbicidal activity in bioassays, rendering them
potential scaffolds for the development of new and selective
pesticides.14−16 Starting from commercially available 2,5-
dimethoxy-4-methylbenzaldehyde, allylic alcohol 2j was
prepared in one step by addition of vinylmagnesium bromide.
Subsequent iridium-catalyzed allylation under the established
conditions afforded γ,δ-unsaturated aldehyde 8 in 74% yield.
Compound 8 was treated sequentially with sodium borohy-
dride and methoxymethyl chloride (MOM-Cl) to furnish
protected alcohol 9, which can be converted into (−)-heli-
annuol C, following a sequence reported by Shishido and co-
workers.17 Additionally, diene 12 was prepared from aldehyde
8 using a modified Julia−Kocienski olefination.18 Subsequent
Sharpless dihydroxylation afforded diol 13 in a highly
diastereoselective manner. Compound 13 was used by Liu
and co-workers as a key intermediate for the total synthesis of
heliannuol E and heliespirones A and C.19,20
a
Reactions run on 0.25 mmol scale under the standard conditions.
b
c
Yields of isolated aldehydes. ee of the corresponding primary
d
alcohol determined by SFC on a chiral stationary phase. Branched/
linear = 10:1.
(3b−3e) and electron deficient (3f and 3g) allylic alcohols
were found to be compatible with this transformation,
affording the corresponding aldehydes in good to moderate
yields and >99% enantiomeric excess. Gratifyingly, also
heteroaromatic allylic alcohol 2h as well as cinnamaldehyde-
derived substrate 2i were tolerated, resulting in equally high
degrees of enantioinduction.
Next, we aimed to utilize this iridium-catalyzed allylation of
acetaldehyde to rapidly gain access to more complex molecules
(Scheme 2). To this end, allylic alcohol 2a was reacted with
acetaldehyde under the previously established conditions, and
the crude reaction mixture was treated with a second amine
catalyst and an electrophile. This two-step procedure gave
access to α-oxygenated11 and α-alkylated12 products 4 and 5,
respectively, in good yields and diastereomeric ratios.
Encouraged by these results, we envisioned that such
transformations could also be carried out in a one-pot
procedure wherein one amine catalyst controls two sequential
α-functionalization reactions. Gratifyingly, treatment of
In conclusion, we have developed conditions for the
enantioselective α-allylation of acetaldehyde under biphasic
conditions. It is noteworthy that the transformation employs
readily available, aqueous solutions of acetaldehyde, rendering
it operationally simple an atom economic. A series of γ,δ-
unsaturated aldehydes could be synthesized with excellent
B
Org. Lett. XXXX, XXX, XXX−XXX