COMMUNICATION
In addition, we have disclosed a Pd-catalyzed, aerobic, oxi-
dative dehydrogenation of saturated aldehydes to enals in
the presence of prolinol or o-anisidine co-catalysts.[9] How-
ever, these methods are not applicable for polyene synthesis,
because of their relative harsh reaction conditions, and thus,
sensitive conjugate systems, particularly ones like the bis-
alkyne and butenolide moieties in dihydroxerulin (1, see
below), cannot be tolerated. Therefore, even milder reaction
conditions are required for the critical transformation.
Moreover, such a method is highly valuable for the synthesis
of a large array of fascinating polyene natural products.[10]
Recently, we and Hayashi independently reported an in-
teresting organocatalytic oxidative enamine-catalysis strat-
egy for directly transforming a saturated-aldehyde-derived
enamine 7 to an iminium ion 8 (Scheme 2 a).[11] According
(Scheme 2 b). This would afford a “one-pot” procedure for
the direct preparation of a,b-unsaturated aldehydes from
readily available simple alcohols. It is recognized that enals
have arguably become the most widely used substrates in
iminium catalysis.[12–14] Although it seems straightforward to
convert simple aldehydes to the corresponding enals based
on the oxidative enamine-catalysis pathway (Scheme 2 a),
significant concern remains about the compatibility of the
reaction conditions for the direct transformation of alcohols
instead of aldehydes to enals. Moreover, it is uncertain if
the highly sensitive conjugated polyene and polyyne struc-
tures would be tolerated with using this chemistry. There-
fore, successful execution of the proposed chemistry allows
us to purse new organic transformations and may afford a
novel, alternative approach to polyenes, which represent
widely distributed molecular architectures featured in a
large array of molecules.[10]
With these considerations in mind and in conjunction with
the total synthesis of dihydroxerulin (1), the model com-
pound 5-(4-chlorophenyl)pent-4-yn-1-ol (11a), consisting of
ꢀ
a C C bond, was designed to probe the feasibility of the
direct transformation of alcohols into enals (Table 1). Treat-
ment of 11a with IBX (2.5 equiv) in the presence of diphe-
nylprolinol trimethylsilyl ether (I, 20 mol%)[15] as catalyst
was performed in our initial attempt. The reaction condi-
tions used initially were similar to our previous studies of
the enantioselective b-functionalization of aldehydes,[11]
except the solvent, where DMSO instead of CH2Cl2 was
used, because for the oxidation of alcohols by IBX essential-
ly DMSO was required.[13] To our delight, the desired enal
product 10a1 was obtained in 69% yield with a good E/Z
ꢀ
ratio, while the C C bond was not affected under the reac-
tion conditions (Table 1, entry 1). Encouraged by the out-
come, we examined the reaction by screening a series of pyr-
rolidine-based catalysts, aiming to improve the reaction effi-
ciency (entries 2–5). Notably, both IV and V among the cata-
lysts probed gave the highest yields (entries 4 and 5, 82 vs.
85%). We decided to use IV[16] for further optimization of
the reaction conditions, because of its ready availability and
it giving slightly better E/Z selectivity than V. To further im-
prove the reaction yield and E/Z selectivity, we surveyed
solvent effects. Since DMSO is the solvent of choice for the
oxidation of alcohols to aldehydes,[13] mixtures of DMSO
with various solvents (v/v=1:1.5) were tested subsequently
(entries 6–10). It was found that the effect was significant. A
mixture of DMSO/CH3CN provided the best results (86%
yield, E/Z=6:1, entry 10). We then examined the influence
of the DMSO/CH3CN ratio. It was observed that increasing
or decreasing the ratio of CH3CN both resulted in lower re-
action yields (entries 11 and 12 vs. entry 10). An attempt to
decrease the loading of either IBX or the catalyst failed to
deliver the product 10a1 in comparable yields, because of
the incomplete conversion of aldehyde 10a2 to 10a1. The
relatively high catalyst loading is presumably owing to some
of the chiral amine catalyst being oxidized to an imine by
IBX.[17] Other hypervalent iodine compounds, including
commonly used Dess–Martin periodinane (DMP) and phe-
Scheme 2. Oxidative enamine catalysis for the synthesis of a,b-unsaturat-
ed aldehydes from aldehydes and alcohols. Nu=nucleophile.
to our preliminary mechanistic investigation, the process in-
volves a 2eÀ transfer.[11a] The preparative power of this pro-
cess has been demonstrated in the context of direct asym-
metric b-functionalizations of simple aldehydes 9 in a cas-
cade manner. The chemistry serves as an alternative to the
extensively studied iminium catalysis by MacMillan,[12]
which relies on the use of a,b-unsaturated aldehydes as es-
sential reactants in a conjugate-addition fashion. In our con-
tinuing effort on exploring this chemistry, we questioned
whether it could be extended to the synthesis of C=C bonds
À
through dehydrogenation of saturated C C bonds, because
the reaction pathway involves the formation of an iminium
species 8. It is conceivable that such an intermediate could
undergo hydrolysis in the absence of a nucleophile to pro-
duce
a,b-unsaturated
aldehydes
10
as
products
(Scheme 2 a). Furthermore, we envisioned that merging the
IBX-mediated oxidation of alcohols to aldehydes[13] with
this amine-catalyzed IBX-oxidation reaction of aldehydes
could lead to the development of a new cascade process
Chem. Eur. J. 2012, 18, 2230 – 2234
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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