Angewandte
Chemie
DOI: 10.1002/anie.201205680
Synthetic Methods
Rhodium-Catalyzed Cross-Aldol Reaction: In Situ Aldehyde-Enolate
Formation from Allyloxyboranes and Primary Allylic Alcohols**
Luqing Lin, Kumiko Yamamoto, Shigeki Matsunaga,* and Motomu Kanai*
The aldol reaction is one of the most fundamental carbon–
carbon bond-forming reactions. cross-aldol reaction
between two different aldehydes, in principle, provides the
methodology, several organocatalytic enantioselective direct
aldehyde–aldehyde cross-aldol reactions have been devel-
A
[5]
oped, but enamine catalysis is realized simply based on the
inherent steric and/or electronic bias between the two differ-
ent aldehydes. Cross-aldol reactions that override the bias, for
example, propanal as an acceptor and other sterically more
[
1]
most straightforward step- and redox-economical access to
[2,3]
[4]
polyketides.
Numerous modern aldol methods, however,
utilize ketones, thioesters, esters, and other carboxylic acid
derivatives as donors to circumvent the problems inherent to
aldehyde–aldehyde cross-aldol reactions. Thus, additional
multistep transformations of aldol products, including pro-
tection and redox processes, are required to generate b-
hydroxy-protected aldehydes. In the cross-aldol reaction
between two different aldehydes, chemoselective activation
of one aldehyde as a donor and the other aldehyde as an
acceptor is difficult, and often affords mixtures of homo- and
heteroaldol products (Scheme 1a). As a state-of-the-art
[6]
hindered aldehydes as donors, are extremely difficult.
A
method to generate an aldehyde-derived enolate from a non-
[7–9]
carbonyl precursor through an orthogonal activation mode
would provide an alternative and complementary approach to
obtaining aldehyde–aldehyde cross-aldol products (Sche-
me 1b). Herein, we report a rhodium-catalyzed one-pot
isomerization/cross-aldol sequence using primary allylic and
homoallylic alcohol borates as well as primary allylic and
homoallylic alcohols as nucleophile precursors. The isomer-
ization and cross-aldol reaction proceeds at ambient temper-
ature, even when using readily enolizable aldehydes, such as
propanal, as acceptors.
Preformed silyl enol ethers derived from aldehydes have
been utilized to avoid the chemoselectivity problem in the
aldehyde–aldehyde cross-aldol process, as demonstrated by
[
10]
[11]
Yamamoto and co-workers, Denmark and co-workers,
[
12]
and others. In contrast, the use of aldehyde-derived enol
boranes is rare because they are unstable and prone to
polymerization. Considering the synthetic utility of other
enol boranes derived from ketones and carboxylic acid
derivatives, the development of a new method to utilize
various aldehyde-derived enol boranes is highly desirable.
To avoid handling unstable aldehyde-derived enol bor-
anes, we first investigated the in situ generation of aldehyde-
[
13]
[14]
Scheme 1. Cross-aldol reaction between two different aldehydes:
a) conventional method starting from two aldehydes, and b) this work
proceeding through the chemoselective generation of aldehyde eno-
lates from primary allylic and homoallylic alcohols and allyloxy and
homoallyloxyboranes.
derived enol boranes through transition-metal-catalyzed
[15]
isomerization of triallyloxyboranes
in the presence of
acceptor aldehydes. Optimization studies of the one-pot
isomerization/cross-aldol sequence using 2-bromobenzalde-
hyde (1a) and triallyloxyborane (2a) are summarized in
Table 1. With [{Rh(cod)Cl} ] (1.25 mol%, 2.5 mol% of [Rh];
2
[
*] L. Lin, K. Yamamoto, Dr. S. Matsunaga, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
cod = 1,5-cyclooctadiene), various phosphine ligands were
screened (entries 1–12). Monodentate phosphines did not
afford the aldol adduct (entries 1–3). Among the bidentate
diarylphosphines (entries 4–7), only dppf gave the desired
product, albeit in poor yield (entry 7). Electronic and steric
modifications of the ferrocene-based ligand effectively
improved the reactivity of the rhodium catalysts (entries 8–
K. Yamamoto, Dr. S. Matsunaga, Prof. Dr. M. Kanai
Kanai Life Science Catalysis Project, ERATO Japan Science and
Technology Agency, Tokyo 113-0033 (Japan)
1
0), and dippf, bearing PiPr units, gave the best results, thus
2
[
**] This work was supported in part by ERATO from JST, a Grant-in-Aid
for Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” from MEXT, and Naito
Foundation. L.L. thanks the Uehara Memorial Foundation for
scholarship.
giving the product 3a in 99% yield and 94:6 d.r. at room
temperature after 23 hours (entry 8). In contrast, the steri-
cally more hindered dtbpf bearing PtBu2 units had poor
reactivity (entry 10). We also examined other bidentate alkyl
phosphines, but the desired reaction did not proceed
(entries 11 and 12). Other rhodium sources, including the
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!