Chiral bronsted acid-catalyzed allylboration of aldehydes

Article abstract of DOI:10.1021/ja104956s

The catalytic enantioselective allylation of aldehydes is a long-standing problem of considerable interest to the chemical community. We disclose a new high-yielding and highly enantioselective chiral Bronsted acid-catalyzed allylboration of aldehydes. Th

Full text of DOI:10.1021/ja104956s

Published on Web 08/06/2010
Chiral Brønsted Acid-Catalyzed Allylboration of Aldehydes
Pankaj Jain and Jon C. Antilla*
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue, Tampa, Florida 33620
Received June 7, 2010; E-mail: jantilla@usf.edu
Table 1. Optimization of the Catalytic Allylboration of Aldehydesa
Abstract: The catalytic enantioselective allylation of aldehydes
is a long-standing problem of considerable interest to the chemical
community. We disclose a new high-yielding and highly enantio-
selective chiral Brønsted acid-catalyzed allylboration of aldehydes.
The reaction is shown to be highly general, with a broad substrate
scope that covers aryl, heteroaryl, R,ꢀ-unsaturated, and aliphatic
aldehydes. The reaction conditions are also shown to be effective
for the catalytic enantioselective crotylation of aldehydes. We
believe that the high reactivity of the allylboronate is due to
protonation of the boronate oxygen by the chiral phosphoric acid
catalyst.
entry
solvent
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
ether
DCM
THF
16
16
48
48
24
48
2
1
4
16
16
16
99
99
51
99
76
55
99
99
99
99
99
99
35
88
6
Asymmetric allylboration of aldehydes has been an invaluable
m-xylene
EtOAc
CH3CN
benzene
toluene
toluened
toluenee
89
29
33
92
93
96
98
97
95
tool for the formation of carbon-carbon bonds with control over
relative and absolute stereochemistry.1 The foundation of this
reaction was provided by Hoffmann’s recognition of the diastereo-
specificity of the reaction when both (E)- and (Z)-crotylboronates
are used2a-c and Brown’s highly stereoselective allylborations using
pinene-derived chiral reagents.2d-f Over the past three decades,
additional methodologies that have relied upon stoichiometric chiral
reagents or mediators have included work by Roush,3a-c
Masamune,3d Corey,3e Seebach,3f Duthaler,3g Panek,3h Leighton,3i,j
Chong,3k Soderquist,3l,m and Aggarwal.3n Catalytic methods have
also emerged, and in part these include work by Yamamoto,4a
Umani-Ronchi,4b Keck,4c Denmark,1b,4d and others.4e,f Also, recent
catalytic allylborations by Hall,5a-g Miyaura,5h Shibasaki,5i and
Schaus5j,k have opened new doors for the synthesis of homoallylic
alcohols. However, most stereoselective methods are limited by
one or more drawbacks. These include the use of stoichiometric
chiral inductors, allylation reagents that are difficult to prepare or
are air/moisture-sensitive, the use of undesirable metal-based
catalysts such as tin, or substrates leading to toxic byproducts.
Hence, the search continues for a competent, catalytic, and practical
solution for the direct enantioselective synthesis of homoallylic
alcohols, an important class of versatile intermediates used in the
synthesis of pharmaceuticals and natural products.1a
Binaphthyl-derived chiral phosphoric acids (PAs) have been
shown to be versatile and efficient catalysts that promote a variety
of enantioselective transformations. Chiral PA catalysts have found
success in a large number of carbon-carbon and carbon-heteroatom
bond-forming processes as well as a variety of oxidation and
reduction reactions.6 Although chiral PA-catalyzed reactions involv-
ing aldehydes are very rare,7,8 we investigated the enantioselective
synthesis of homoallylic alcohols by reacting aldehydes with
allylboronic acid pinacol ester 2 using chiral acid-catalyzed
conditions. Boronate 2 is a relatively stable, nontoxic, commercially
available reagent, so it was an ideal choice for our evaluation of
the chemistry.
10
11
12
toluenee f
,
toluenee g
,
a Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), 5 mol %
(R)-TRIP-PA, unless otherwise specified. b Isolated yield. c Determined
by chiral HPLC analysis. d Reaction conducted at 0 °C. e Reaction
conducted at -30 °C. f Using 2.5 mol % catalyst. g Using 1 mol %
catalyst.
very effective promoter.9 Upon solvent screening, we found that
toluene, m-xylene, benzene, and methylene chloride were effective
for the asymmetric synthesis of alcohol 3a (Table 1). It was
determined that toluene was the most suitable solvent, allowing
for a 93% ee of 3a at room temperature in a reaction time of 1 h
(entry 8). The enantioselectivity was further improved by reducing
the temperature to 0 °C (96% ee; entry 9) and -30 °C (98% ee;
entry 10) in the presence of 5 mol % catalyst. It was fascinating to
find that lowering the catalyst loading to 2.5 mol % allowed for a
97% ee (entry 11), and further lowering to 1 mol % (entry 12) still
allowed for an impressive 95% enantioselectivity.
The optimized reaction conditions were effective in promoting
the asymmetric allylboration of a wide range of aldehydes, allowing
for an extremely efficient reaction (Table 2). The substrate scope
extended to electron-rich and electron-poor aromatic aldehydes
(entries 1-11). An ester functional group was tolerated in the
chemistry (entry 8), and several hindered aldehydes also were
effectively allylated (entries 7, 9, and 10). We were particularly
pleased to find that heteroaryl (entry 12), R,ꢀ-unsaturated (entries
13 and 14), and aliphatic (entries 15 and 16) aldehydes were found
to be allylated efficiently with high enantioselectivity. The only
limits on enantioselectivity were found upon further evaluation of
aliphatic aldehydes (entries 17 and 18).
During the initial investigations leading to a catalytic reaction
between benzaldehyde and 2, (R)-TRIP-PA (4) was found to be a
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C O M M U N I C A T I O N S
Table 2. Asymmetric Allylboration of Aldehydesa
proceeds via a type-I mechanism involving a chairlike six-
membered cyclic transition state, similar to previous uncatalyzed
reactions involving allylboronates.11 Recent work by Hall5f,g and
Schaus5k suggested that activation by protonation of the boronate
oxygen could be involved. Similarly, Lewis acid-promoted boronate
activation has also been invoked previously.5b As the basis of a
working hypothesis, we also propose that activation via protonation
of the boronate oxygen by the chiral phosphoric acid catalyst would
provide a reasonable explanation for the reactivity (Figure 1).
Figure 1. Plausible transition-state assembly for chiral phosphoric acid-
catalyzed allylation of aldehydes.
In conclusion, we have developed a simple and highly efficient
chiral phosphoric acid-catalyzed allylboration of aldehydes. The
protocol provides a highly enantioselective method for the synthesis
of homoallylic alcohols from simple starting materials. The usefulness
of this organocatalytic reaction is highlighted by the stability and
commercial availability of the substrates and the catalyst. This work
also has the potential to open new vistas for chiral phosphoric acid-
catalyzed activation that were not previously evident. Mechanistic
investigations and theoretical considerations are in progress and will
be reported in due course.
a Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), 5 mol %
(R)-TRIP-PA. b Isolated yield. c The products were determined to be R
by chiral HPLC analysis and optical rotation data in the literature.
d With (S)-TRIP-PA the opposite (S) enantiomer of 3a was also
obtained in 98% yield and 97% ee under otherwise identical conditions.
e In three cases, the opposite (S) enantiomer was produced in excess
using the (R)-TRIP-PA catalyst.
Acknowledgment. We thank the National Institutes of Health
(NIH GM-082935) and the National Science Foundation CAREER
Program (NSF-0847108) for financial support. We also thank Tao
Liang for preparation of the catalyst and Matthew J. Kaplan for
helpful suggestions.
Table 3. Asymmetric Crotylboration of Benzaldehydea
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
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