The vinylogous aldol reaction of unsaturated esters and enolizable aldehydes using the novel Lewis acid aluminum tris(2,6-di-2-naphthylphenoxide)

Article abstract of DOI:10.1021/ol300738f

The synthesis of the novel Lewis acid, aluminum tris(2,6-di-2- naphthylphenoxide) (ATNP), and its use in the vinylogous aldol reaction between methyl crotonate and enolizable aldehydes are described. ATNP is related to Yamamoto's Lewis acid, aluminum tris(2,6-diphenylphenoxide) (ATPH), but the 2-naphthyl groups more effectively block the α-position of aldehydes, enabling the selective enolization of crotonate esters in the presence of enolizable aldehydes. Vinylogous aldol reactions then proceed smoothly and in high yields with a variety of substrates.

Full text of DOI:10.1021/ol300738f

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2678–2681
The Vinylogous Aldol Reaction of
Unsaturated Esters and Enolizable
Aldehydes Using the Novel Lewis Acid
Aluminum Tris(2,6-di-2-naphthylphenoxide)
Jeffrey A. Gazaille and Tarek Sammakia*
Department of Chemistry and Biochemistry, University of Colorado,
Boulder, Colorado 80309-0215, United States
sammakia@colorado.edu
Received March 22, 2012
ABSTRACT
The synthesis of the novel Lewis acid, aluminum tris(2,6-di-2-naphthylphenoxide) (ATNP), and its use in the vinylogous aldol reaction between
methyl crotonate and enolizable aldehydes are described. ATNP is related to Yamamoto’s Lewis acid, aluminum tris(2,6-diphenylphenoxide)
(ATPH), but the 2-naphthyl groups more effectively block the R-position of aldehydes, enabling the selective enolization of crotonate esters in the
presence of enolizable aldehydes. Vinylogous aldol reactions then proceed smoothly and in high yields with a variety of substrates.
The aldol reaction is a versatile carbonÀcarbon bond
forming transformation that is widely used and of great
importance in organic synthesis.1 The extension of this
reaction to its vinylog (i.e., the vinylogous aldol reaction)
is well-known and, in its simplest form, proceeds via
a dienolate and an aldehyde.2 The product, a δ-hydroxy-
R,β-unsaturated carbonyl compound, is rich in function-
ality, and as this bond construction occurs in an uncommon
position (between the γ- and δ-carbons of the product),
it offers novel strategic disconnections in synthetic plan-
ning. In recent years, the reaction has gained signi-
ficant attention from the organic community, and an
important advance was described by Hisashi Yamamoto
with the use of the very bulky Lewis acid, aluminum
tris(2,6-diphenylphenoxide) (ATPH 1, Scheme 1).3 ATPH
is used in reactions of lithium enolates and aldehydes, and
it is thought to bind to both the dienolate and the aldehyde
components of the reaction. Due to its bulk, it prevents
reaction at the R-carbon of the dienolate, thereby forcing
the reaction to occur at the distal γ-carbon (Scheme 1).
Remarkably, Yamamoto has used ATPH to direct reac-
tivity to the terminal carbon in substrates as large as
hexaenolates derived from pentaenoates.3b
An important feature of the Yamamoto protocol is that
the components must all be combined prior to the addition
of the base; attempts to conduct the reaction in a stepwise
fashion wherein the enolate is first formed and then the
aldehyde is added provide significantly diminished yields.3b,4
Because this reaction is not amenable to a two-step
(1) For recent reviews on the aldol reaction, see: (a) Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004. (b) Paterson, I.
Total Synthesis of Polyketides using Asymmetric Aldol Reactions. In
Asymmetric Synthesis, 2nd ed.; Christmann, M., Brase, S., Eds.; Wiley-
VCH Verlag GmbH & Co.: Weinheim, Germany, 2008; pp 293À298.
(2) For recent reviews on the vinylogous aldol reaction, see: (a) Casiraghi,
G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111,
3076. (b) Denmark, S. E.; Heemstra, J. R.; Beutner, G. L. Angew. Chem., Int.
Ed. 2005, 44, 4682.
(3) (a) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem.
Soc. 1998, 120, 813. (b) Saito, S.; Shiozawa, M.; Yamamoto, H. Angew.
Chem., Int. Ed. 1999, 38, 1769. (c) Saito, S.; Shiozawa, M.; Nagahara, T.;
Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 7847.
(d) Saito, S.; Nagahara, T.; Shiozawa, M.; Nakadai, M.; Yamamoto,
H. J. Am. Chem. Soc. 2003, 125, 6200. (e) Takikawa, H.; Ishihara, K.;
Saito, S.; Yamamoto, H. Synlett 2004, 732.
r
10.1021/ol300738f
Published on Web 05/23/2012
2012 American Chemical Society

Table 1. Vinylogous Aldol Reaction of Enolizable Aldehydes
with Various Known Lewis Acidsa
Scheme 1. Yamamoto Vinylogous Aldol Reaction with ATPH
enolization/aldehyde addition protocol, if the aldehyde com-
ponent is enolizable, there must be selectivity in the initial
deprotonation step; otherwise, a mixture of enolates will
result, providing a mixture of products. While Yamamoto
has described notable selectivity with many substrate combi-
nations, in the case of crotonate esters, the reaction provides
low yields when the aldehyde is enolizable and unhindered at
the R-carbon. For example, attempted vinylogous aldol reac-
tion between methyl crotonate (2) and valeraldehyde (3)
provides the desired product in a yield of only 22% (Table 1,
entry 1).3b This significantly limits the scope of this reaction,
and we recently needed to apply this method to an unbranched
enolizable aldehyde. We have, therefore, devised a Lewis acid
to overcome this limitation and describe our results herein.
In order to use enolizable aldehydes in this reaction, we
required a Lewis acid that upon binding to an aldehyde
renders it immune to enolization by bulky kinetic bases
such as LDA or LTMP. We, therefore, studied a number
of Lewis acids as surrogates for ATPH in a model vinylo-
gous aldol reaction between 2 and 3 in search of one
possessing the right combination of tight binding and bulk
(Table 1). Under standard reaction conditions (addition of
a cooled solution of LTMP (2.3 equiv) in THF to a toluene
solution of the Lewis acid (3.3 equiv), ester (2 equiv), and
aldehyde at À78 °C), none of the known bulky Lewis acids
that we studied, including those devised by Yamamoto
(MAD5 5, MABR6 6, MAT7 7, ATD8 8, Me-ATPH9 9),
were successful (Table 1).
a See text for reaction conditions. b A complex mixture was observed.
We wished to maintain the major design features of
ATPH and sought a Lewis acid with comparable bulk in
the vicinity of the aluminum, but with an extended “reach”
such that, upon binding to an aldehyde, there is greater
hindrance of the protons on the R-carbon and limited
accessibility to base. We, therefore, considered replac-
ing the phenyl groups of ATPH with 2-naphthyl groups
and devised aluminum tris(2,6-di-2-naphthylphenoxide)
(ATNP, 10, Scheme 2) wherein the naphthyl groups are
expected to extend further forward toward the R-carbon
of the aldehyde.
To examine this hypothesis, we modeled the ATNP/
valeraldehyde complex. We began with the crystal struc-
ture of Yamamoto’s ATPH/methyl crotonate complex,3d,10
added the corresponding 2-naphthyl groups, and replaced
the ester with valeraldehyde. We then adjusted the com-
plexation bond lengths and bond angles to the known
values for ATPH/aldehyde complexes.3d Energy minimi-
zation of this structure (MM2 force field, see Supporting
(4) Yamamoto’s procedure wherein formation of the enolate occurs
in the presence of the aldehyde suggested to us that intramolecular
reactions are feasible, and we have described the intramolecular vinylo-
gous aldol reaction for the synthesis of up to 15-membered macrolides.
See: (a) Gazaille, J. A.; Abramite, J. A.; Sammakia, T. Org. Lett. 2011,
14, 178. (b) Abramite, J. A.; Sammakia, T. Org. Lett. 2007, 9, 2103.
ꢀ
ꢀ
(5) Starowieyski, K. B.; Pasynkiewicz, S.; Skowronska-Ptasinska, M.
J. Organomet. Chem. 1975, 90, C43.
(6) Maruoka, K.; Nonoshita, K.; Banno, H.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 7922.
(7) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto,
H. J. Am. Chem. Soc. 1988, 110, 3588.
(8) Healy, M. D.; Barron, A. R. Angew. Chem., Int. Ed. Engl. 1992,
31, 921.
(9) Takikawa, H.; Ishihara, K.; Saito, S.; Yamamoto, H. Synlett
2004, 732.
(10) This structure is available from the Cambridge Crystallographic
Data Centre CIF Depository.
Org. Lett., Vol. 14, No. 11, 2012
2679

Information) provided the model of ATNP bound to
valeraldehyde shown in Figure 1. This structure reveals
that the additional reach of the 2-naphthyl groups can
effectively block the enolizable protons of the aldehyde.
Scheme 2. Synthesis of ATNP and Its Use in a Vinylogous Aldol
Reaction with an Enolizable Aldehyde
added to the LTMP was beneficial (Table 2, entries 4, 5,
and 6). Finally, the reaction requires lower temperatures to
proceed cleanly; at À20 °C, the reaction produces greater
amounts of byproducts and proceeds in 54% yield
(Table 2, entry 7).
Figure 1. Model of ATNP bound to valeraldehyde. In this
model, the aluminum atom (light blue) of ATNP is shown
coordinated to phenoxide oxygens (red) as well as to the oxygen
of valeraldehyde (carbons shown in yellow). The distal phenyl
rings of the 2-naphthyl groups are shown in green and can be
seen blocking the enolizable protons (highlighted in blue). The
aldehydic proton is also shown in blue; all other hydrogens have
been omitted for clarity.
Table 2. Optimization of Reaction Conditions
As in the case of ATPH, ATNP is prepared in situ
immediately prior to use by stirring the corresponding
phenol with trimethylaluminum(Scheme2). The precursor
to ATNP, phenol 13, can, in turn, be prepared by a one-
step Suzuki cross-coupling using RuPhos11 as the ligand in
excellent yield (>95%) from 2,6-dibromophenol (11) and
2-naphthylboronic acid (12), both of which are commer-
cially available. Gratifyingly, with ATNP using the condi-
tions described in Scheme 1, the vinylogous aldol reaction
of methyl crotonate (2) and valeraldehyde (3) proceeds
cleanly to provide the desired γ-adduct (4) in 82% yield
(Scheme 2). This is a substantial improvement over the
22% yield observed by Yamamoto using ATPH.
ester
ATNP
LTMP
mode of
temp
yield
(%)
entry
(equiv)
(equiv)
(equiv)
additiona
(°C)
1
2
3
4
5
6
7
2
3.3
2.7
2.3
2.3
2.3
3.3
3.3
2.3
1.7
1.3
1.3
1.3
2.3
2.3
std
À78
À78
À78
À78
À78
À78
À20
82
76
60
55
44
61
54
1.5
1.1
1.1
1.1
2
std
std
slow std
inverse
inverse
std
2
a Mode of addition refers to the manner in which the complex and
base were combined; std = cooled solution of LTMP added rapidly by
cannula to ATNP-complex; slow std = cooled solution of LTMP added
dropwise by cannula to ATNP-complex; inverse = cooled solution of
ATNP-complex added rapidly by cannula to LTMP.
With ATNP identified, we wished to optimize the reac-
tion conditions and minimize the loading of methyl croto-
nate. Typically, 2 equiv of the crotonate are used by
Yamamoto with approximately equal amounts of LTMP,
and we wished to optimize this reaction using lower
loadings of crotonate, which would require a correspond-
ing decrease in LTMP and ATNP. We find that a modest
decrease in yield is observed with the use of 1.5 equiv of
crotonate (76%, Table 2, entry 2) and a more significant
decrease with 1.1 equiv (60%, Table 2, entry 3). Neither
slow addition of the base nor changing the order of
addition such that the ATNP complexed substrates are
Our optimized conditions are very similar to those of
Yamamoto and consist of running the reaction at À78 °C
using 2 equiv of the ester, 2.3 equiv of LTMP, and 3.3 equiv
of ATNP for every equivalent of aldehyde. With these
conditions identified, we studied the scope of the reac-
tion with a variety of aldehydes. Our results are shown
in Table 3.
Other unbranched, enolizable, aliphatic aldehydes, such
as heptanal (5) and hydrocinnamaldehyde (7), provided
comparable results to valeraldehyde (76% and 82% yields,
respectively, Table 3, entries 2 and 3). The R-branched
(11) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
2680
Org. Lett., Vol. 14, No. 11, 2012

hyde (97%, Table 3 entry 5), and as expected, benzalde-
hyde (13) was an efficient reaction partner and provided
the product in excellent yield (97%, Table 3, entry 6). We
also studied oxygenation at the R- and β-positions of the
aldehyde and found in both cases that the reaction is
tolerant of silyl as well as benzyl protecting groups. For
example, the R-oxygenated substrate, triethylsiloxyacetal-
dehyde (15), provided the product in good yield (77%,
Table 3, entry 7) while the R-benzylated substrates 17 and
19 also provided the products in yields of 77% and 87%
(Table 3, entries 8 and 9, respectively). Compounds 17 and
19 also provided the opportunity to study asymmetric
induction with stereogenicity at the R-position. We find
that β-branching is required for high levels of selectivity;
unbranched aldehyde 17 provided the product with a
modest 2.4:1 dr while branched aldehyde 19 provided
the product with a 10:1 dr (Table 3, entries 8 and 9,
respectively). In both cases, the major isomer was the
anti-diastereomer. In addition, we find that β-oxygenated
substrates 21 and 23 provide the product in good chemical
yields with no evidence of β-elimination, but with low to
moderate levels of asymmetric induction (Table 3, entry
10, 65% yield, 1.3:1 dr; entry 11, 78% yield, 3.4:1 dr).
Finally, cinnamaldehyde provided the desired product in
modest yield due to competitive conjugate addition
(Table 3, entry 12).12
Table 3. Scope of the Vinylogous Aldol Reaction with ATNP
In conclusion, we have described a new Lewis acid,
ATNP, capable of promoting the selective enolization of
methyl crotonate in the presence of enolizable aldehydes.
The subsequent vinylogous aldol reaction proceeds in high
yields with a variety of substrates including those that are
hindered, R-branched, and oxygenated in the R- and
β-positions. Additions to R-oxygenated substrates require
β-branching for high levels of diastereoselectivity, and
R,β-unsaturated aldehydes undergo competitive conjugate
addition, thereby limiting the yield. We are currently study-
ing the application of this reaction to complex molecule
synthesis.
Acknowledgment. This work was supported in part by a
generous grant from the NIH (GM 48498). We thank Dr.
Joseph Abramite for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and full characterization of products for the
reactions described in Scheme 2 and Table 3, details of
the structure determination of compounds 18, 20, 22, and
24, and computational data for the structure in Figure 1
are provided. The material is available free of charge via
the Internet at http://pubs.acs.org.
aldehyde, cyclohexylcarboxaldehyde (9), was also an
excellent partner and provided the product in 96% yield
(Table 3, entry 4). The reaction proceeded cleanly using
pivaldehyde (11), a highly congested nonenolizable alde-
(12) Saito, S.; Yamamoto, H. Chem. Commun. 1997, 1585.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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