Highly anti-selective catalytic aldol reactions of amides with aldehydes

Article abstract of DOI:10.1021/ja061221t

Barium phenoxide-catalyzed, highly anti-selective direct-type aldol reactions of amides with aldehydes have been developed. In the presence of a slight excess amount of an amide, the desired reactions proceeded smoothly under mild conditions, and a wide r

Full text of DOI:10.1021/ja061221t

Published on Web 06/17/2006
Highly anti-Selective Catalytic Aldol Reactions of Amides with Aldehydes
Susumu Saito and Shu Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, The HFRE DiVision, ERATO, Japan Science
Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received February 20, 2006; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Table 1. Effect of Metal Sources
Aldol reactions are among the most powerful and efficient
methods for carbon-carbon bond formation, and continuous efforts
have been devoted to the development of catalytic asymmetric aldol
reactions.1 While almost all of these catalytic asymmetric reactions
require the preconversion of ketone or ester moieties into more
reactive species, such as silyl enol ethers or ketene silyl acetals,
using more than stoichiometric amounts of bases and silicon
sources, a great deal of effort has been put into the development
of direct-type aldol reactions using metal catalysts or organocata-
lysts.2 In such cases, however, the donor substrates are limited to
specific ketones or aldehydes, which have relatively low pKa values.
Furthermore, conversion of the resulting â-hydroxy ketones into
more useful â-hydroxy carbonyl compounds such as â-hydroxy
esters, carboxylic acids, amides, and aldehydes requires an oxidation
step, for example, a Baeyer-Villiger reaction, using more than
stoichiometric amounts of oxidizing agents. Therefore, direct-type
aldol reactions using ester equivalents have recently been attracting
much attention. However, the use of ester equivalents is still very
difficult, because the pKa values of the R-protons of ester equivalents
are much higher than those of ketones and aldehydes, and only
isolated examples have been reported.3-5 Herein, we disclose direct-
type catalytic aldol reactions of amides with aldehydes. The
procedure only requires a slight excess of (N-Boc)acylanisidides
(1.2 equiv), which are effective in generating metal enolates in situ,
in contrast to other procedures. Moreover, the first highly anti-
selective direct-type catalytic aldol reactions of (N-Boc)propioa-
nisidide with aldehydes are also described.
entry
metal alkoxide
PhOH (x mol %)
yield (%)
1
2
3
4
5
6
Y(Oi-Pr)3
66
66
44
44
44
44
N. R.
N. R.
10
28
33
La(Oi-Pr)3
Mg(On-Pr)2
Ca(Oi-Pr)2
Sr(Oi-Pr)2
Ba(Ot-Bu)2
50
Table 2. Catalytic Aldol Reactions of an Amide with Various
Aldehydes and a Ketone
In the initial investigation, we selected (N-Boc)acetanilide
derivatives as donor substrates. We expected that these substrates
would be suitable, because in situ enolate formation might be
facilitated Via a bidentate chelation based on appropriate metals.
We first examined alkaline earth and rare earth metals as catalysts
in the reaction of benzaldehyde with (N-Boc)acetanilide derivative
1a, as shown in Table 1. In the case of rare earth metals, the reaction
did not proceed at all. On the other hand, when alkaline earth metals
were used, we were pleased to find that the desired direct-type
catalytic aldol reaction was found to proceed through an intramo-
lecular Boc-transfer process. In particular, barium alkoxide6 gave
the highest yield among the alkaline earth metals tested.7
After screening several ligands, substrates, and additives, it was
found that a combination of a barium complex prepared from Ba-
(O-t-Bu)2, p-methoxyphenol, and (N-Boc)acetanisidide (1a) was
effective for this catalytic reaction. Under the optimized reaction
conditions, a wide range of aromatic, heterocyclic, R,â-unsaturated,
and aliphatic aldehydes were applicable, including even a ketone
(Table 2, entry 15). It is notable that the catalyst loading could be
reduced to 5 mol % and that bulky pivalaldehyde (entry 12) reacted
smoothly to afford the desired adducts in high yields. Secondary
and primary aliphatic aldehydes having acidic R-protons also reacted
to afford the desired aldol adducts in moderate yields. Remarkably,
a slight excess amount of (N-Boc)acetanisidide (1a, 1.2 equiv) was
enough to obtain the desired aldol adducts effectively in all cases.8
a 72 h. b Room temperature. c -20 °C. d DME was used as a solvent.
Next, direct-type aldol reactions of (N-Boc)propioanisidide (1b)
were investigated. In the presence of 10 mol % of Ba(O-t-Bu)2
and 22 mol % of p-methoxyphenol, 1b reacted with benzaldehyde
in THF at 0 °C to afford the desired aldol product in 87% yield
with good anti-diastereoselectivity (syn/anti ) 13/87). After screen-
ing several ligands, ortho-substituted phenols were found to be
effective to give the desired product in high yield with high anti-
selectivity (Table 3). While a bigger ortho-substituted ligand 3 gave
the desired aldol adduct in high yield and with excellent anti-
selectivity (entry 7). The ortho-disubstituted ligand gave higher anti-
selectivity, though in moderate yield (entry 8). Under the optimized
reaction conditions, a wide range of aromatic, heterocyclic, and R,â-
unsaturated aldehydes reacted with 1b to afford the corresponding
anti-aldol adducts in high yields with high diastereoselectivities
(Table 4). (N-Boc)-3-methylbutanoanisidide (1c) also worked well
(entry 2). It should be noted that this is the first example of highly
anti-selective direct-type catalytic aldol reactions of amides with
aldehydes. The product was readily converted to the corresponding
â-hydroxy carboxylic acid (eq 1). Furthermore, low-loading catalyst
9
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J. AM. CHEM. SOC. 2006, 128, 8704-8705
10.1021/ja061221t CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Effect of ortho-Substituents of Phenol Ligands
Scheme 1. Assumed Catalytic Cycle
entry
X
yield (%)
dr (syn/anti)
1
2
3
4
5
6
7
8
H
81
87
98
68
61
99
87
64
17/83
13/87
8/92
5/95
4/96
6/94
5/95
2/98
H (p-MeOC6H4OH)
Me
i-Pr
i-Bu
Ph
o-MeOC6H4 (3)
2,6-dimethylphenol
Table 4. Highly anti-Selective Catalytic Aldol Reactions of an
Amide with Various Aldehydes
reactions proceeded smoothly in the presence of a catalytic amount
of barium phenoxide under mild conditions (at 0 °C for 24-48 h
in most cases). The use of (N-Boc)acylanisidides is key, and a wide
range of aromatic, heterocyclic, R,â-unsaturated aldehydes were
applicable to afford the desired adducts in high yields with high
anti-selectivities. Further investigations to clarify the precise
mechanism of this reaction as well as to improve the enantiose-
lectivity of the asymmetric version are now in progress.
Acknowledgment. This work was partially supported by a
Grant-in-aid for Scientific Research from Japan Society of the
Promotion of Science (JSPS). S.S. thanks the JSPS Research
Fellowship for Young Scientists.
a Room temperature in DME. b Relative configuration was assigned by
Supporting Information Available: Experimental procedures and
product characterization (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
analogy. c 2,6-Dimethylphenol was used instead of ligand 3.
(1∼2 mol %) could work well to afford the desired adducts in
moderate yields with high anti-selectivities (eq 2).
References
(1) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2004.
(2) Reviews for direct-type catalytic asymmetric aldol reactions: (a) Alcalde,
B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595. (b) List, B. Acc. Chem.
Res. 2004, 37, 548. (c) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc.
Chem. Res. 2004, 37, 580. (d) Shibasaki, M.; Kanai, M.; Funabashi, K.
Chem. Commum. 2002, 1989. (e) Shibasaki, M.; Yoshikawa, N. Chem.
ReV. 2002, 102, 2187.
(3) Evans et al. reported that aldol reactions of esters proceeded in excellent
yields and diastereoselectivity using more than stoichiometric amounts
of chiral auxiliaries, silylating reagents, and amines without preconversion
of ester equivalents (See ref 4). Ιn other cases, excess amounts of R-oxy
carbonyl compounds (2.0 equiv), which have relatively low pKa values
of R-protons of ester equivalents, are generally used as suitable substrates
(See ref 5). Thus, a breakthrough in this field is strongly desired.
(4) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392. (b) Evans, D. A.; Downey, C. W.; Shaw, J. T.;
Tedrow, J. S. Org. Lett. 2002, 4, 1127. (c) Evans, D. A.; Downey, C. W.;
Habbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706.
(5) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b) Kumagai,
N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett.
2001, 3, 1539. (c) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll,
G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
2466. (d) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001,
123, 3367. (e) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260. (f) Yoshikawa, N.; Suzuki, T.; Shibasaki,
M. J. Org. Chem. 2002, 67, 2556. (g) Kumagai, N.; Matsunaga, S.;
Kinoshita, T.; Harada, S.; Okuda, S.; Sakamoto, S.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169.
The proposed catalytic cycle is outlined in Scheme 1. At first,
barium alkoxide removes the R-proton of acylamide (1b) to give a
barium enolate (5)9 in situ. This barium enolate formed then reacts
with an aldehyde to afford the initial aldol adduct (6). Subsequent
intramolecular Boc-transfer10 then occurs spontaneously with con-
comitant release of steric strain, followed by a protonation reaction
to afford the desired adduct along with regeneration of the catalyst.
The present reaction could be extended to a catalytic enantiose-
lective version using a chiral ligand. Indeed, using a chiral ligand
7, the desired product 2k was obtained in 73% yield with 33% ee.
Although the enentioselectivity is not satisfactory, the possiblity
of a direct-type, catalytic enantioselective aldol reaction of amides
with aldehydes has been demonstrated (eq 3).
(6) Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561.
(7) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi, K.;
Shibasaki, M.; Noyori, R. Tetrahedron Lett. 2001, 42, 4669.
(8) Even direct-type reactions of ketones or aldehydes often use large excess
amounts of the donors (as solvents). See ref 2. Quite recently, an efficient
method using organocatalysts has been reported. Mase, N.; Nakai, Y.;
Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 734.
(9) (a) Yanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 6130. (b) Yanagisawa, A.; Takahashi, H.; Arai, T. Chem.
Commun. 2004, 580. See also, ref 6.
(10) Similar N- to O-Boc migrations were reported. Bew, S. P.; Bull, S. D.;
Davies, S. G.; Savory, E. D.; Watkin, D. J. Tetrahedron 2002, 58, 9387.
In summary, we have developed the first highly anti-selective
direct-type catalytic aldol reactions of amides with aldehydes. The
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