Organocatalytic highly enantioselective conjugate addition of aldehydes to alkylidine malonates

Article abstract of DOI:10.1002/adsc.200700570

The first highly enantioselective, direct organocatalytic conjugate addition of unmodified aldehydes to alkylidinemalonates is presented. The reaction gives access to β-formyl-substituted malonates and highly functionalized lactones with up to 14:1 dr and

Full text of DOI:10.1002/adsc.200700570

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DOI: 10.1002/adsc.200700570
Organocatalytic Highly Enantioselective Conjugate Addition of
Aldehydes to Alkylidine Malonates
Gui-Ling Zhao,a,c Jan Vesely,a,c Junliang Sun,b,c Kirsten E. Christensen,b,c
Charlotte Bonneau,b,c and Armando Córdovaa,c,*
a
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Fax : (+46)-8-154908; e-mail: acordova@organ.su.se
Structural Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Berzelii Center EXSELENT on Porous Materials, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
b
c
Sweden
Received: December 4, 2007; Published online: March 17, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The first highly enantioselective, direct
organocatalytic conjugate addition of unmodified
aldehydes to alkylidinemalonates is presented. The
reaction gives access to b-formyl-substituted malo-
nates and highly functionalized lactones with up to
14:1 dr and generally 94 to >99% ee.
scope of enamine catalysis to the use of aldehyde
donors and to this class of Michael acceptors is a
useful and challenging objective. Based on this, and
the synthetic utility and biological importance of
chiral malonates and lactones,[1,13] we began the task
of developing an organocatalytic asymmetric conju-
gate addition of unmodified aldehydes to alkylidine-
malonates [Eq. (1)].
Keywords: aldehydes; alkylidenemalonates; asym-
metric catalysis; chiral lactones; conjugate additions
Herein, we report the first highly enantioselective
chiral amine-catalyzed conjugate addition of unmodi-
fied aldehydes to alkylidenemalonates (generally 94
to >99% ee).
In an initial catalyst screen for the reaction between
The catalytic asymmetric conjugate addition of propionaldehyde 1a (0.25 mmol) and alkylidine malo-
carbon-centered nucleophiles to alkylidinemalonates nate 2a (0.125 mmol), we found that proline, dipepti-
provides a practical route to synthetically and biologi- des and chiral pyrrolidines such as 4–7 catalyzed the
cally important chiral compounds.[1] Most of these cat- asymmetric formation of formyl-substituted malo-
alytic asymmetric strategies utilize organometallic- nates 3a and 3a’ (Table 1). It should be mentioned
complexes as the catalysts.[1]
that the solvent that we believed would be best for
In the research field of organocatalysis,[2,3] there are each catalyst based on our previous experience was
several elegant reports on the amine-catalyzed asym- used. Of the screened catalysts, the protected diaryl-
metric addition of ketones and aldehydes to nitrostyr-
prolinol 7[14] catalyzed the formation of the anti-
enes.[4–6] Moreover, well-designed catalytic enantiose- isomer 3a with high chemo- and enantioselectivity
lective conjugate additions of aldehydes to vinyl sul- under several reaction conditions as determined by
fones,[7] maleimides,[8] benzoquinones,[9] enones[10] and 1H NMR and chiral-phase HPLC analysis (entries 6–
vinyl phosphonates[11] have recently been reported. 10). For example, the reaction in CHCl3 at À208C
However, only the amine-catalyzed conjugate addi- gave 3a in 82% yield with 95% ee (entry 8). Decreas-
tion of ketones to alkylidinemalonates is known.[12] In ing the catalyst loading increased the diastereoselec-
fact, initial attempts at employing unmodified alde- tivity from 5:1 to 10:1 at the expense of the efficiency
hydes as donors failed.[12c] Thus, expansion of the (entry 9). To our delight, chiral amine 7 catalyzed the
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Gui-Ling Zhao et al.
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Table 1. Selected reactions for the 4a-catalyzed enantioselective domino reactions between 1a
and 2a.
[a]
Combined isolated yield of compounds 3a and 3a’.
[b]
[c]
[d]
[e]
[f]
The dr (anti/syn) was determined by NMR analysis.
Determined by chiral-phase HPLC analysis (OJ column).
10 equiv. H2O were added.
ent-3a was formed.
10 mol% catalyst.
asymmetric formation of 3a in 88% yield with 10:1 dr were isolated in high yields with up to 14:1 dr and 95
(anti/syn) and 95% ee in CH3CN at 48C (entry 10). to >99% ee. The reaction worked well for various
We also screened the conjugate reactions with functionalized aldehyde donors and both aliphatic
chiral amine 7 at different temperatures and found and aromatic substituted alkylidenemalonates could
that the conditions shown in entry 8 and entry 10 be used as acceptors. For example, aldehyde 3i was
were optimal in CHCl3 and CH3CN, respectively. catalytically assembled from the reaction between al-
Thus, we decided to investigate the scope of the cata- dehyde 1d and alkylidene malonate 2a in 86% yield
lytic asymmetric conjugate addition in CHCl3 at and 98% ee (entry 9). The products 3 can also be con-
À208C or in CH3CN at 48C employing chiral amine 7 verted to highly substituted lactones. To exemplify
as the catalyst (Table 2).
this, the aldehydes 3a and 3j and were converted to
The organocatalytic asymmetric conjugate additions the corresponding lactones 8a and 8j with three con-
of aldehydes 1 to alkylidenemalonates 2 were highly tiguous chiral centers in 85 and 80% yield, respective-
chemo- and enantioselective and the corresponding ly [Eq. (2)]. The relative configuration of chiral lac-
a-aryl- or a-alkyl-b-formyl-substituted malonates 3a–j tone 8j was established by NOE experiments. The ab-
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Table 2. Scope of the organocatalytic conjugate addition of aldehydes to alkylidinemalo-
nates. (Conditions A: CHCl3, À208C; Conditions B: CH3CN, 48C.)
[a]
Isolated yield of the pure product 3 after silica gel chromatography.
Determined by H NMR analysis.
Determined by chiral-phase HPLC analysis.
The isolated yield based on recovered starting material.
Determined by chiral-phase GC analysis after conversion to lactone 8. Bn=benzyl.
[b]
[c]
[d]
[e]
1
solute and relative configuration of acid 9, generated
Based on the absolute configuration of the product
from the mild oxidation of 3h and recrystallization, 9, which was determined by X-ray analysis, we pro-
was assigned by X-ray crystallographic analysis and pose transition state I (Figure 2) to account for the
comparison to the literature[8,11] {[Eq. (3)], stereochemical outcome of the chiral amine 7-cata-
Figure 1}.[15]
lyzed reactions in Table 1. The Si-face of the chiral
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Gui-Ling Zhao et al.
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other organocatalytic enantioselective conjugate addi-
tion reactions are ongoing in our laboratory.
Experimental Section
General Procedure for Chiral Amine 7-Catalyzed
Conjugate Addition of Unmodified Aldehydes to
Different Alkylidene Malonates
To a stirred solution of the catalyst 7 (20 mol%) in CHCl3
(0.5 mL) at À208C or CH3CN (0.5 mL) at +48C was added
aldehyde
1
(0.25 mmol)
and
alkylidenemalonate
(0.125 mmol). The reaction mixture was vigorously stirred
for the time shown in Table 2 and monitored by TLC analy-
sis. Next, the reaction mixture was directly loaded on the
silica gel column and purified by silica gel chromatography
(pentane: ethyl acetate=8:1–4:1) to give product 3.
Acknowledgements
We gratefully acknowledge the Swedish Research Council
(VR) and Carl-Trygger Foundation for financial support.
The Berzelii Center EXSELENT is financially supported by
VR and the Swedish Governmental Agency for Innovation
Systems (VINNOVA).
Figure 1. ORTEP picture of carboxylic acid 9 with ellipsoids
at the 50% level. H atoms are drawn as sphere of arbitrary
radii.
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