Highly diastereo- and enantioselective additions of homoenolates to nitrones catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja710521m

The diastereo- and enantioselective addition of N-heterocyclic carbene-generated homoenolates to nitrones is reported. This formal [3 + 3] addition of α,β-unsaturated aldehydes and nitrones generates unusual morpholinone heterocycles which are converted i

Full text of DOI:10.1021/ja710521m

Published on Web 01/31/2008
Highly Diastereo- and Enantioselective Additions of Homoenolates to
Nitrones Catalyzed by N-Heterocyclic Carbenes
Eric M. Phillips, Troy E. Reynolds, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received November 21, 2007; E-mail: scheidt@northwestern.edu
Table 1. Optimization of Conditions
Harnessing unconventional reactivity for new bond-forming
processes provides unusual avenues for the synthesis of target
molecules. Non-traditional cycloadditions outside the venerable [4
+ 2] and [3 + 2] processes also facilitate access to desired
compounds in a highly convergent manner by combining at least
two simple starting materials.1 A relatively unexplored class of
powerful transformations utilizes unusual reactivity patterns, such
as homoenolates, in the context of non-traditional, formal cycload-
ditions. In this communication, we report the highly diastereo- and
enantioselective combination of R,â-unsaturated aldehydes (1) with
nitrones (2) catalyzed by N-heterocyclic carbenes to afford γ-amino
esters, such as 4, upon the addition of an alcohol (eq 1). A unique
aspect of this process is the rare six-membered heterocycle that is
generated as the initial product of the reaction (3).
azolium
salt
temp
C)
yielda
(%)
eec
(%)
entry
(
°
drb
1
2
3
4
5
6
A
B
C
D
D
De
0
75d
46d
52d
51d
49d
70f
4:1
8:1
8:1
8:1
20:1
20:1
0
0
0
-65
-33
87
93
93
-25
-25
a Isolated yields. b Diastereomeric ratio determined by 500 MHz NMR
spectroscopy. c Enantiomeric excess determined by HPLC Chiracel AD-
H. d 2:1 ratio of 1a to 2a. e 20 mol % of D, Et3N used instead of DBU.f 2:1
ratio of 2a to 1a, NaOMe/MeOH used in place of DBU/MeOH.
The successful addition of homoenolate species to nitrones would
be a significant transformation since the products are potentially
γ-amino acids. These molecules are used clinically as modulators
of neurotransmission,2 and the related γ-lactam structure is a key
constituent of many natural products (e.g., lactacystin)3 as well as
pharmaceutical agents. To our knowledge, there are no reports of
homoenolate additions to nitrones under either catalytic or sto-
ichiometric conditions.4
Our efforts5 and those of others6 investigating the area of
N-heterocyclic carbene (NHC) catalysis have recently yielded
innovative methods to access unique homoenolate reactivity. In
these processes, an R,â-unsaturated aldehyde possesses nucleophilic
character at the â-carbon which upon addition to an electrophile
yields an activated ester. In light of our experience with these
atypical nucleophiles, we envisioned that nitrones should be
productive in a formal [3 + 3] reaction since they are useful
reactants in a variety of cycloaddition reactions.7
We initiated these investigations by combining cinnamaldehyde
(1a) and diphenyl nitrone (2a) while surveying different triazolium
salts and reaction conditions (Table 1). While thiazolium and
imidazolium salts did not produce desired products, the use of
achiral triazolium salt A at 10 mol % afforded complete consump-
tion of the nitrone (entry 1). Initially, a challenging aspect of this
processes was the characterization and manipulation of the first
product formed in the reaction (i.e., 3). This unusual heterocycle
was unstable to chromatography, but by adding methanol and DBU
to the reaction after consumption of the nitrone, the γ-hydroxyl
amino ester (5) could be isolated in 75% yield. With this protocol,
a screen of chiral triazolium salts revealed that azolium D, originally
developed in our laboratory,5c generated 5 with high levels of
stereoselectivity (8:1 dr, 87% ee) but only moderate yield (entry
4). Lowering the temperature provided increased selectivity (20:1
dr, 93% ee) and yield of 5 with 20 mol % of D necessary for
consumption of 1a (entry 6). Last, changing the MeOH/DBU
addition at the end of the reaction to NaOMe provided the methyl
ester products in consistently higher yield.8
Our current model for this reaction (Scheme 1) involves the
addition of the homoenolate equivalent (I, formed in situ from the
combination of the NHC and unsaturated aldehyde) to the nitrone
(2). After this stereochemical-determining step, catalyst turnover
is promoted by an intramolecular acylation after the tautomerization
of enol II to acyl azolium III. As in a majority of recent carbene-
catalyzed processes, the success of this pathway relies on (a) a
nonproductiVe interaction between the secondary electrophile in
the reaction (nitrone) and the in situ generated catalyst, and (b) a
productiVe interaction between the catalyst and primary electrophile
(R,â-unsaturated aldehyde).
We first examined the scope of this reaction with regard to
nitrone substituents (Table 2). The reaction accommodates both
electron-withdrawing and -donating aromatic substitution on the
carbon (R1) with high levels of dr and %ee (entries 1-5).9 Nitrones
derived from saturated aldehydes were not suitable substrates. An
electron-withdrawing aromatic ring (4-chlorophenyl) on the nitrogen
of the nitrone provided the methyl ester in moderate yield with
high selectivity (entry 7). Electron-donating groups on the nitrogen,
such as 4-methoxyphenyl or 4-methylphenyl, resulted in no product
formation (not shown).
We then varied the aldehyde component of this new reaction
(Table 3). Electron-withdrawing and -donating groups on the
aromatic ring of the aldehyde are tolerated well (entries 1 and 2).
Importantly, R,â-unsaturated aldehydes with alkyl groups in the
9
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J. AM. CHEM. SOC. 2008, 130, 2416-2417
10.1021/ja710521m CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Reaction Pathway
In summary, we have developed the first highly diastereo- and
enantioselective homoenolate addition to nitrones catalyzed by chiral
N-heterocyclic carbenes. This formal [3 + 3] addition delivers
γ-amino ester derivatives and is the first general and highly selective
strategy for the addition of homoenolate nucleophiles to nitrones.
Electron-rich and electron-poor aryl groups are suitable substituents
on the carbon of the nitrone, and alkyl and aryl groups are tolerated
on the R,â-unsaturated aldehyde. Scission of the N-O bond under
mild conditions results in the formation of γ-amino esters that
quickly close in the presence of acid to form γ-lactams in good
yields. N-Heterocyclic carbene catalysis is a powerful approach that
provides new directions for synthesis through innovative bond
construction.
Acknowledgment. Support for this work was generously
provided by NIGMS (RO1 GM73072), Abbott Laboratories,
Amgen, 3M, GlaxoSmithKline, AstraZeneca, and Boehringer
Ingelheim. Funding for the NU Analytical Services Laboratory has
been furnished in part by the NSF (CHE-9871268). We thank Dr.
William J. Morris for helpful discussions. K.A.S. is a Fellow of
the Sloan Foundation. T.E.R. is a recipient of a 2007-2008 ACS
Division of Organic Chemistry fellowship sponsored by Bristol-
Myers Squibb.
Table 2. Nitrone Reaction Scope
yielda
(%)
eeb
(%)
entry
R1
R2
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
70 (5)
71 (6)
68 (7)
62 (8)
69 (9)
0
93
90
84
90
81
4-Me-C6H4
4-Br-C6H4
4-MeO-C6H4
2-naphthyl
cyclohexyl
Ph
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a Isolated yields. b Enantiomeric excess determined by HPLC Chiracel
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yielda
(%)
eeb
(%)
entry
R
1
2
3
4
5
4-Cl-C6H4
4-MeO-C6H4
2-naphthyl
Mec
78 (11)
72 (12)
73 (13)
73 (14)
64 (15)
90
89
94
94
92
c
C3H7
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a Isolated yields. b Enantiomeric excess determined by HPLC Chiracel
OD-H or AD-H. c DBU used in place of Et3N.
â-position afford the desired γ-hydroxy amino esters with high
selectivity and good yields (entries 4 and 5).
With an efficient pathway to γ-hydroxy amino methyl esters,
we envisaged that cleavage of the N-O bond would facilitate clean
access to γ-amino esters (eq 2). The N-O bond is easily cleaved
under a hydrogen atmosphere in the presence of Pd(OH)2, and
subsequent exposure of the amino ester to aqueous HCl in methanol
provides the corresponding lactam 17 in 88% yield and 93% ee.10
(9) Relative and absolute configuration of 7 was determined by X-ray
crystallography; see Supporting Information for details. Additional ster-
eochemistry assigned by analogy.
(10) For a racemic synthesis of 17, see ref 4c.
JA710521M
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