Highly Diastereo- and Enantioselective Additions of Homoenolates to Nitrones Catalyzed by N-Heterocyclic Carbenes

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 cycloadditions. In this communication, we report the highly diastereo- and enantioselective combination of α,β-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).

(1)

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 stoichiometric 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 α,β-unsaturated aldehyde possesses nucleophilic character at the β-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 consumption 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

Table 1.

Optimization of Conditions

entry	azolium salt	temp (°C)	yielda (%)	drb	eec (%)
1	A	0	75d	4:1
2	B	0	46d	8:1	−65
3	C	0	52d	8:1	−33
4	D	0	51d	8:1	87
5	D	−25	49d	20:1	93
6	De	−25	70f	20:1	93

^aIsolated yields.

^bDiastereomeric ratio determined by 500 MHz NMR spectroscopy.

^cEnantiomeric excess determined by HPLC Chiracel AD-H.

^d2:1 ratio of 1a to 2a.

^e20 mol % of D, Et₃N used instead of DBU.

^f2:1 ratio of 2a to 1a, NaOMe/MeOH used in place of DBU/MeOH.

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 (α,β-unsaturated aldehyde).

Scheme 1.

Reaction Pathway

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).

Table 2.

Nitrone Reaction Scope

entry	R1	R2	yielda (%)	eeb (%)
1	Ph	Ph	70 (5)	93
2	4-Me–C6H4	Ph	71 (6)	90
3	4-Br–C6H4	Ph	68 (7)	84
4	4-MeO-C6H4	Ph	62 (8)	90
5	2-naphthyl	Ph	69 (9)	81
6	cyclohexyl	Ph	0
7	Ph	4Cl-Ph	80 (10)	93

^aIsolated yields.

^bEnantiomeric excess determined by HPLC Chiracel OD-H or AD-H. Diastereomeric ratio determined by ¹H NMR spectroscopy (500 MHz).

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, α,β-unsaturated aldehydes with alkyl groups in the β-position afford the desired γ-hydroxy amino esters with high selectivity and good yields (entries 4 and 5).

Table 3.

Aldehyde Reaction Scope

entry	R	yielda (%)	eeb (%)
1	4-Cl–C6H4	78 (11)	90
2	4-MeO–C6H4	72 (12)	89
3	2-naphthyl	73 (13)	94
4	Mec	73 (14)	94
5	C3H7c	64 (15)	92

^aIsolated yields.

^bEnantiomeric excess determined by HPLC Chiracel OD-H or AD-H.

^cDBU used in place of Et₃N.

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

(2)

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 α,β-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.